This article discusses tuberculosis (TB) in SOTR and donors. This is particularly important because the risk of tuberculosis increases after SOT, notably for lung transplant recipients.
The incidence of tuberculosis in SOTR typically results from the reactivation of latent TB. Due to the recipient’s immunocompromised state, both nosocomial and primary infections from the environment are also conceivable. A limited percentage of cases can be transmitted by donors.
Discussion
A recipient’s risk of contracting tuberculosis (TB) may be increased by travel from endemic TB countries. Immigration influences the risk of donor-transmitted diseases.
Current guidelines advise screening for LTBI in both SOT recipients and living donors. This is accomplished with the tuberculin skin test, or TST. The IFN-gamma release assay is a contemporary diagnostic instrument. The latter instrument has advantages over the TST, such as avoiding interpretation bias and reducing false-positive results associated with prior TB or BCG vaccination exposure. In some centers, the higher cost of conducting these assays can be a deterrent, preventing standardization.
Recommendations include administering IGRA alone to patients at low risk and both TST and IGRA to patients at high risk. In order to maximize the sensitivity and accuracy of screening protocols, this is performed.
TB infection is diagnosed by directly detecting Mycobacterium tuberculosis bacilli through culture and nucleic acid testing. IGRA and TST are not recommended for the patient’s active TB infection diagnosis.
The extrapulmonary manifestation of tuberculosis in SOT recipients is an additional factor to consider. This is typically more difficult to diagnose than the classic presentation of tuberculosis. One recommendation is to consider tuberculosis in patients with an unexplained fever. Due to its high specificity and sensitivity, the availability of an MTB/RIF assay can aid in the management of these patients.
False-positive results in patients who have been successfully treated for tuberculosis are among the limitations of this method of diagnosis.
Preventive and therapeutic measures
Prevention of tuberculosis in the recipient requires a thorough evaluation of the donor, including IGRA and TST. Additionally, appropriate risk assessment profiles must be created to prevent both donor transmission and primary incidence in the recipient from other sources.
Oral INH 300 mg per day for nine months, along with oral pyridoxine 25–50 mg per day An extended period of nine months is preferred to six months because it provides greater patient protection.
Monitoring for hepatotoxicity is essential in these patients, with serum ALT being measured every two weeks for the first six weeks and then every month thereafter.
Alternative regimens Pre-transplant medications include rifamycin, which should be avoided post-transplant to prevent drug-drug interactions. Fluoroquinolones are recommended for the treatment of LTBI.
Reactivation of latent TB infection is the main cause of post-transplant TB. Primary infection which is acquired in the community is responsible for a considerable proportion of the cases especially in endemic areas, a minor portion of primary infections may result from donor-recipient transmission especially in cases of deceased donor with active TB infection or donor with untreated latent TB
International travel and post-transplant TB
International travel to endemic areas may affect the risk of TB after SOT.
Transplant recipients originating from endemic areas have a higher prevelance of LTBI so they are at an increased risk of developing active TB infection after SOT.
Transplant recipients from low incidence countries may exposed to primary infection while traveling to endemic areal. Long time spent in the endemic area , work with high risk population as prisoners increase risk of infection.
Diagnosis of latent TB infection
Tuberculin skin test is the best test for screening of LTBI in solid organ transplant recipients and donors.
IGRAs is a new diagnostic tool that offers some advantages over tuberculin test ( avoid interpretating bias, reduce false positive results related to previous exposure to non tuberculous mycobacterium or BCG vaccination and more sensitive in patients with advanced cirrhosis and CKD patients. But the negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI.
So in low risk patient,IGRAs could be the sole approach
In high risk patient both test should be performed and one of them positive is satisfactory
Diagnosis of TB infection
By detection of organism by direct observation, by culture, by nucleic acid testing.
Risk assessment of transplant recipients
History of clinical or radiological TB, history of treatment
If there is no history , test for LTBI by TST ( induration 5 mm or greater after 48 hous considered positive, IGRAs
Risk assessment of donor
As recipients but the induration more than 10 mm considered positive
Treatment
Treatment of transplant candidates with positive TST or IGRAs is recommended.
Those with high pretransplant TB exposure should be considered even if the screening test are negative
Those with history of inadequate treatment of active TB
Recipients of donor who are inadequately treated
For treatment of LTBI, the preferred regimen is oral INH for 9 months along with oral pyridoxine
The patient should be monitored for hepatoxicity
If recently transplant recipients are planning to move to high endemic area ,INH preventive treatment should be considered
Treatment of active TB
INH and Rifampcin are most powerful first line drug for 9 months ,hepatoxicity should be considered and drug interactions of Rifampcin
There is no diagnostic standard test for LTBI and the tuberculin skin test remains the best studied test. The current guidelines recommend its use for the screening of LTBI in solid organ transplantation
IFN-γ release assays (IGRAs) can avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients.But the negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI. It has higher cost and the frequent occurrence of conversions and reversions of test results when serial screening is performed, which may complicate the interpretation of their results among SOT candidates. In low-risk patients, IGRAs could be considered as the sole approach. In high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture and nucleic acid testing. Neither TST nor IGRAs are recommended for diagnosing active infection. TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin. The Xpert MTB/RIF assay, is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively. Xpert MTB/ RIF assay is a useful rule-in diagnostic test for extrapulmonary TB. It also allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB. One limitation of this assay is that false-positive results have been observed among patients who had been successfully treated for TB and it cannot fully replace the execution of conventional drug susceptibility tests.
Prevention is through risk assessment using history of clinical or radiological TB and the treatment received. If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA. If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion. Candidates who have low risk for LTBI should preferably be tested solely with IGRA. In high-risk candidates (ie, patients originated from endemic countries, household contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), both tests could be performed and any positive reaction considered an evidence of LTBI. Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started. This evaluation includes checking the presence of symptoms and signs suggestive of TB, performing a chest radiograph and, in cases with extrapulmonary manifestations, imaging of other body sites. If any evidence of active infection is found in this workup, appropriate clinical specimens should be collected for microbiological confirmation of the diagnosis. Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
Risk assessment of deceased and living donors living donors should undergo the same evaluation with the exception that the cutoff for TST should be 10 mm or greater. Organs from donors with known active TB infection should be discarded. If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines. Drug susceptibility tests should be performed on any M. tuberculosis specimen isolated from the donor, since the detection of drug resistance may be of critical importance for guiding therapy in the recipients. Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted. Lungs with residual tuberculous lesions should not be used for transplantation. A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, especially for lung recipients. The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, therefore, transplant recipients from such donors can be clinically monitored without receiving LTBI therapy.
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated. the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily. Nine months of therapy is preferred over 6 months because of better protection. Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine aminotransferase checked every 2 weeks for 6 weeks, then monthly thereafter. Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks. Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy. When possible, treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist. If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible until completion of the originally planned course, with the caveat that rifamycins are usually avoided after transplant. If recently transplanted patients are planning to move to a highly endemic area (ie, those with prevalence ≥100/ 100000), INH preventive therapy should be considered during the first posttransplant year, especially for those planning to take part in medical or humanitarian care, given the higher risk of primary TB acquisition. There is no indication for BCG vaccine before travel, and it is contraindicated in transplant recipients.
Treatment of active TB infection should follow local guidelines for the general population.in most cases, a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB for at least 9 months. close monitoring is highly recommended, mainly during the first 2 months of treatment when it should be performed biweekly.
Rifampin has the most potent enzyme induction effect. Two to 5-fold increments in the daily dose of cyclosporine, tacrolimus, and mammalian target of rapamycin inhibitors are generally necessary to maintain trough levels of the drug in the therapeutic range. Although enzyme induction start within hours after the first dose of rifampin, maximum effect is reached in about 1 to 2 weeks and slowly declines over 2 weeks after stopping its use.
This is a narrative review of level 5 evidence regarding : Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. The incidence rate of TB infection is increased after solid organ transplantation SOT. -Guidelines recommend that in low-risk patients IFN-γ release assays (IGRAs ) should be considered as the preferred method. Active TB Infectionculture, and nucleic acid testing , Xpert MTB/RIF assay is highly specific Treatment of in Transplant Candidates and Recipients: – The preferred regimen for LTBI is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily. – Alternative regimens containing rifampicin can be considered pre-transplant, these regimens include RIF 600mg daily for 4 months or INH and rifapentine weekly for 12 weeks( Rifabutin has an advantage over Rifampicin that it is less drug inducer but still drugs should be monitored)
The estimated absolute number of prevalent cases in the latin countries are declined from approximately 600000 to 342000 between years 1990 and 2014, with a parallel reduction in the
number of TB-associated deaths from 43000 to 22. Nevertheless, TB remains a relevant public health problem in this region.
Emergence of multidrug-resistant (MDR) TB, which is a resistance to rifampicin and isoniazid (INH), is a global challenge. It is about 3% in most countries of this region.
TB AFTER SOLID-ORGAN TRANSPLANTATION
The incidence of TB increases after transplantation (SOT), the risk is highest in
lung transplantation.
In one study, TB incidence is 0.9% to 5.9% of the recipients.
Reactivation of latent TB infection is the main cause of post-transplant TB.
International Travel and Post-transplant TB:
Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB after transplantation.
Transplant candidates originating from endemic areas have a higher prevalence of LTBI and are, hence, at an increased risk of developing active TB infection after SOT.
DIAGNOSIS: Diagnosis of LTBI:
There is no diagnostic reference standard for LTBI. The tuberculin skin test (TST) remains the best studied test. IFN release assays (IGRAs) have emerged as new diagnostic tools in the last decade.
However, despite their better yield, thenegative predictive value of IGRAs is not optimal to rule out infection.
Diagnosis of Active TB Infection:
The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing. Neither TST nor IGRAs are recommended for diagnosing active infection.
PREVENTION: Risk Assessment of the Transplant Candidate
A history of clinical or radiological TB and the treatment received should be assessed in all recipients. If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TSTor IGRA.
the screening strategy may be adapted per the patient’s characteristics. Candi
dates who have low risk for LTBI should preferably be tested solely with IGRA. In high-risk candidates , both tests could be performed and any positive reaction considered an evidence of LTBI.
Active TB infectionmust be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
Risk Assessment of Deceased and Living Donors:
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
The evaluation of the deceased donor for TB relies on:
1- Medical history.
2- Endemic exposures.
3- Radiographic findings.
Time does not allow for a TST and IGRAs have not been validated in deceased donors. Active TB infection should be ruled out in donors at increased risk by obtaining samples, for example, sputum or bronchoalveolar lavage, to test for the presence of M. tuberculosis.
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients Criteria to Start Treatment:
Therapy for LTBI is an effective strategy for the prevention of active TB infection in transplant recipients.
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated. Chest imaging suggestive of previous untreated TB should prompt consideration for therapy.
Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
In considering treatment for LTBI, it is imperative to first rule out active TB infection.
Therapeutic Regimens:
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
Nine months of therapy is preferred over 6months because of better protection.
Alternative regimens containing rifamycins can be considered pre-transplant, but should be avoided post-transplant because of immunosuppressive drug interactions. These regimens include RIF 600mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
Treatment of Active TB Infection:
Treatment should follow local guidelines for the general population. A 4-drug regimen is recommended.
INH and rifampicin are the most powerful first-line drugs against TB.
In renal transplantation , the hepatotoxicity related to the antituberculous
treatment and drug interactions of rifampicin should be kept in mind .
The optimal length of treatment of TB in transplant recipients is not defined. Many specialists recommend that treatment duration should be at least 9 months,
2- What is the level of evidence provided by this article?
The level is five.
The incidence rate of TB markedly increases after solid organ transplantation (SOT)5 the risk being highest among lung recipients.Reactivation of foci of latent TB infection (LTBI) is probably the main cause of posttransplant TB. Primary infection acquired in the community, and less frequently in the nosocomial environment, may also account for a considerable proportion of the cases, especially among patients living in endemic areas.A minor proportion of primary infections result from donor-recipient transmission. Most of these cases were documented in patients who received a graft from a deceased donor with active TB infection, a situation that has been associated with a risk of transmission of approximately 30%
Diagnosis of LTBI
The tuberculin skin test (TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.2 IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade. They offer some advantages as compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis. Negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI.Thus, in low-risk patients, IGRAs could be considered as the sole approach, because the use of a more specific test might reduce the rate of false-positive results and, consequently, the number of patients who will unnecessarily be exposed to LTBI therapy. On the other hand, in high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
Diagnosis of Active TB Infection
The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture.and nucleic acid testing. Neither TST nor IGRAs are recommended for diagnosing active infection.In this regard, the availability of a rapid molecular test, such as the Xpert MTB/RIF assay, may have a major impact in the management of these patients. This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively. A similar performance has been observed when testing nonrespiratory samples, such as tissue biopsies and cerebrospinal fluid, indicating that Xpert MTB/ RIF assay is a useful rule-in diagnostic test for extrapulmonary TB.It also allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB. One limitation of this assay is that false-positive results have been observed among patients who had been successfully treated for TB.
Risk Assessment of the Transplant Candidate
If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA. If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion. .Whenever this dual-test approach is used, IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses.Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
Risk Assessment of Deceased and Living Donors
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
The evaluation of the deceased donor for TB relies on:Medical history,Endemic exposures-Travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the last 2 years and Radiographic findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening.Active TB infection should be ruled out in donors at increased risk by obtaining samples, for example, sputum or bronchoalveolar lavage, to test for the presence of M. tuberculosis. Because the results of microbiological investigation will more often be available after procurement, it must be ensured that all data will be forwarded to transplant teams as soon as possible to enable appropriate actions.Organs from donors with known active TB infection should be discarded.
Treatment of LTBI in Transplant Candidates and Recipients
LTBI therapy is recommended for transplant candidates withpositive TST or IGRA who have not been previously treated.Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated. Chest imaging suggestive of previous untreated TB should prompt consideration for therapy, especially in areas where endemic mycoses are uncommon.Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.In considering treatment for LTBI, it is imperative to first rule out active TB infection.For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
Treatment of Active TB Infection
, In most cases, a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB. The optimal length of treatment of TB in transplant recipients is not defined. Many specialists recommend that treatment duration should be at least 9 months, based on the results of a few studies that have suggested an association between shorter regimens and greater recurrence and mortality
What is the level of evidence provided by this article?
In the last 2 decades, the burden of tuberculosis (TB) has been considerably reduced in Latin America (LA) countries. The estimated absolute number of prevalent cases in the re- gion declined from approximately 600000 to 342000 be- tween years 1990 and 2014, with a parallel reduction in the number of TB-associated deaths from 43000 to 22000.1 Nevertheless, TB remains a relevant public health problem in this region. Per World Health Organization estimates for 2014,2 Brazil remains in the group of 22 countries with the highest TB burden in the world, with 110 000 prevalent cases and 7700 TB deaths.
TBAFTERSOLID-ORGANTRANSPLANTATION The incidence rate of TB markedly increases after solid organ transplantation (SOT), the risk being highest among lung recipients.4 The proportion of patients affected by active TB infection also varies widely among transplant centers in correspondence with the local prevalence of the disease. In studies carried out in LA SOT centers in the last decade, TB was diagnosed in 0.9% to 5.9% of the recipients.
DIAGNOSIS Diagnosis of LTBI Thereis nodiagnostic reference standard for LTBI. Thetuberculin skin test (TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors. IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade. They offer some advantages as compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients.
Diagnosis of Active TB Infection The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture and nucleic acid testing. Neither TST nor IGRAs are recommended for diagnosing active infection. Probably the most challenging situation lies on the clinical suspicion of active infection. SOT recipients may present unusual manifestations, with a greater proportion of extrapulmonary involvement. TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin. Invasive diagnostic procedures are more frequently required in this population, resulting in a delayofthe properdiagnosis and higher mortality.
Risk Assessment of the Transplant Candidate Ahistory of clinical or radiological TB and the treatment received should be assessed in all recipients. If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TSTor IGRA. IfTSTis selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
TREATMENT Treatment of LTBI in Transplant Candidates and Recipients Criteria to Start Treatment Therapy for LTBIisaneffective strategy for the prevention of active TB infection in transplant recipients.49,50 LTBI therapy is recommended for transplant candidates with positive TST or IGRAwho have not been previously treated. Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated.
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
Guilherme S and colleagues in this review article examines the recommendations for the management of tuberculosis for organ transplant recipients and donors. EPIDEMIOLOGY Epidemiology in Latin America
In the last 2 decades, the burden of tuberculosis (TB) has been considerably reduced in Latin America (LA) countries. Although the estimated proportion of MDR infection among new TB cases remains below 3% in most countries of the region, higher prevalence (between 3.0% and 6.0%) has been found in Ecuador, Guatemala, and Peru. Emergence of multidrug-resistant (MDR) TB, which is defined by the isolation of a causative strain of Mycobacterium tuberculosis resistant to rifampicin and isoniazid (INH), is a global challenge. Recent reports from the latter country provide evidence of ongoing community transmission of MDR infection with significant impact on mortality. Moreover, the prevalence of MDR infection is expectedly higher among patients who were previously treated for TB. In those 3 countries, this prevalence has been estimated to range from 20% to 26%. TB AFTER SOLID-ORGAN TRANSPLANTATION
The incidence rate of TB markedly increases after solid organ transplantation (SOT), the risk being highest among lung recipients. The proportion of patients affected by active TB infection also varies widely among transplant centers in correspondence with the local prevalence of the disease. In studies carried out in LA SOT centers in the last decade, TB was diagnosed in 0.9% to 5.9% of the recipients. International Travel and Posttransplant TB
Transplant recipients from low-incidence countries may be exposed to primary infection while traveling to an endemic area. Among immunocompetent travelers returning from endemic countries, the estimated risk of acquisition of TB infection has generally ranged from 0.4% to 2.0%.20-22 Higher rates (1.8% to 4.2%) were reported among travelers who were involved in healthcare or academic medical exchange programs.
Transplant candidates originating from endemic areas have a higher prevalence of LTBI and are, hence are at an increased risk of developing active TB infection after SOT. DIAGNOSIS Diagnosis of LTBI
There is no diagnostic reference standard for LTBI. Most current guidelines still recommend tuberculin skin testing for the screening of LTBI in solid organ candidates/recipients and living donor.
IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade. It has numerous advantages over tuberculin skin testing because it: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination. They are also probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients. Despite these advantages, the negative predictive value is not sufficient to rule out LTBI in high-risk patients such as those who were born to or lived in endemic countries, household contacts of a case of active TB infection, and those who work or live in high-risk settings, such as correctional facilities and homeless shelters. Other limitations of these assays include their higher cost and the frequent occurrence of conversions and reversions of test results when serial screening is performed, which may complicate the interpretation of their results among SOT candidates. Diagnosis of Active TB Infection
The diagnosis of active TB infection relies on high index clinical suspicion and the detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing. SOT recipients may present unusual manifestations, with a greater proportion of extrapulmonary involvement. TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin. Invasive diagnostic procedures are more frequently required in this population, resulting in a delay of the proper diagnosis and higher mortality. PREVENTION Risk Assessment of the Transplant Candidate
First step is adequate and thorough history including radiological investigations in the past. If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA. If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
Candidates who have low risk for LTBI should preferably be tested solely with IGRA. In high-risk candidates (i.e., patients originated from endemic countries, household contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), both tests could be performed, and any positive reaction considered evidence of LTBI. Whenever this dual-test approach is used, IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses.
Treatment of LTBI should be commenced only when active TB has been excluded. Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative. Despite this, active infection may not be an absolute contraindication when transplantation is urgently needed. Risk Assessment of Deceased and Living Donors
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater. The evaluation of the deceased donor for TB relies on: thorough history, physical examination and radiological testing. Organs from donors with known active TB infection should be discarded. If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines. Drug susceptibility tests should be performed on any M. tuberculosis specimen isolated from the donor, since the detection of drug resistance may be of critical importance for guiding therapy in the recipients. Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted. Lungs with residual tuberculous lesions should not be used for transplantation. A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, especially for lung recipients. TREATMENT Treatment of LTBI in Transplant Candidates and Recipients Criteria to Start Treatment
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated. Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated. Chest imaging suggestive of previous untreated TB should prompt consideration for therapy, especially in areas where endemic mycoses are uncommon. Treatment is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation. Therapeutic Regimens
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily. Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine aminotransferase checked every 2 weeks for 6 weeks, then monthly thereafter. Alternative regimens containing rifamycins can be considered pretransplant but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks. Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy. Timing of Treatment
Balancing the risk of infection and benefit of transplantation is important. It’s preferred to treat before transplantation but urgent need for transplantation might warrant treatment commencing in the perioperative period. Recommendations for Transplanted Patients Who Travel to Endemic Areas
Those traveling to endemic regions after transplantation should use INH prophylaxis in the first post-transplant year. BCG vaccination iscontraindicated. Those with possible TB exposure should be evaluated on return, and anyone with symptoms of infection should seek medical evaluation immediately. Treatment of Active TB Infection
Treatment should follow local guideline just like in general population. However, there is need for monitoring for drug interaction and toxicity.
What is the level of evidence provided by this article?
Summary
Introduction:
TB is a public health problem . The burden of TB has reduced in the Latin American continent in the last few decades. However, according to WHO classification, Brazil remains one of the countries with highest burden of the disease with 110,000 prevalence for disease and 7700 for TB death. The national incidence varies from as low as 11 cases per 100000 in the capital city to as high as 300 per 100000 in lower socio-economic communities. A more challenging issue is the emergence of MDR which is known to be common in those previously treated with TB. Reactivation of latent TB is the main cause of post-transplant TB, primary infection and infection from donor-recipient transmission are less common.
Latent TB diagnosis:
TST
IGRA
TST is recommended for diagnosing latent TB but IGRA is new and has some advantages; avoidance of interpreting bias, less false positive results and more sensitive in CKD and liver cirrhosis.
TST alone used in 48% ; IGRA alone in 30% .
TST with IGRA in 16%.
TST then IGRA in 6% cases.
Active TB diagnosis:
Culture
NAT
Molecular test : gene-expert – limitation is detection of false positive results in previously treated TB cases.. Gene expert test MTB/RIF assay is highly specific and sensitivity depend on if smear positive sensitivity 98% ,if smear negative 67%.
-Risk assessment of transplant patient-recipients:
History taking , clinical examination and radiology for TB
TST and IGRA in case of suspected LTBI
. Active TB infection to be excluded from transplantation.
-Risk assessment of transplant patient-donors and diseased donor:
History of exposure to and treatment of TB
History of diagnosis or treatment for LTBI
Radiological findings
TST, IGRA
-Treatment for LTBI in transplant & recipient:
For any positive TST or IGRA therapy is recommended .
INH 300mg/ day plus pyridoxine 25-30mg for 9 months (close LFT monitoring) OR Rifampicin 600mg daily for 4 months OR INH + Rifapentine weekly for 4 months
Transplant patient that travelling to endemic area during the first year following-Kidney transplantation, should be given INH for prophylaxis.
-Treatment of active infection:
Based on the general local guidelines has been advised that the treatment should not less than 9 months. The treatment includes intensive phase (INH plus RIF plus PYRAZINAMIDE plus EHTAMBUTO), for 2 months, followed by 6 to 9 months of maintenance phase of INH plus RIF.
-Monitoring of adverse events:
· Hepatotoxicity ,if liver enzymes increase by 3 – 5 fold ,therapy to be stopped..
· Rifampicin drug -drug interaction with CNIs, mTORs& corticosteroids by reducing trough level and may result in allograft rejection and/or loss.
Level of evidence: V.
1. Summarise this article Epidemiology of tuberculosis (TB): TB burden in Latin America although reducing, is still high with Brazil, having the highest burden of TB in the world. Variable prevalence in different geographical areas is seen; multi-drug resistant strain (MDR-TB) especially in previously treated patients, is emerging at high prevalence (20-26%). TB after solid organ transplantation (SOT): Incidence of TB post-SOT is increased from 0.9% to 5.9% in LA countries, highest after lung transplant. The main cause of post-transplant TB is reactivation of latent TB infection (LTBI), but it could be due to a primary infection or a donor-derived infection. International travel and post-transplant TB: Travel to TB endemic regions can increase risk of exposure to TB (0.4-2%); increases to 1.8-4.2% in healthcare workers. Prospective recipients and donors from TB endemic regions have high prevalence of LTBI. A higher risk has been seen with cumulative history of travel to high-incidence area for more than 3 months. Public transportation has also been shown to be a risk factor for TB transmission. Diagnosis of LTBI: There is no standard diagnostic test for LTBI. Tuberculin skin test (TST) and interferon gamma release assay (IGRA) are used for screening. IGRA increased sensitivity in CKD, CLD, reduced false positives without interpretation bias, but its negative predictive value is not optimal (can’t rule out LTBI in high-risk patients). In low-risk patients, IGRA alone can be used. In high-risk patients, both TST and IGRA should be used – any positive result should be taken as evidence of LTBI. Diagnosis of Active TB requires either microscopic observation, culture, or nucleic acid testing (NAAT). As patients may have atypical presentation, high index of suspicion is required. Rapid molecular test (Gene X-pert / TB-Gold) is highly specific with good sensitivity (98% in smear positive and 67% in smear negative) in respiratory samples as well as non-respiratory samples (extrapulmonary TB). It also helps detection of rifampicin resistance. False-positive results are seen in patients previously treated for TB. Risk assessment of transplant candidate: · Detail evaluation ofprospective transplant recipients should include clinical history, radiological findings and treatment received. · In absence of clinical history – LTBI evaluation in form of TST (>5mm induration at 48-72 hours) or IGRA should be done. A second TST after 7-10 days of first TST should be done to assess boosted-related skin conversion. · It is preferable to use IGRA alone for low-risk candidates, and combination of IGRA (performed first) and TST for high-risk candidates. · Active TB evaluation involves checking symptoms and signs, imaging, and microbiological tests. · Transplantation should be postponed till an active TB is fully treated. Risk assessment of donors: · Living donors should be evaluated like the recipient, with TST cut off >10mm induration at 48-72 hours. · Deceased donor evaluation includes medical history, history of exposure to TB patient, and radiological findings, and ruling out active TB by taking samples for M. tuberculosis testing. · Donors with known active TB should be declined. · Donors with history of TB successfully treated for 6 months can be accepted. · Donor with untreated LTBI can be accepted with preventive therapy administration to the recipient, especially lung recipient. Treatment: LTBI in transplant candidates and post-transplant recipients should be treated, if · positive TST or IGRA, and not received ATT before · High-risk pre-transplant exposure · history of inadequately treated active TB · chest imaging showing previous untreated TB · exposed to TB after transplant · donor had any history of untreated, incompletely treated LTBI or TB. Treatment of LTBI involves INH (+pyridoxine) for 9 months, or INH + Rifampicin weekly once for 3months or Rifampicin alone daily for 4 months. Whenever possible LTBI should be treated pre-transplant, with preferably combined regimen. Isoniazid preventive therapy should be given to those travelling to endemic areas, and they should be evaluated on their return, if symptomatic. Treatment of active TB infection should follow local TB guidelines according to sensitivity – involves intensive phase of 4 drugs regimen, and drugs (preferably Rifampicin + INH); total duration of therapy for at least 9 months in transplant recipients. Monitoring of liver enzymes every 2weekly x 6 weeks, then monthly thereafter. Hepatotoxicity – 5 times rise of liver enzymes or 3 times rise with symptoms, warrants stopping of ATT. Drug interactions with rifampicin in transplant recipients is important due to effect on CYP3A4, requiring increase in doses of calcineurin inhibitors, mTOR inhibitors, and steroids. Rifabutin, with limited enzyme induction, can be used in place of rifampicin. 2. What is the level of evidence provided by this article? Level of evidence: level 5 – Narrative review.
TB AFTER SOT
●The incidence rate of TB markedly increases after (SOT),
● It may corresponde with the local prevalence of the disease.
● In studies in LA SOT centers in the last decade, TB was diagnosed in 0.9% to 5.9% of the recipients.
● Reactivation of foci of (LTBI) is probably the main cause of posttransplant TB.
● A minor proportion of primary infections result from donor-recipient transmission.
●Most of these cases were in patients who received a graft from deceased donor with active TB infection
● a risk of transmission of approximately 30%.
the influence of donor LTBI on the risk of posttransplant TB is undetermined yet. DIAGNOSIS
There’s nodiagnostic reference standard for LTBI.
■(TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.
■(IGRAs) have emerged as new diagnostic tools in the last decade. advantages
♡avoid interpreting bias,
♡ reduce false-positive
♡more sensitive in candidates with chronic renal failure and advanced cirrhosis,
◇ the negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high riskf or LTBI Per a recent European survey,
•TST alone was used in 48%
•IGRA alone in 30%,
•TSTand IGRA simultaneously in 16%
• TST followed by IGRA in 6%.
●In low-risk patients, IGRAs could be considered as the sole approach,
.
● In high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening Diagnosis of Active TB Infection
○the detection by direct observation, by culture, and nucleic acid testing.
○Neither TST nor IGRAs are recommended for diagnosing active infection.
○The availability of a rapid molecular test, such as the Xpert MTB/RIF assay, may have a major impact in the management the Xpert MTB/RIF assay
□It is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98%and67%,respectively.
□Testing non respiratory samples, such as tissue biopsies and cerebrospinal fluid, is a useful rule-in diagnostic test for extrapulmonary TB.
□It also allows the simultaneous detection of MDR-TB.
□ One limitation of this assay is that false-positive results have been observed among patients who had been successfully treated for TB. PREVENTION Risk Assessment of the Transplant Candidate
●A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
●If negative ==> undergo evaluation for LTBI with either TSTor IGRA.
●If TST , an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction.
●a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
□Candidates low risk for LTBI should preferably be tested solely with IGRA.
□in high-risk candidates
both tests could be performed and any positive reaction considered an evidence of LTBI.
IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses.
□Active TB infection
transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative. active infection may not be considered an absolute contraindication to transplantation for candidates who urgently need it. Risk Assessment of Deceased and Living Donors
Living donors should undergo the same evaluation as candidates
the cut off for TST should be 10 mm or greater.
• Radiographic findings
* apical fibronodular lesions,
*calcified solitary nodules,
* calcified lymph nodes,
* pleural thickening.
* Time does not allow for a TST and IGRAs have not been validated in deceased donors.
●Active TB infection should be ruled out in donors ( sputum or bronchoalveolar lavage).
● Therapy for active infection should be immediately started in the recipient per local guidelines.
●Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
● Lungs with residual tuberculous lesions should not be used for transplantation.
● A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, .
●The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation TREATMENT Treatment of LTBI in Transplant Candidates and Recipients
■ LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
■Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive.
■Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
Therapeutic Regimens For treatment of LTBI
●The preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mgdaily.
(ALT checked every 2 weeks for 6 weeks, then monthly thereafter. )
●Alternative regimens rifamycins, but should be avoided posttransplant because of immunosuppressive drug interactions.
These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
● Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy. Timing of Treatment
○treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist.
○ If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible until completion of the originally planned course Recommendations for Transplanted Patients Who Travel to Endemic Areas
(ie, those with prevalence ≥100/ 100000), INH preventive therapy should be considered during the first posttransplant year,
There is no indication for BCGvaccine before travel, and it is contraindicated in transplant recipients. Treatment of Active TB Infection
●Treatment should follow local guidelines for the general population.
●in most cases, a 4-drug regimen is recommended.
●INH and rifampicin are the most powerful first-line drugs against TB.
●In the context of SOT, many factors should be carefully considered, such as the risk of hepatotoxicity and drug interactions of rifampicin.
●treatment duration should be at least 9 months, Monitoring of Adverse Events Related to Therapy
Low-grade elevation of aminotransferases can be observed during the first 2 months of treatment, but a 3-fold increase accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation. Drug Interactions
Rifamycins (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids).
■A lower blood level of these drugs is associated with higher risk of graft rejection.
■Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin
■It has been demonstrated to be as effective as rifampin for the treatment of TB
Nonetheless, the same recommendation for close therapeutic drug monitorings of these immunosuppressive drugs apply when rifabutin is used.
TB AFTER SOLID-ORGAN TRANSPLANTATION
The main reason for increase in incidence of Tuberculosis post transplantation is reactivation of foci of latent TB infection (LTBI), Other risk factors are immigration, travel to endemic countries, medical tourism, and humanitarian work . DIAGNOSIS
Diagnosis of LTBI: No gold standard test available for diagnosis of LTBI-TST and IGRA assays are available test and both have their own pitfalls and limitations but IGRA is better compared to TST.IGRA assays should be done alone in low-risk patients, however ,in high risk cases-both tests should be done and if any one of them is positive ,then it should be considered as a case of LTBI. Diagnosis of Active TB Infection:
Confirmed diagnosis is done by microscopy, culture and nucleic acid testing of M. tuberculosis bacilli. Xpert MTB/RIF assay has a very good specificity and almost 98% sensitivity for smear positive and 67% 67% for smear negative respiratory samples. It has also good sensitivity for non-respiratory samples. PREVENTION Risk Assessment of the Transplant Candidate
Active T.B must be ruled out by taking detailed history and doing examination ,then X-ray chest ,other imaging studies like CT scan Abdomen as per needed and microbiological examination before labeling the patient as LTBI. Transplantation should be withheld till the patient is asymptomatic and smear is negative. Risk Assessment of Deceased and Living Donors Living Donors:
Same assessment as normal candidates-just the TT value should be 10mm or greater than 10mm. Deceased Donors:
LTBI is difficult to diagnose in the,however,for active T.B, sputum or bronchoalveolar lavage for microbiological diagnosis should be done.
Active TB infection donors,and with residual tuberculosis should be discarded.
Donors with past treated history of TB for at least 6 months can be considered.
Patients with untreated LTBI should not be discarded and in such cases preventive therapy to all recipients should be done TREATMENT Treatment of LTBI in Transplant Candidates and Recipients Criteria to Start Treatment
1-Transplant candidates with positive TST or IGRA
2-high-risk pre-transplant TB exposure(history of active TB infection that was inadequately treated)
3- Chest imaging suggestive of previous untreated TB
1- transplant recipients having donor with untreated or incompletely treated LTBI or TB
2- Exposure of T.B to recipient. Therapeutic Regimens
1- oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily (preferred regimen)
2- RIF 600 mg daily for 4 months or
3- INH and rifapentine weekly for 12 weeks Timing of Treatment
LTBI treatment should be started before transplant.
Treatment should be wiheld perioperatively and resumed when medically possible if transplant is planned immediately. Recommendations for Transplanted Patients Who Travel to Endemic Areas
INH should be started in such cases. Treatment of Active TB Infection
Treatment should be according to national guidelines .Generally a 4-drug regimen is preferred and continued for at least 09 months.But should be cautious of the drug-drug interaction especially with Rifamycins for which close monitoring and continuous dose adjustment is required. Rifampicin belongs to rifamycins group and is a potent inducer that’s why 2-5 fold increments in the daily dose of cyclosporine, tacrolimus, and mammalian target of rapamycin inhibitors are generally required to keep drug level in the range. Monitoring of Adverse Events Related to Therapy
Side effects related to drug should be kept in mind and monitoring in the first 02 months should be done closely. Hepatotoxicity is usually observed with INH, rifampicin, and pyrazinamide.Drugs should be discontinued where there is 3 fold rise in ALT with asymptomatic patient and 5 fold rise in symptomatic patient. Level of evidence: V narrative review .
The incidence rate of TB increases markedly after transplantation…. the current article describes the TB incidence rates in Brazil and Latin America…Brazil is one of the 22 countries in the world as per WHO to have a high burden of tuberculosis…. The risk of TB after Solid organ transplantation is highest in lung transplant recipients…. The proportion of patients with active TB may vary with each transplant center…In studies carried out in LA the incidence of 0.5-5% of all the recipients…
Reactivation of Latent TB seems the most common cause of pulmonary TB after transplant….Primary infection in those living in endemic areas are very common.. .Among transplant patients donor recipient transmission is quite rare….The risk of transmission of TB from a donor who has Latent TB, the transmission rate is quite high as upto 30%… but large scale studies are needed to ascertain the donor derived LTBI in TB transmission…..
International travel to endemic countries and Transplant tourism favor more incidence of TB in SOT recipients…. Transplant patients who are endemic for TB are at increased risk of course… Travel for more than 3 months from a low endemic to high endemic areas increases the contact exposure time and has been shown to be a risk factor for post Transplant TB…Immigrant children post transplant have shown increased risk of Post Transplant TB especially whose parents have migrated to US from an endemic region….In general the long air travel exposure, occupational health hazards for TB like health care personnel, working with prisoners and old age home persons increases the risk of TB in general and the same applies to post renal transplant patients too…Spain has reported high incidence of LTBI in those donors whose cadavers have migrated from countries in Eastern Europe…
Diagnosis of Latent TB infection: There is no standard recommendations, however the tuberculin skin test is the widely used and recommended in all solid organ transplant recipients… TST requires an intradermal injection….Interferon gamma release assay (IGRA) has been used in the place of TST in many centers… The advantages are better precision and yield, avoids bias in interpretation, avoids false positives in BCG vaccinated individuals and those with, infect and those with primary infection…. But this test is expensive and no international standardized assay are available for the same…the negative predictive value of IGRA is not optimal enough to diagnose the latent TB infection… Due to above variations in TST and IGRA various transplant centers use various protocols… In those low risk individuals TST was sufficient and in high risk individuals both IGRA and TST were done to improve the sensitivity and specificity…
Diagnosis of Active TB infection: this relies on detection of TB by AFB stain, Culture or NAT. Neither IGRA or TST can diagnose active infection.. The most challenging situation is when there is clinical suspicion of TB..It can present as pyrexia of unknown origin and can have pleural effusion or ascites… the availability of RIF/Xpert MTB as a diagnostic tool improves the sensitivity and specificity of the TB diagnosis…. the rifampicin resistance can also defined in this test… the utilization of the this is maximum in CSF and pleural fluid….One limitation of the test is the presence of false positive in those already treated for TB….
Risk assessment for transplant candidate: If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation with TST or IGRA… TST >5mm after 48-72 hours is positive for LTBI…in addition a second TST should be performed after 7-10 days after the first TST to evaluate for boosted related skin conversion….
In those with low risk of TB, patients maybe tested with IGRA itself…. In those with high risk (in those residing in endemic areas, household contacts, prisoners and shelterless people) recommendation is to do both TST and IGRA and any positive reaction on either is considered LTBI… when following this dual approach the IGRA should be done first to avoid TST mediated immune boosting response to IGRA… Active TB should always be ruled out by history and physical examination…Sputum examination should be done and CT scan of the chest should be done to rule out cavity consolidation…
Risk assessment of living and deceased donors:
Living donors should be assessed by TST in endemic areas except that the cut off for TST is greater than 10mm… In deceased donor also needs physical examination and history of past exposure to TB…TST and IGRA are not used in cadaveric donors as the results may not be available…. Organs from donors with active TB infection must be discarded.. those organs from patients whom TB is treated for more than 6 months can be used… In the rare case the transplant happens treatment has to happen immediately and care should be take to avoid drug interaction of immunosuppressive and Rifampicin….Special mention for lungs with residual TB sjhould not be used for transplantation…. Any history of treated LTBI in the donors should be enquired and the risk of transmission is less from these donors…
Treatment of LTBI: It is recommended in all transplant patients with positive TST or IGRA in those who have not been treated…. those with high risk pre transplant exposure to TB should be treated even if TST or IGRA is negative…. Treatment for LTBI is recommended in those from whom donors have been treated with partial TB or not completed TB treatment… in consideration of Active TB should be ruled out before starting treatment for active TB…
Treatment is 9 months of INH 300mg/day with pyridoxine 25 to 50 mg /day…9 months are preferred to 6 months for therapy… Other agents like Rifampicin are also used but immunosuppressive drug interaction remains a problem… Rifapentine and INH, levofloxacin have been used but not validated across many studies… The timing of the treatment is to start as early as possible… for patients on the waiting list treatment can be started before transplant and continued later after transplant…
BCG vaccination is contraindicated in renal transplant recipients… those transplant patient who desire to travel to endemic area need INH prophylaxis’s for 9 months
Treatment for active TB infection should be done based on the local/national guidelines for TB…. Rifampicin is an enzyme inducer and will reduce the level of steroid and tacrolimus exposure and it may lead to rejection of the graft… Hepatotoxicity needs to be monitored while on TB treatment
The incidence rate of TB increases markedly after solid organ transplantation (SOT),4,5 with the highest risk among lung recipients. The proportion of patients affected by active TB infection also varies widely between transplant centers in correspondence with the local prevalence of the disease. In the last 2 decades, the burden of tuberculosis (TB) has been considerably reduced in Latin America (LA) countries. It is important to be aware that national average incidence estimates may mask wide variations within a country and marked variation may sometimes occur even within the same city.
Reactivation of foci of latent TB infection (LTBI) is probably the main cause of posttransplant TB. Primary infection acquired in the community, and less frequently in the nosocomial environment, may also account for a considerable proportion of the cases, especially among patients living in endemic areas. A minor proportion of primary infections result from donor-recipient transmission.12 Most of these cases were documented in patients who received a graft from a deceased donor with active TB infection, a situation that has been associated with a risk of transmission of approximately 30%.
Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB after SOT. Transplant candidates originating from endemic areas have a higher prevalence of LTBI and are, hence, at an increased risk of developing active TB infection after SOT and transplant recipients from low-incidence countries may be exposed to primary infection while traveling to an endemic area, but the actual impact of such exposure in this specific population has not been assessed. And the time spent in the endemic area influences the risk of TB infection. A cumulative history longer than 3 months of travel to high-incidence areas is associated with a significantly higher risk. Humanitarian work with high-risk populations, such as prisoners and homeless people, may also be a significant risk factor. The impact of other possible types of exposure is not well defined.
Diagnosis of LTBI
There is no diagnostic reference standard for LTBI. The tuberculin skin test (TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.
IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade. They offer some advantages as compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients.
However, despite their better yield, the negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI, which includes those who were born to or lived in endemic countries, household contacts of a case of active TB infection, and those who work or live in high-risk settings, such as correctional facilities and homeless shelters.
Diagnosis of TB ative infection
The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing. Neither TST nor IGRAs are recommended for diagnosing active infection. Probably the most challenging situation lies on the clinical suspicion of active infection. SOT recipients may present unusual manifestations, with a greater proportion of extrapulmonary involvement. TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin.
PREVENTION
Risk Assessment of the Transplant Candidate
A history of clinical or radiological TB and the treatment received should be assessed in all recipients. If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA. Candidates who have low risk for LTBI should preferably be tested solely with IGRA. In high-risk candidates (ie, patients originated from endemic countries, household contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), both tests could be performed and any positive reaction considered an evidence of LTBI. Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
Risk Assessment of Deceased and Living Donors
Deceased donors should have their assessment based on epidemiological risk (medical history and endemic exposures) and chest X-ray, while living donors should undergo TST, but with a cutoff point of 10mm.
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated. Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated. Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily. Nine months of therapy is preferred over 6 months because of better protection. Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
Treatment of Active TB Infection
The optimal length of treatment of TB in transplant recipients is not defined. Many specialists recommend that treatment duration should be at least 9 months, based on the results of a few studies that have suggested an association between shorter regimens and greater recurrence and mortality. The number of drugs used in the intensive phase regimen should be defined per the prevalence of drug resistance in each population. Nevertheless, in most cases, a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB.
Rifamycins have an induction effect on different drugmetabolizing enzyme systems, most notably the cytochrome P450 (CYP) 3A4, which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids). A lower blood level of these drugs is associated with higher risk of graft rejection. Therefore, close monitoring and continuous dose adjustment are highly recommended.
2. What is the level of evidence provided by this article?
This is a narrative review – level 05.
●The incidence rate of TB markedly increases after (SOT),
● It may corresponde with the local prevalence of the disease.
● In studies in LA SOT centers in the last decade, TB was diagnosed in 0.9% to 5.9% of the recipients.
● Reactivation of foci of (LTBI) is probably the main cause of posttransplant TB.
● A minor proportion of primary infections result from donor-recipient transmission.
●Most of these cases were in patients who received a graft from deceased donor with active TB infection
● a risk of transmission of approximately 30%.
the influence of donor LTBI on the risk of posttransplant TB is undetermined yet.
DIAGNOSIS
There’s nodiagnostic reference standard for LTBI.
■(TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.
■(IGRAs) have emerged as new diagnostic tools in the last decade.
advantages
♡avoid interpreting bias,
♡ reduce false-positive
♡more sensitive in candidates with chronic renal failure and advanced cirrhosis,
◇ the negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high riskf or LTBI
Per a recent European survey,
•TST alone was used in 48%
•IGRA alone in 30%,
•TSTand IGRA simultaneously in 16%
• TST followed by IGRA in 6%.
●In low-risk patients, IGRAs could be considered as the sole approach,
.
● In high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening
Diagnosis of Active TB Infection
○the detection by direct observation, by culture, and nucleic acid testing.
○Neither TST nor IGRAs are recommended for diagnosing active infection.
○The availability of a rapid molecular test, such as the Xpert MTB/RIF assay, may have a major impact in the management
the Xpert MTB/RIF assay
□It is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98%and67%,respectively.
□Testing non respiratory samples, such as tissue biopsies and cerebrospinal fluid, is a useful rule-in diagnostic test for extrapulmonary TB.
□It also allows the simultaneous detection of MDR-TB.
□ One limitation of this assay is that false-positive results have been observed among patients who had been successfully treated for TB.
PREVENTION
Risk Assessment of the Transplant Candidate
●A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
●If negative ==> undergo evaluation for LTBI with either TSTor IGRA.
●If TST , an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction.
●a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
□Candidates low risk for LTBI should preferably be tested solely with IGRA.
□in high-risk candidates
both tests could be performed and any positive reaction considered an evidence of LTBI.
IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses.
□Active TB infection
transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
active infection may not be considered an absolute contraindication to transplantation for candidates who urgently need it.
Risk Assessment of Deceased and Living Donors
Living donors should undergo the same evaluation as candidates
the cut off for TST should be 10 mm or greater.
• Radiographic findings
* apical fibronodular lesions,
*calcified solitary nodules,
* calcified lymph nodes,
* pleural thickening.
* Time does not allow for a TST and IGRAs have not been validated in deceased donors.
●Active TB infection should be ruled out in donors ( sputum or bronchoalveolar lavage).
● Therapy for active infection should be immediately started in the recipient per local guidelines.
●Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
● Lungs with residual tuberculous lesions should not be used for transplantation.
● A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, .
●The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients
■ LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
■Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive.
■Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
Therapeutic Regimens For treatment of LTBI
●The preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mgdaily.
(ALT checked every 2 weeks for 6 weeks, then monthly thereafter. )
●Alternative regimens rifamycins, but should be avoided posttransplant because of immunosuppressive drug interactions.
These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
● Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
Timing of Treatment
○treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist.
○ If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible until completion of the originally planned course
Recommendations for Transplanted Patients Who Travel to Endemic Areas
(ie, those with prevalence ≥100/ 100000), INH preventive therapy should be considered during the first posttransplant year,
There is no indication for BCGvaccine before travel, and it is contraindicated in transplant recipients.
Treatment of Active TB Infection
●Treatment should follow local guidelines for the general population.
●in most cases, a 4-drug regimen is recommended.
●INH and rifampicin are the most powerful first-line drugs against TB.
●In the context of SOT, many factors should be carefully considered, such as the risk of hepatotoxicity and drug interactions of rifampicin.
●treatment duration should be at least 9 months,
Monitoring of Adverse Events Related to Therapy
Low-grade elevation of aminotransferases can be observed during the first 2 months of treatment, but a 3-fold increase accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation.
Drug Interactions
Rifamycins (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids).
■A lower blood level of these drugs is associated with higher risk of graft rejection.
■Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin
■It has been demonstrated to be as effective as rifampin for the treatment of TB
Nonetheless, the same recommendation for close therapeutic drug monitorings of these immunosuppressive drugs apply when rifabutin is used.
Epidemiology of tuberculosis (TB) in Latin America (LA): TB burden in LA countries, despite considerable reduction, is still significant with Brazil having the highest burden of TB in the world. Marked variation in different geographical areas is seen with increased emergence of multi-drug resistant TB (MDR-TB) especially in patients previously treated for TB having prevalence as high as 20% to 26%.
TB post solid organ transplantation (SOT): TB incidence post-SOT increases markedly, with range from 0.9% to 5.9% in LA countries, being highest in lung recipients. The main cause of post-transplant TB is reactivation of latent TB infection (LTBI), but it could be due to a primary infection or a donor-derived infection.
International travel and post-transplant TB: Travel to TB endemic regions can increase risk of TB (0.4% to 2%, increasing to 1.8% to 4.2% in those involved in healthcare). Prospective recipients and donors from TB endemic regions have high prevalence of LTBI. A higher risk has been seen with cumulative history of travel to high-incidence area for more than 3 months. Public transportation has also been shown to be a risk factor for TB transmission.
Diagnosis of LTBI: There is no diagnostic standard for LTBI. Tuberculin skin test (TST) and interferon gamma release assays (IGRAs) are used for LTBI screening. IGRAs do not have interpretation bias, have reduced false positives and increased sensitivity in chronic kidney disease and chronic live disease, but their negative predictive value is not optimal to rule out LTBI in patients considered high-risk. So, in low-rsik patients, IGRA alone can be used, while in high-risk patients, it is prudent to use both TST and IGRA and any positive result should be taken as evidence of LTBI.
Diagnosis of active TB: It requires either microscopic observation, culture, or nucleic acid testing (NAAT). As patients may have atypical presentation, high index of suspicion is required. Rapid molecular test (Xpert MTB/RIF) is highly specific with good sensitivity (98% in smear positive and 67% in smear negative) in respiratory samples. It can be utilized for extrapulmonary TB (by using on non-respiratory samples). It also helps detection of rifampicin resistance simultaneously, although false-positive results are seen in patients previously treated for TB.
Risk assessment of the transplant candidate: All prospective transplant receipts should undergo evaluation including history of clinical or radiological TB and any treatment received. If no history, LTBI evaluation in form of TST (>5mm induration at 48-72 hours) or IGRA should be done. A second TST after 7-10 days of first TST should be done to assess boosted-related skin conversion. It is preferable to use IGRA alone for low-risk candidates, and combination of IGRA (performed first) and TST for high-risk candidates. Active T valuation involves checking signs and symptoms, imaging, and microbiological tests. Transplantation should be postponed till an active TB is treated except in those who require transplant urgently.
Risk assessment of donors: Living donors should be evaluated like the recipient with TST cutoff >10mm induration at 48-72 hours. Deceased donor evaluation includes medical history, history of endemic exposure, and radiological findings, and ruling out active TB by taking samples for M. tuberculosis testing. Donors with known active TB should be declined. Donors with history of TB successfully treated for 6 months can be transplanted. Donor with untreated LTBI can be accepted with preventive therapy administration to the recipient, especially lung recipient.
Treatment: Treatment of LTBI in transplant candidates and recipients should be started if they have positive TST or IGRA (and have not been treated previously), in those with high-risk pre-transplant exposure, with history of inadequately treated active TB, with chest imaging showing previous untreated TB, if exposed to TB after transplant, or if the donor had any history of untreated, incompletely treated LTBI or TB. The treatment of LTBI involves isoniazid with pyridoxine for 9 months, or weekly isoniazid and rifampicin for 12 weeks, or rifampicin alone for 4 months. Whenever possible, LTBI should be treated pre-transplant. Isoniazid preventive therapy should be given to those travelling to endemic areas, and they should be evaluated on their return, if symptomatic. Treatment of active TB infection involves 4 drug regimen for at least 9 months in transplant recipients, with biweekly monitoring of liver enzymes in first 2 months. 3 times rise with symptoms, and 5 times rise of liver enzymes without symptoms would warrant discontinuation of medication. Drug interactions with rifampicin in transplant recipients is important due to effect on CYP3A4, requiring increase in doses of calcineurin inhibitors, mTOR inhibitors, and steroids. Rifabutin, with limited enzyme induction, can be used in place of rifampicin.
2. What is the level of evidence provided by this article?
The incidence rate of TB markedly increases after solid organ transplantation (SOT),4,5 the risk being highest among lung recipients.
Reactivation of foci of latent TB infection (LTBI) is probably the main cause of posttransplant TB.
Diagnosis of LTBI There is no diagnostic reference standard for LTBI. The tuberculin skin test (TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors. IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade. They offer some advantages as compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients.
Diagnosis of Active TB Infection The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture,and nucleic acid testing. Neither TST nor IGRAs are recommended for diagnosing active infection
PREVENTION
Risk Assessment of the Transplant Candidate: A history of clinical or radiological TB and the treatment received should be assessed in all recipients. If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA. If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
Risk Assessment of Deceased and Living Donors:
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
The evaluation of the deceased donor for TB relies on: • Medical history and previous reactive IGRA or TST. • Endemic exposures. Travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the last 2 years, homeless or refugee status, incarceration and alcoholism may be associated with LTBI. In this regard, • Radiographic findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening.
TREATMENT :
Treatment of LTBI in Transplant Candidates and Recipients:
Criteria to Start Treatment Therapy for LTBI is an effective strategy for the prevention of active TB infection in transplant recipients.LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated. Chest imaging suggestive of previous untreated TB should prompt consideration for therapy, especially in endemic area.
Therapeutic Regimens For treatment of LTBI:
the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily. Nine months of therapy is preferred over 6 months because of better protection. Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine aminotransferase checked every 2 weeks for 6 weeks, then monthly thereafter. Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.51,52 Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
Treatment of Active TB Infection : in most cases, a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB. In the context of SOT, many factors should be carefully considered, such as the risk of hepatotoxicity related to the antituberculous treatment and drug interactions of rifampicin.The optimal length of treatment of TB in transplant recipients is not defined. Many specialists recommend that treatment duration should be at least 9 month This is a narrative review, with level 5
background
Although TB prevalence is reducing it is a major health problem in Latin America
TB was diagnosed in 0.9% -5.9% of recipients
TRAVEL/ MIGRATION history is important
Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB
more than 3 months of cumulative travel to endemic are is high risk for LTBI
Children of parents from endemic area are high risk for LTBI ,which is a concern in pediatric SOT
DIAGNOSIS
IRGA are better than TST
more sensitive and unbiased in ESRD patients
low risk patient s- IGRA is preferred
high risk – TST OR IGRA can be done , any positive result is suggestive of LTBI
ACTIVE TB
Documentation of M Tubercle bacillus my smear and culture is time taking
GEBE X PERT/ RIF is more specific and time saving
given rifampicin resistance to diagnose MDR TB
risk stratification in all recipients
both tests are done
TST SHOULD NOT BE DONE BEFORE IGRA
ACTIVE TB is ruled out before starting treating for LTBI
DONOR SCREENING
LIVE = TST MORE THAN 10 MM
DECEASED DONORS
medical history
endemic exposure/ homeless / incarcerated / alcoholic
radiology and microbiology
TST – can t be done due to time constrains
IGRA – NOT VALIDATED
TREATMENT FO LTBI
recipient with TST AND IGRA positive
also high risk with negative results
ORAL INH 300 MG/DAY FOR 9 MONTHS IN POST TRANSPLANT SETTING
INH AND RIFAMPETIN FOR 3 MONTH OR ONLY RIFAMPICIN 4 MONTH IN PRE TRANSPLANT SETTING
POST TRANSPLANT CARE
NO BCG vaccine
travel to endemic are – INH preventive therapy
TREATMENT OF ACTIVE TB
4 DRUS
9 MONTHS
FOLLOW NATIONAL GUIDLINES
5X ELEVATION OF LIVER ENZYMS – DISCONTINUE
RIFAMPICIN CAN REDUCE THE LEVEL OF CNI OR STEROID so drug level require monitoring
Refabutin is an alternative with less effect on drugs
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors EPIDEMIOLOGY Epidemiology in Latin America
· The incidence of TB is declining in Latin America, also the mortality from TB, but Brazil remains one of 22 countries with the highest TB burden in the world
· Estimated multidrug-resistant (MDR) TB is below 3%, it is > 3% in Ecuador, Guatemala, and Peru.
TB AFTER SOLID-ORGAN TRANSPLANTATION
· The risk of TB increased post solid organ transplant, which is highest in lung recipients.
· The main cause of posttransplant TB is reactivation of latent TB
· Primary infection acquired from the community is common, mainly in patients living in endemic areas.
· primary infections from donor-recipient transmission may occur, mainly from a deceased donor with active TB infection
International Travel and Posttransplant TB
· Transplant candidates from endemic areas have a higher prevalence of LTBI and have higher risk of developing active TB infection after SOT.
· In Spain, the prevalence of active TB infection was markedly increased in deceased donors who originated from a high-incidence country in eastern Europe.
· Travelling to endemic areas increased risk of TB, also prisoners and homeless people.
· the use of public transportation in a high-incidence area in Peru was an independent risk factor for active TB infection.
DIAGNOSIS
· The tuberculin skin test is still used for the screening of LTBI in solid organ candidates/recipients and living donors
· Advantages of IFN-γ release assays (IGRAs) over TST: 1) avoid interpreting bias, 2) reduce false-positive results 3) probably more sensitive in candidates with chronic renal failure and advanced cirrhosis
· IGRAs should be used for low-risk patients, but in high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI
Diagnosis of Active TB Infection
· Invasive diagnostic procedures are mostly needed but it delays the proper diagnosis
· Rapid molecular test, such as the Xpert MTB/RIF assay is highly specific and sensitive
· It can also detect rifampicin resistance, with its prediction of MDR-TB and early treatment for MDR-TB until the culture result is available.
· This assay may have false positive results, and cannot replace other drug susceptibility tests.
PREVENTION Risk Assessment of the Transplant Candidate
· If the candidates have no history of past TB or treatment for LTBI, they should be evaluated for LTBI with either TST or IGRA.
· Candidates who have low risk for LTBI should preferably be tested solely with IGRA.
· In high-risk candidates, both tests could be performed and any positive reaction considered suggestive of LTBI.
· Active TB infection must be excluded in all candidates with a positive result before starting treatment for LTBI.
· Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
· But if transplant is needed urgently, active infection will not be an absolute contraindication to transplantation
Risk Assessment of Deceased and Living Donors
· The evaluation of the deceased donor for TB relies on: Medical history, Endemic exposures, and Radiographic findings.
· Active TB infection should be ruled out in donors at increased risk by obtaining sputum or bronchoalveolar lavage,
· Results of microbiological investigation should be forwarded to transplant teams as soon as possible, to take action if it was positive for TB.
· Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
· Lungs with residual TB lesions should not be used for transplantation.
· A history of untreated LTBI without active infection is not a contraindication to donation, but all recipients should be given drugs for prevention, especially for lung recipients.
Treatment of LTBI in Transplant Candidates and Recipients
· LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated
· Candidates with high-risk pretransplant TB exposure should be treated even if the TST or IGRA is not positive, also those with history of active TB infection and not treated adequately.
· Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
Therapeutic Regimens
· The preferred regimen for LTBI is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
· Nine months of therapy is preferred over 6 months because of better protection.
· Transplant candidates and recipients on INH should be monitored for hepatotoxicity with liver enzymes be checked every 2 weeks for 6 weeks, then monthly thereafter.
· Rifamycins regimen can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions.
· A recent study of pretransplant levofloxacin versus posttransplant INH in liver transplant recipients was stopped early because of excessive adverse events in the levofloxacin arm Timing of Treatment
· When possible, treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist.
· If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible, with the avoidance of rifamycins after transplant.
Recommendations for Transplanted Patients Who Travel to Endemic Areas
· If recently transplanted patients are planning to move to a highly endemic area, INH preventive therapy should be considered during the first posttransplant year.
· There is no indication for BCG vaccine before travel, and it is contraindicated in transplant recipients
Treatment of Active TB Infection
· In most cases, a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB
· Many specialists recommend that treatment duration should be at least 9 months Monitoring of Adverse Events Related to Therapy
· Biweekly monitoring for drugs interaction should be done during the first 2 months of treatment.
· Low-grade elevation of aminotransferases can be observed during the first 2 months of treatment, but a 3-fold increase accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation
Drug Interactions
· Rifamycins are drug inducer of cytochrome P450 which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT
· Rifampin has the most potent enzyme induction effect, so daily dose of cyclosporine, tacrolimus, and mTORi are generally necessary to maintain trough levels of the drug in the therapeutic range
· Rifabutin, is an alternative for rifampin, and can be as effective as rifampin for the treatment of TB
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
TB AFTER SOLID-ORGAN TRANSPLANTATION
The incidence rate of TB markedly increases after solid organ transplantation (SOT), the risk being highest among lung recipients. The proportion of patients affected by active TB infection also varies widely among transplant centers in correspondence with the local prevalence of the disease.
Reactivation of foci of latent TB infection (LTBI) is probably the main cause of posttransplant TB.
DIAGNOSIS
Diagnosis of LTBI
There is no diagnostic reference standard for LTBI. The tuberculin skin test (TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.
IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade. They offer some advantages as compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients.
Per a recent European survey, TST alone was used in 48% of the participating centers, IGRA alone in 30%, TST and IGRA simultaneously in 16% and TST followed by IGRA in 6%.
low-risk patients, IGRAs could be considered as the sole approach, because the use of a more specific test might reduce the rate of false-positive results and, consequently, the number of patients who will unnecessarily be exposed to LTBI therapy. On the other hand, in high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
Diagnosis of Active TB Infection
Neither TST nor IGRAs are recommended for diagnosing active infection.
TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin.
the Xpert MTB/RIF assay, may have a major impact in the management of these patients. This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively.
One limitation of this assay is that false-positive results have been observed among patients who had been successfully treated for TB.
PREVENTION
Risk Assessment of the Transplant Candidate
A history of clinical or radiological TB and the treatment received should be assessed in all recipients. If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TSTor IGRA. If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction.
Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started. This evaluation includes checking the presence of symptoms and signs suggestive of TB, performing a chest radiograph and, in cases with extrapulmonary manifestations, imaging of other body sites. If any evidence of active infection is found in this workup, appropriate clinical specimens should be collected for microbiological confirmation of the diagnosis. Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative. Nevertheless, active infection may not be considered an absolute contraindication to transplantation for candidates who urgently need it.
Risk Assessment of Deceased and Living Donors
evaluation of the deceased donor for TB relies on:
• Medical history. The history of untreated or insufficiently treated TB should be investigated, as well as previous reactive IGRA or TST.
• Endemic exposures.
Radiographic
Organs from donors with known active TB infection should be discarded. If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines.
Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, especially for lung recipients. The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, therefore, transplant recipients from such donors can be clinically monitored without receiving LTBI therapy.
Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation. In considering treatment for LTBI, it is imperative to first rule out active TB infection
Therapeutic Regimens
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
Nine months of therapy is preferred over 6 months because of better protection. Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine aminotransferase checked every 2 weeks for 6 weeks, then monthly thereafter. Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks. Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy. However, a recent randomized study of pretransplant levofloxacin versus posttransplant INH in liver transplant recipients was stopped early because of excessive adverse events in the levofloxacin arm.
Nevertheless, in most cases, a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB. In the context of SOT, many factors should be carefully considered, such as the risk of hepatotoxicity related to the antituberculous treatment and drug interactions of rifampicin.
The optimal length of treatment of TB in transplant recipients is not defined. Many specialists recommend that treatment duration should be at least 9 months
Drug Interactions
Rifamycins have an induction effect on different drugmetabolizing enzyme systems, most notably the cytochrome P450 (CYP) 3A4, which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids). A lower blood level of these drugs is associated with higher risk of graft rejection.
Twoto 5-fold increments in the daily dose of cyclosporine, tacrolimus, and mammalian target of rapamycin inhibitors are generally necessary to maintain trough levels of the drug in the therapeutic range. Although enzyme induction start within hours after the first dose of rifampin, maximum effect is reached in about 1 to 2 weeks and slowly declines over 2 weeks after stopping its use. Thus, therapeutic drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption. Despite these drug interactions, rifampicin is not contraindicated in SOT recipients.
Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin. It has been demonstrated to be as effective as rifampin for the treatment of TB in trials conducted in nontransplant patients.
● The risk is highest among lung recipients
● TB was diagnosed in 0.9% to 5.9% of the recipients
● Reactivation of foci of latent TB infection is the main cause of posttransplant TB.
● Primary infection especially among patients living in endemic area and in graft from a deceased donor
● Transplant candidates originating from endemic areas have a higher prevalence of LTBI are at an increased risk of developing active TB infection after SOT.
● Immigration impact the risk of donor transmission.
● Risk factors for active TB infection:
☆ A cumulative history longer than 3 months of travel to high-incidence areas
☆ Prisoners and homeless people
☆ Use of public transportation in a high-incidence area in Peru
☆ Visiting friends and relatives and traveler’s diarrhea
Diagnosis of LTBI
● TST is the best studied test in SO candidates/recipients and living donors
● IGRAs is a new diagnostic tools
● Advantages of IGRA compared to TST:
☆ Avoid interpreting bias
☆ Reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination
☆ More sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield
and a better correlation with clinical risk factors for LTBI in these patients.
● Patients with high risk for LTBI includes
☆ who were born to or lived in endemic countries
☆ Household contacts of a case of active TB infection
☆ who work or live in high-risk settings
● Limitations of these assays include
☆ Higher cost
☆ Occurrence of conversions and reversions of test results when serial
screening is performed
● In low-risk patients, IGRAs is the sole approach
● In high-risk patients, both tests could be performed
Diagnosis of active TB infection
● Relies on the detection of MTB bacilli by direct observation, by culture and nucleic acid testing.
● TST and IGRAs are recommended for diagnosing active infection
● In SOT recipients TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin.
● Xpert MTB/RIF assay is a useful rule-in diagnostic test for extrapulmonary TB and detection of rifampicin resistance
● One limitation is the false-positive results in patients whohad treated for TB
PREVENTION
● If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA.
● If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. A second TST should be performed 7 to10 days after the first TST
● Candidates who have low risk for LTBI should preferably be tested solely with IGRA.
● In high-risk candidates both tests could be performed and any positive reaction considered an evidence of LTBI.
● IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses
● Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
● This evaluation includes :
☆ checking the presence of symptoms and signs suggestive of TB
☆ performing a chest radiograph
☆ in cases with extrapulmonary manifestations, imaging of other body sites.
● If any evidence of active infection is found in this workup, appropriate clinical specimens should be collected for microbiological confirmation of the diagnosis.
● Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
● Active infection may not be considered an absolute contraindication to transplantation for candidates who urgently need it
Risk Assessment of Deceased and Living Donors
● Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
● The evaluation of the deceased donor for TB relies on:
☆ Medical history.
☆ Endemic exposures.
☆ Radiographic findings
▪︎apical fibronodular lesions
▪︎calcified solitary nodules
▪︎calcified lymph nodes
▪︎pleural thickening.
● Obtaining samples bronchoalveolar or sputum lavage, to test for MTB
● Organs from donors with known active TB infection should be discarded.
● Therapy for active infection should be immediately started in the recipient If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation
● Organs from donors with a history of TB
successfully treated for at least 6 months can be transplanted.
● Lungs with residual tuberculous lesions should not be used for transplantation.
● A history of untreated LTBI without evidence of active infection is not a contraindication to donation
but administration of preventive therapy to all recipients should be considered
TREATMENT
● LTBI therapy is recommended for
☆ Candidates with positive TST or IGRA who have not been previously treated
☆ High-risk pretransplant TB exposure if the TST or IGRA is not positive
☆ A history of active TB infection that was inadequately treated.
☆ Chest imaging suggestive of previous untreated TB especially in endemic areas
☆ Recipients whose donor has untreated or incompletely treated LTBI or TB
☆ Recipient is exposed to TB after
transplantation
Therapeutic Regimens
● For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
● Monitore ALT every 2 weeks for 6 weeks, then monthly
● Tegimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy pretransplant, but should be avoided posttransplant
● Treatment for LTBI should be started before transplant, and If urgent transplant
is indicated, the treatment can be held perioperatively and resumed when medically possible avoiding rifamycins
Recommendations for Transplanted Patients Who Travel to Endemic Areas
● INH preventive therapy should be considered during the first posttransplant year
● BCG vaccine is contraindicated in transplant recipients.
Treatment of Active TB Infection
● A 4-drug regimen is recommended.
● In SOT, many factors should be carefully considered, such as INH and rifambicin
● Concomitant use of INH, rifampicin, and pyrazinamide is associated with an increased risk of hepatotoxicity, especially in liver recipients
● 3-fold increase in ALT accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation.
Drug Interactions
● Rifamycins lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus,sirolimus cyclosporine, everolimus, and steroids).
● Close monitoring and continuous dose adjustment are highly recommended.
● Rifampin has the most potent enzyme induction effect. But it isn’t contraindicated in SOT recipients.
● Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin.
Introduction
Tuberculosis is a public health problem and the burden of TB in the Latin has reduced in the Latin American continent in the last decades, although according to WHO classification, Bazil still remains one of the countries with the highest burden of the disease with 110,000 prevalence disease and 7700 TB death. The national incidence varies from as low as 11 cases per 100000 in the capital city to as high as 300 per 100000 in underprivileged communities. A more challenging situation is the emergence of MDR which is known to be quite common among those previously treated with TB. Reactivation latent TB is the main cause of post-transplant TB, primary infection and infection from donor-recipient transmission is less common.
Diagnosis of Latent TB:
Two options
TST
IGRA
TST is still recommended for diagnosing latent TB whether IGRA is new and there are some advantages; avoid interpreting bias, reduce false positive results and more sensitive in CKD and cirrhotic liver.
TST alone used in 48% whether IGRA alone in 30% .
TST and IGRA simultaneously in 16%.
TST followed by IGRA in 6% cases.
Diagnosis of active TB
Options are
Culture
Nucleic acid testing
Molecular test like gene-Xpert – limitation is the detection of false positives in previously treated TB patient. Gene expert test MTB/RIF assay is highly specific and sensitivity depend on if smear positive sensitivity 98% ,if smear negative respiratory sample 67%.
Risk assessment of transplant patient-recipients:
History, clinical examination and radiological test for TB
TST and IGRA in suspected LTBI
Exclude active TB infection from transplantation
Risk assessment of transplant patient-donors and diseased donor:
History of exposure and treatment of TB
History of diagnosis or treatment for LTBI
Radiological investigation
TST, IGRA
Treatment for LTBI in transplant and recipient patient
Any positive TST or IGRA therapy is recommended .
INH 300mg/ day + pyridoxine 25-30mg for 9 months (close LFT check) OR
Rifampicin 600mg daily for 4 months OR
INH + Rifapentine weekly for 4 months
Transplant patient that travels to an endemic country during the first year post-KTP, should take INH as a prophylaxis
Treatment of active infection:
According to the general local guidelines has been advised that the treatment should be at least 9 months. The treatment comprises the intensive phase (INH+RIF+ PYRAZINAMIDE + EHTAMBUTO), for 2 months then followed by 6-9 months of the maintenance phase of INH + RIF.
Monitoring of adverse events related to therapy:
· Monitoring for hepatotoxicity ,if liver enzymes increase by 3 to 5 fold ,stop the therapy.
· Rifampicin drug interaction with CNIs, mTORs, and corticosteroids by reducing their trough level and this could result in allograft rejection or loss.
-Prevalence of TB decreased from 600000-342000 btn 1990-2014.
TB AFTER SOT.
-TB in la estimated to affect 0.9% to 5.9% of recipients with LTBI being the most common source of post transplant TB.
INTERNATIONAL TRAVEL AND POST TRANSPLANT TB.
-KTR from endemic areas considered at more risk of LTBI and active TB post transplant.
DIAGNOSIS.
DIAGNOSIS OF LTBI.
-TST best studied and recommended for screening SOT candidates. IGRA better with less false +VE ,no interpretation bias and more sensitive in CKD and cirrhosis. IGRA is not sensitive to R/O infection in those at high risk of LTBI.
-IGRA used as sole test in low risk and both in high risk to R/O infection and reduce false +VE.
DIAGNOSIS OF ACTIVE TB.
-Dependent on detection of MTB bacilli by direct observation, culture or nucleic acid testing. TST and IGRA are not useful. Gene xpert/RIF assay is highly specific and sensitive with a sensitivity of 98% and 67% in smear +VE and -VE resp samples respectively.
-RIF sensitivity is highly predictive of MDR.
PREVENTION.
Risk assessment of transplant candidates.
-Evaluate for LTBI with TST and IGRA with an induration of >5mm IN 48-72hrs being +VE, Rpt a second TST in 7-10/7 to evaluate for a boosted related skin conversion. Exclude active infection before LTBI treatment and postpone transplant in cases of active TB tx.
2.Risk assessment of deceased and living donor.
-TST cutoff in living donor is 10mm or greater. Deceased donor evaluation for TB based on; Medical hx of partially tx TB, Previous TST or IGRA, Endemic exposure and Radiographic finding of a fibronodular lesion, lung nodule, calcified LN or pleural thickening.
-Samples should be obtained to R/O an active infection in those at high risk of active infection.
-TX should be started ASAP if donor diagnosed with TB post transplant.
-Donor who completed 6/12 of treatment can be successfully transplanted. Lungs with residual TB lesions should not be used for transplantation.
-Those with untreated LTBI without active infection should be given preventive therapy.
TREATMENT.
>LTBI
-Criteria for initiating treatment;
+VE TST or IGRA without prior tx.
High pre transplant TB exposure irrespective of TST or IGRA.
Post TB that was partially treated.
CXR suspicious of previously untreated TB.
Recipient with donor with untreated or partially treated LTBI or TB.
-Therapeutic regimen ;
>INH -9/12 +Pyridoxine.
>Other regimens ;RIF OD for 4/12,INH and Rifapentine weekly for 12/52,Fluoroquinolones +/- ethambutol.
-Timing of treatment.
Done pre transplant.
In urgent transplant, resume once pt stable esp in liver transplant.
-Transplanted pts who travel to endemic areas.
Consider INH in 1st post transplanted year. BCG vaccine is contraindicated post transplant.
>ACTIVE TB.
-Adopt local guidelines.
-4 rug regimen recommended in intensive phase.
-Duration; atleast 9/12 to decrease recurrence and mortality.
-Monitor ADE from TB and closely monitor in 1st 2/12 and monitor for hepatotoxicity. Discontinue tx if transaminases increase by x3 with symptoms or x5 without symptoms.
DI.
-Rifampicin induces cytochrome p450 and decreases CNI,MTOR inhibitor and steroids and thus increase CNI by x2-3,double steroids dose and monitor trough levels to avoid graft dysfunction. Rifampicin should be substituted with rifabutin where available as it has less drug interaction.
III. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
Summarise the article
Epidemiology
– burden of TB has reduced considerably in Latin America countries, nonetheless, TB remains a relevant public health problem in this region
– emergence of MDR TB has become a global challenge
TB after solid organ transplantation
– incidence of TB increases markedly after SOT with the incidence being highest among lung transplant recipients
– LTBI reactivation is main cause of post-transplant TB
– in endemic areas, primary TB infection can be acquired in the community and less frequently in the nosocomial environment
– a few cases of donor-recipient transmission do occur, this has been reported in patients who received a graft from a deceased donor with active TB infection
– the effect of donor LTBI on the risk of post-transplant TB is yet to be determined
Diagnosis
o Diagnosis of LTBI
– currently, there is no standard diagnostic reference for LTBI
– TST and IGRA are commonly used to screen for LTBI
– IGRA is more sensitive than TST in patients with CKD
– IGRA cannot optimally rule out infection in patients with a high risk of LTBI due to its low negative predictive value
– both TST and IGRA should be performed in high-risk patients while in low-risk patients consider IGRA to reduce the rate of false positive results and as such reduce the number of patients being exposed to LTBI treatment unnecessarily
o Diagnosis of active TB
– diagnosis of active TB infection is based on detection of M.Tb bacilli by direct observation, culture and nucleic acid testing
– TST and IGRA are not recommended in the diagnosis of active TB
– SOT recipients have an unusual presentation due to extrapulmonary involvement
– invasive diagnostic procedures are required in some cases and this can lead to a delay in diagnosis and initiation of treatment resulting in higher mortality rates
– rapid molecular tests like the xpert MTB/ RIF assay has helped overcome this challenge
– Xpert MTB/ RIF assay is highly specific and has a sensitivity of 98% in smear positive respiratory samples and 67% in smear negative samples
– in extrapulmonary TB, Xpert MTB/ RIF assay is a useful rule-in diagnostic test since it is highly specific
– Xpert MTB/ RIF assay assesses for rifampicin resistance allowing for a timely initiation of MDR-TB treatment as the culture results and the DST (drug susceptibility test) is pending
– false positive Xpert MTB/ RIF assay can occur among patients who have been treated for TB successfully
– Xpert MTB/ RIF assay cannot replace DSTs
Prevention
o Risk assessment of transplant candidates
– assess for history of clinical or radiological TB, any treatment received
– TST and IGRA should be done to screen for LTBI in patients without a history of past TB or LTBI treatment
– TST cut off is an induraion of ≥5mm at 48-72 hours
– active TB should be ruled out in patients with a positive TST or IGRA test before initiating LTBI treatment
– in patients who have active TB, transplant should be postponed until the TB is well controlled with negative smears
– in patients who urgently need a kidney transplant, active TB is not an absolute contraindication to transplantation
o Risk assessment of deceased and living donors
– living donors should undergo LTBI screening using TST and IGRA like transplant candidates but the TST cut off is 10mm or greater
– evaluation of a deceased donor for TB relies on: –
history of untreated or incompletely treated TB, previous positive TST or IGRA test
endemic exposures associated with LTBI e.g., living in an endemic area, exposure to active TB at home/ work in the last 2 years, homelessness, alcoholism, incarceration
– in deceased donors, time does not allow for TST, and IGRAs have not been validated
– always rule out active TB in high-risk donors using sputum or BAL
– data on the microbiological tests should be shared with the transplant teams for appropriate action
– discard organs from deceased donors with known active TB infection
– if the diagnosis of TB becomes available after organ transplantation, then initiate TB treatment immediately as per the local guidelines
– drug sensitivity test should be done to guide treatment
– accept organs from donors who have been successfully treated for at least 6 months
– history of untreated LBTI without evidence of active TB is not a contraindication to donation but consider using preventive therapy in the recipient
– risk of transmission is low if LTBI treatment had been completed before organ donation so such recipients can be clinically monitored without giving them LTBI therapy
Treatment
o Treatment of LTBI in transplant candidates and recipients
– always rule out active TB before initiating LTBI therapy
– LTBI treatment is recommended in the following instances: –
transplant candidates with a positive TST or IGRA who have never been previously treatedtransplant candidates at high-risk of pretransplant TB exposure (even if the TST and IGRA are negative)
those with history of inadequately treated active TB
those with suggestive CXRs
those with a donor who has history of untreated or incompletely treated LTBI or TB
– treatment options include: –
oral isoniazid 300mg OD + Pyridoxine 25-50mg OD for 6-9months; 9month treatment offers better protection; monitor LFTs for hepatotoxicity
oral rifampicin 600mg OD for 4 months
INH + rifapentine weekly for 12 weeks
Fluoroquinolones ± ethambutol have been suggested for LTBI therapy
– avoid rifamycins post-transplant due to the drug-drug interactions with the immunosuppressive agents
– LTBI treatment should begin pretransplant
– offer IPT (INH preventive therapy) in the 1st year post-transplant in patients who are at increased risk of exposure
o Treatment of active TB infection
– treat as per the local guidelines; 2RHZE + 4RH
– rifampicin and isoniazid are the most potent 1st line drugs against TB
– rifampicin has a strong sterilizing activity
– optimal duration of treatment of TB in KTRs is not defined but most specialists recommend at least 9 months of treatment based on the results of a few studies that showed an association between shorter regimens and greater recurrence and mortality
– consider the drug adverse effects hence close monitoring is advised
– rifamycins are potent inducers of cytochrome P450 3A4 and P-glycoprotein which lead to reduced blood levels of most immunosuppressive agents (CNIs, mTORi, corticosteroids)
– the doses of these immunosuppressive agents (CNIs, mTORi) should be increased by 2-5-fold so as to maintain the therapeutic trough levels
– enzyme induction by rifampicin starts within hours after the 1st dose but the maximum effect is reached in 1-2 weeks and it slowly declines over 2 weeks after stopping rifampicin so close monitoring of trough levels should be frequent in the first 2weeks of treatment initiation and in the first 2 weeks after stopping rifampicin
– low blood levels of the immunosuppressive agents predispose the patient to graft rejection thereby close monitoring and continuous dose adjustment is advised
– rifampicin is not contraindicated in SOT recipients and the rejection and mortality rates are not affected by treatment with rifampicin-based regimens
– rifabutin is an alternative to rifampicin, it is a weaker enzyme inducer, is as effective as rifampicin in treatment of TB among nontransplant patients
– its weaker effect on CYP3A4 males it easier to maintain therapeutic levels of CNIs and mTORi
Epidemiology in Latin America
As Per World Health Organization report of 2014,2 Brazil remains in the group of 22 countries with the highest TB burden in the world, with 110 000 prevalent cases and 7700 TB deaths. Haiti, Bolivia, and Peru are still moderately to highly endemic, with incidence remaining over 100 cases per 100 000.Higher prevalence (between 3.0% and 6.0%) of MDR infection among new TB cases has been found in Ecuador, Guatemala, and Peru. Ongoing community transmission of MDR infection have significant impact on mortality.
TB AFTER SOLID-ORGAN TRANSPLANTATION
In studies carried out in LA, SOT centers in the last decade, TB was diagnosed in 0.9% to 5.9% of the recipients.
Most of these cases were documented in patients who received a graft from a deceased donor with active TB infection. Although it is probable that donors with untreated LTBI may also be a source of TB transmission, the influence of donor LTBI on the risk of posttransplant TB is undetermined yet.Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB after SOT. Transplant candidates originating from endemic areas have a higher prevalence of LTBI. DIAGNOSIS Diagnosis of LTBI
The tuberculin skin test (TST)
IFN-γ release assays (IGRAs) they offer some advantages as compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis.
The negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI. Diagnosis of Active TB Infection
M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing
Xpert MTB/RIF assay-This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively. It also allows the simultaneous detection of rifampicin resistance but the limitation is false-positive results have been observed among patients who had been successfully treated for TB
PREVENTION Risk Assessment of the Transplant Candidate
A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA
In high-risk candidates (ie, patients originated from endemic countries, household contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), both tests could be performed and any positive reaction considered evidence of LTBI
Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
Risk Assessment of Deceased and Living Donors
The history of untreated or insufficiently treated TB should be investigated, as well as previous reactive IGRA or TST
Endemic exposures. Travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the last 2 years, homeless or refugee status, incarceration and alcoholism may be associated with LTBI. Radiographic findings, such as apical fibronodular lesions or calcified solitary is also the risk factor.
Time does not allow for a TST and IGRAs so, have not been validated in deceased donors.
Active TB infection should be ruled out in donors at increased risk by obtaining samples, for sputum or bronchoalveolar lavage. As microbiological investigation often be available after procurement, all data should be forwarded to transplant teams as soon as possible.
Organs from donors with active TB infection should be rejected.
If the microbiologic diagnosis of TB in the donor becomes available after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines.
Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
Lungs with residual tuberculous lesions should not be used for transplantation.
A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered.
TREATMENT Treatment of LTBI in Transplant Candidates and Recipients
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
Chest imaging suggestive of previous untreated TB should prompt consideration for therapy, especially in areas where endemic mycoses are uncommon.
Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
Therapeutic Regimens
For treatment of LTBI, oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
Or RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks
Or INH and rifapentine weekly for 12 weeks.
Recommendations for Transplanted Patients Who Travel to Endemic Areas
If recently transplanted patients are planning to move to a highly endemic area (ie, those with prevalence ≥100/ 100000), INH preventive therapy should be considered during the first posttransplant year.
BCG is contraindicated in transplant recipients.
Treatment of Active TB Infection
The number of drugs used in the intensive phase regimen should be defined per the prevalence of drug resistance in each population.
4-drug regimen is recommended.
Treatment duration should be at least 9 months.
Monitoring of Adverse Events Related to Therapy
Concomitant use of INH, rifampicin, and pyrazinamide is associated with an increased risk of hepatotoxicity.
3-fold increase in liver enzymes accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation.
Drug Interactions
Two to 5-fold increments in the daily dose of cyclosporine, tacrolimus, and mammalian target of rapamycin inhibitors are necessary to maintain trough levels of the drug in the therapeutic range.
Although enzyme induction starts within hours after the first dose of rifampin, maximum effect is reached in about 1 to 2 weeks and slowly declines over 2 weeks after stopping its use.
The same recommendation for close therapeutic drug monitorings of drugs apply when rifabutin is used even it is weaker effect on CYP3A4
prevalence and death reduced in laten America in the last two decades, still higher prevalence in Brazil ,moderate high in over 100 cases per 100 000 in Haiti, Bolivia, and Peru.
(MDR) TB, which is defined by the isolation of a causative strain of Mycobacterium tuberculosis resistant to rifampicin and isoniazid (INH), is a global challenge.
Although the estimated proportion of MDR infection among new TB cases remains below 3% in most countries of the region, higher prevalence (between 3.0% and 6.0%) has been found in Ecuador, Guatemala, and Peru.
TB after organ transplantation:
The incidence rate of TB after SOT,
the risk being highest among lung recipients.
In studies carried out in LA SOT centers in the last decade, TB was diagnosed in 0.9% to 5.9% of the recipients.
Reactivation of foci of latent TB infection (LTBI).main
. Primary infection acquired in the community, and less frequently in the nosocomial , especially among patients living in endemic areas.
A miner proportion of primary infections result from donor-recipient transmission.
LTBI.
International Travel and Posttransplant TB:
Immigration, international travel too reside at endemic countries, and transplant tourism may influence the risk of TB after SOT.
Children of immigrants parent also increased incidence of TB
Immigration may also impact the risk of donor transmission.
DIAGNOSIS Diagnosis of LTBI
low-risk patients, IGRAs could be considered as the sole approach, because the use of a more specific test might reduce the rate of false-positive results .
in high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
Diagnosis of Active TB Infection:
detection of M. tuberculosis bacilli by direct observation, by culture d nucleic acid testing.
Xpert MTB/RIF assay, is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively.
PREVENTION Risk Assessment of the Transplant Candidate A
history of clinical or radiological TB and the treatment received should be assessed in all recipients.
If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA.
If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction.
In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
If any evidence of active infection is found in this workup, appropriate clinical specimens should be collected for microbiological confirmation of the diagnosis.
Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
Risk Assessment of Deceased and Living Donors:
the cutoff for TST should be 10 mm or greater.
The evaluation of the deceased donor for TB relies on:
• Medical history. The history of untreated or insufficiently treated TB should be investigated, as well as previous reactive IGRA or TST.
• Endemic exposures. Travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the last 2 years, homeless or refugee status, incarceration and alcoholism may be associated with LTBI.
• Radiographic finding.
Organs from donors with known active TB infection should be discarded.
If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines
. Drug susceptibility tests should be performed on any M. tuberculosis specimen isolated from the donor. Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted. Lungs with residual tuberculous lesions should not be used for transplantation.
A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, especially for lung recipients.
The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, therefore, transplant recipients from such donors can be clinically monitored without receiving LTBI therapy.
TREATMENT:
Treatment of LTBI in Transplant Candidates and Recipients :
Criteria to Start Treatment :
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
Those with high-risk peri transplant TB exposure should be treated even if TST and IGRA is negative.
Chest imaging suggestive of previous untreated TB .
transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB.
the recipient is exposed to TB after transplantation.
Therapeutic Regimens :
For treatment of LTBI the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
Alternative :
RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
Start of treatment:
Should be before transplants.
If urgent ,stop during transplant and resume. After ,consider RF free regime.
Treatment of Active TB Infection :
Treatment should follow local guidelines for the general population
. The Monitor for drugs AE And interaction.
Rifamycin have an induction effect on different drug metabolizing enzyme systems, most notably the cytochrome P450 (CYP) 3A4, which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus, cyclosporine, sirolimus, Everolimus, and even corticosteroids).
Therefore, close monitoring and continuous dose adjustment are highly recommended.
Epidemiology in Latin America: Latin America (LA) countries have lowered their TB burden during the past two decades. In 2014, 110,000 Brazilians developed TB and 7700 died. Haiti, Bolivia, and Peru are highly endemic. Based on notification numbers, Brazil’s estimated 2015 national incidence was 31 cases per 100,000. Rifampicin- and isoniazid-resistant Mycobacterium tuberculosis causes MDR TB worldwide. Ecuador, Guatemala, and Peru have 3.0%–6.0% MDR new TB cases. These nations have high-mortality community-transmitted MDR. TB AFTER SOLID-ORGAN TRANSPLANTATION: Lung transplant recipients have the highest TB risk. Local disease incidence affects transplant facilities’ active TB infection rates. infection post-transplant may be donor derived, reactivation of LTB or de-novo infection. Most of these occurred in patients who received grafts from deceased donors with active TB, which has a 30% transfer risk. Untreated LTBI donors may transmit TB. Diagnosis of LTBI: – The tuberculin skin test (TST) is suggested for LTBI screening in solid organ candidates/recipients and living donors. – IGRAs has better connection with clinical risk factors for LTBI, they reduce bias, reduce false-positive results from nontuberculous mycobacteria or BCG vaccination, and may be more sensitive in those with chronic renal failure and severe cirrhosis. – however, IGRAs’ negative predictive value is not optimal to rule out infection in patients at high risk for LTBI, including those born to or living in endemic countries, household contacts of active TB cases, and those who work or live in high-risk settings like correctional facilities and homeless shelters. – greater cost and numerous test result conversions and reversions during serial screening may make interpretation difficult. – in low-risk individuals, IGRAs may be used, but to maximize screening sensitivity, high-risk patients can have both tests, and any positive result should be considered LTBI. Diagnosis of active TB: – M. tuberculosis bacilli are detected by direct observation, culture, and nucleic acid testing to diagnose active TB. TST and IGRA are not indicated for active infection diagnosis. – SOT recipients may have more extrapulmonary involvement. Patients with unexplained fever should be evaluated for TB. – The Xpert MTB/RIF assay, a fast molecular diagnostic, may improve patient management. This test has a 98% sensitivity in smear positive respiratory samples and 67% in smear negative samples. Xpert MTB/ RIF assay is a good rule-in diagnostic test for extrapulmonary TB since it performs similarly on Non respiratory samples such tissue biopsies and cerebrospinal fluid. It detects MDR-TB-predictive rifampicin resistance simultaneously. Hence, it may help start MDR-TB treatment quickly while conventional culture and drug susceptibility findings are awaited. – This assay can produce false-positive results in TB-treated patients. – It also cannot replace drug susceptibility tests. Risk Assessment of the Transplant Candidate: – A history of clinical or radiological TB and the treatment received should be assessed in all recipients. – If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA. – If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion. Risk Assessment of Deceased and Living Donors: – living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater. – risk factors: • Medical history. • Endemic exposures, homeless status, incarceration and alcoholism. • Radiographic findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening Treatment of LTBI in Transplant Candidates and Recipients: – LTBI therapy is advised for untreated transplant candidates with a positive TST or IGRA who have not been treated previously. – Even if the TST or IGRA is negative, those with high-risk pretransplant TB exposure should be evaluated for medication, as should those with a history of active TB infection that was inadequately managed. – Chest imaging findings suggestive of prior untreated tuberculosis may prompt therapeutic consideration, particularly in regions where endemic mycoses are infrequent. – If the donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation, therapy is advised. – Prior to start treatment for LTBI, it is crucial to exclude active TB infection. Therapeutic regimens: – Oral INH 300 mg/d for 9 months and oral pyridoxine 25–50 mg daily are recommended for LTBI treatment. – 9 months of therapy is safer than six. – Hepatotoxicity should be monitored with serum ALT every 2 weeks for 6 weeks, then monthly for transplant candidates and recipients on INH. – RIF 600 mg daily for 4 months or INH and rifapentine monthly for 12 weeks. – Fluoroquinolones (ethambutol) may be used for LTBI. Recommendations for Transplanted Patients Who Travel to Endemic Areas: – If recently transplanted patients intend to consider moving to a highly endemic area,INH preventive therapy should be considered during the first posttransplant year. – Prior to travel, there is no justification for BCG immunization. – To prevent nosocomial transmission of tuberculosis, transplant recipients who travel to TB-endemic regions in order to provide medical or humanitarian aid should take basic precautions. Upon their return, anyone who may have been exposed to tuberculosis should be evaluated, and anyone exhibiting symptoms of infection should seek prompt medical assistance. Treatment of Active TB Infection: – Local guidelines should be followed. – The intensive phase regimen should use medications based on drug resistance in each group. A 4-drug regimen is usually advised. – INH and rifampicin are the strongest first-line TB medicines. Rifampicin medication interactions and Anti tuberculous therapy hepatotoxicity should be evaluated in SOT. – TB treatment in transplant recipients has no recommended duration. – duration recommend at least 9 months of treatment.
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
1. Summarise this article.
2. What is the level of evidence provided by this article?
Summary of this Article :
EPIDEMIOLOGY:
TB after Solid-organ transplantation: In Latin America, TB continues to be a significant public health issue. The incidence of TB increases after SOT, the highest risk among lung recipients. TB was diagnosed in 0.9% to 5.9% of the recipients. Reactivation of latent TB infection (LTBI) is probably the main cause of posttransplant TB.
Primary infection acquired in the community, and less frequently in the nosocomial environment, may also account for a considerable proportion of the cases, especially among patients living in endemic areas.
A minor proportion of primary infections result from donor-recipient transmission. The risk of TB may be impacted by immigration, travel to endemic regions, and transplant tourism.
Working with high-risk populations (convicts and the homeless can pose a potential risk. Diagnosis of LTBI:
There is no diagnostic reference standard for LTBI.
The tuberculin skin test (TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.
IFN-γ release assays (IGRAs) offer some advantages as compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination,more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients Diagnosis of Active TB Infection: Fever of unknown origin Rapid molecular test, such as the Xpert MTB/RIF assay This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively. Tissue biopsies and cerebrospinal fluid, indicating that Xpert MTB/ RIF assay is a useful rule-in diagnostic test for extrapulmonary TB. Risk Assessment of the Transplant Candidate:
A history of clinical or radiological TB and the treatment received should be assessed in all recipients. If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA. If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion. In high-risk candidates (ie, patients originated from endemic countries, household contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), both tests could be performed and any positive reaction considered an evidence of LTBI If any evidence of active infection is found in this workup, appropriate clinical specimens should be collected for microbiological confirmation of the diagnosis. Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative. Risk Assessment of Deceased and Living Donors:
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
The evaluation of the deceased donor for TB relies on:
Medical history.: The history of untreated or insufficiently treated TB should be investigated, as well as previous reactive IGRA or TST. Endemic exposures: within last 2 years Radiographic findings: such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening. Active TB infection should be ruled out in donors at increased risk by obtaining samples, for example, sputum or bronchoalveolar lavage, to test for the presence of M. tuberculosis. Organs from donors with known active TB infection should be discarded. If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines. Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted. The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, therefore, transplant recipients from such donors can be clinically monitored without receiving LTBI therapy. Treatment of LTBI in Transplant Candidates and Recipients: Criteria to Start Treatment Therapy for LTBI is an effective strategy for the prevention of active TB infection in transplant recipients. LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated. Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated. Chest imaging suggestive of previous untreated TB should prompt consideration for therapy, especially in areas where endemic mycoses are uncommon. Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation. Therapeutic Regimens For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily. Nine months of therapy is preferred over 6 months because of better protection. Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine aminotransferase checked every 2 weeks for 6 weeks, then monthly thereafter. Timing of treatmentof LTBI:
Preferably started before transplant and can often be completed while the patient is on the waitlist.
It can be started. Perioperatively or when medically possible until completion of the course. Recommendations for Transplanted Patients Who Travel to Endemic Areas:
If recently transplanted patients are planning to move to a highly endemic area (ie, those with prevalence ≥100/ 100000), INH preventive therapy should be considered during the first posttransplant year, especially for those planning to take part in medical or humanitarian care, given the higher risk of primary TB acquisition. There is no indication for BCG vaccine before travel, and it is contraindicated in transplant recipient. Treatment of Active TB Infection: Four-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB for at least 9 months. Side effects: hepatotoxicity Drug interactions: Rifampin has the most potent enzyme induction effect. Two-to 5-fold increments in the daily dose of cyclosporine, tacrolimus, and mammalian target of rapamycin inhibitors are generally necessary to maintain trough levels of the drug in the therapeutic range. Thus, therapeutic drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption. What is the level of evidence provided by this article?
Summary ofTuberculosis Recommendations for Solid Organ Transplant Recipients and DonorsEpidemiology
The cases in the region declined from about 600,000 to 342,000 between 1990-2014.
The prevalence of MDR infection in Ecuador, Guatemala, and Peru has been estimated to range from 20 -26% T.B. after SOT the highest risk of T.B. among lung recipients, the most common of T.B post-transplant is the reactivation of foci of laten T.B infection. Patients living in the endemic area have a reasonable number of they got the disease by the nosocomial environment. International Travel and posttransplant T.B
Immigration, international travel to endemic countries, and transplant tourism may influence the risk of T.B after SOT. Diagnosis of LTBI
No standard diagnostic test for LTBI but current guidelines recommend TST test be used for screening LTBI in SOT candidates/recipients.
IFN-Y realize assays (IGRAs) also is used in the diagnosis of LTBI, it has some advantages as compared with TST avoiding interpretation bias reducing the false-positive result to previous exposure to non-tuberculous mycobacteria or BCG vaccination, and more sensitive in CKD and advanced liver cirrhosis. but the negative predictive value of IGTAs is not accurate to rule out infection in high-risk patients for LTBI.
Limitation of IGRAs :
1- It has a higher cost.
2- Occurrence of conversion and reversion of test result when serial screening is performed. Diagnosis of active TB infection
1- Culture to detect mycobacterium T.B.
2- Nucleic acid testing, rapid molecular test such as Xpert MTBIRIF assays is highly sensitively 98% and specifically 67% .
The limitation of this test is a false positive result. Prevention
Risk assessment of the transplant candidate,a history of clinical or radiological T.B and should be assessed in all recipients.
If no history of past T.B or treatment for LTBI so candidate should have TST or IGRA,TST if induration is 5 mm or more at 48 to 72 hours so considered positive second TST should be repeated 7 days to 10 days after the first TST to evaluate boosted -related skin conversion.in high-risk groups patients both TST&IGRA should be performed. Risk assessment of deceased living donors
Living donors should evaluate as recipients with the exception cut off TST should be 10 mm or greater. Evaluation of the deceased donors:
Medical history of untreated or insufficiency-treated TB previous reactive IGRAs or TST.
Endemic exposure travel or residence in an endemic area or exposure to active T.B. infection in the household or workplace in last 2 years , homeless, refugee, increation and alcoholism associated with LTBI.
Radiological findings include:
The apical fibronodular lesion, calcified solitary nodules, calcified lymph node, and pleural thickening. untreated LTBI without active infection is not contraindicated but should start preventive therapy for all recipients. Treatment of LTBI in transplant candidates and recipients:
Criteria to start treatment of LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
High-risk exposure pretransplant T.B considered for therapy even if the TST or IGRA is not positive and also those with a history of active T.B infection were inadequately treated. Therapeutic regimen
INH regimen 300 mg /day for 9 months plus pyridoxine 25 -50 mg po od
Transplant candidates and recipients on INH should be monitored for alanine aminotransferase every 2 weeks for 6 weeks then monthly.
Rifampicin 600 mg daily for 4 months (pretransplant).
INH plus rifapentine weekly for 12 months. Timing of treatment
Should treat LTBI before transplant, if urgent transplant treatment can be perioperative and resume when medically possible. Recommendation for transplant patients who travel to the endemic area:
If recent transplant patients are planning to move to a highly endemic area (prevalence > or more 100 /100.000 )INH preventive therapy is given in the posttransplant year.
BCG is contraindicated in a transplant recipient Treatment of active T.B infection
Four drug regimens include INH, and rifampicin optimal treatment therapy is not defined but specialized advice should be a 9-month duration. Monitoring adverse event-related therapy
First 2 months monthly biweekly.INH, Rifampicin, and pyrazinamide are associated with a risk of hepatotoxicity
3 -5 fold increase of liver enzyme requires discontinuation. Drug interaction
Rifampicin enzyme inducer and decrease level of CNI and mTOR.
2 to 5 fold increase of the dose of CNI or mTOR to maintain the target trough level.
Rifabutin weaker enzyme induction and alternative therapy for rifampicin level of evidence 5
The burden of tuberculosis (TB) has been reduced in Latin America (LA) countries, but is still a relevant public health problem. A group of 22 countries including Brazil with the highest TB burden, with 110 000 prevalent cases and 7700 TB deaths. The national average incidence estimates may mask wide variations within a country. Emergence of multidrug-resistant (MDR) TB is a global challenge, with higher prevalence in Ecuador, Guatemala, and Peru.
TB after solid organ transplantation :
The incidence rate of TB after solid-organ transplantation (SOT) is highest among lung recipients , with active TB infection affecting 0.9% to 5.9% of SOT recipient . Reactivation of latent TB infection (LTBI) is the main cause of post-transplant TB, but donor LTBI may also be a source of transmission.
International Travel and Posttransplant TB:
The risk of TB after SOT Immigration is influenced by international travel to endemic countries, and transplant tourism . Transplant candidates originating from endemic areas are at an increased risk of developing active TB infection and a higher prevalence of LTBI . Transplant tourism is also associated with donor transmission of TB .In low-incidence countries travel-related acquisition may account for a substantial proportion of new infections among peoples there .There is increased risk of TB infection associated with a cumulative history longer than 3 months of travel to high-incidence areas . Humanitarian work with high-risk populations, long-distance flights, ground transportation, and visiting friends and relatives are all risk factors for active TB infection.
DIAGNOSIS : the tuberculin teast is the best studied test for LTBI sceening but IGRA offer advantages such as avoiding bias,reducing false-positive result and being more sensitive to chronic renal failure and advanced cirrhosis.
Diagnosis of Active TB Infection : The diagnosis of active TB infection based on the detection of M. tuberculosis bacilli by direct observation, culture, and nucleic acid testing. The Xpert MTB/RIF assay is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively. It also allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB. However, false-positive results have been observed among patients who had been successfully treated for TB
Risk Assessment of the Transplant Candidate:
All recipients should be assessed regarding history of clinical or radiological TB and the treatment received . If history is negative, candidates should undergo evaluation for LTBI with either TST or IGRA. Candidates who have low risk for LTBI should preferably be tested solely with IGRA, in high risk patients a dual test may be used . Transplantation should be postponed if candidates proved to have active TB , until the disease is well controlled with adequate treatment and smears are negative.
Risk Assessment of Deceased and Living Donors:
The evaluation of the deceased donor for TB relies on: medical history. The history of untreated or insufficiently treated TB should be investigated, as well as previous reactive IGRA or TST. • Active TB infection should be ruled out in donors at increased risk by obtaining samples, for example, sputum or bronchoalveolar lavage, to test for the presence of M. tuberculosis.
A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, especially for lung recipients.
TREATMENT:
Treatment of LTBI in Transplant Candidatesand Recipients: Therapy for LTBI is proved to be effective strategy for the prevention of active TB infection in transplant recipients, and is recommended for transplant candidates with positive TST or IGRA and those with high-risk pretransplant TB exposure.
Therapeutic Regimens:
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to50 mg daily. Nine months of therapy is preferred over 6 months because of better protection, monitoring for hepatotoxicity is mandatory . A recent randomized study of pretransplant levofloxacin versus posttransplant INH in liver transplant recipients was stopped early because of excessive adverse events in the levofloxacin arm.
Timing of treatment :
The timing of LTBI treatment requires balancing risks and benefits for each patient, especially liver transplant recipients .When possible, treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist.It is particularly challenging to treat liver transplant candidates before transplant.
Recommendations for Transplanted Patients Who Travel to Endemic Areas:
INH preventive therapy should be considered for transplant recipients who travel to endemic areas to provide medical or humanitarian care, and those with possible TB exposure should be evaluated on return and seek medical evaluation immediately.
Treatment of Active TB Infection:
Treatment of Active TB Infection with a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB, but there is risk of hepatotoxicity and drug interactions. The optimal length of treatment of TB in transplant recipients is not defined depend on severity and site of infection . Monitoring of adverse events is recommended, especially during the first 2 months of treatment, due to increased risk of hepatotoxicity.
Drug Interactions:
Rifampicin is a potent enzyme inducer which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids). Rifabutin,is as effective as rifampin for the treatment of TB in trials conducted in non-transplant patients with weaker and more limited spectrum of enzyme induction.
What is the level of evidence provided by this article? Level V
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
1. TB after solid-organ transplantation · TB was diagnosed in 0.9% to 5.9% of the recipients. · Reactivation of foci of latent TB infection (LTBI) is probably the main cause of post-transplant TB. · A minor proportion of primary infections result from donor-recipient transmission. · Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB after SOT. 2. Diagnosis
Diagnosis of LTBI · There is no diagnostic reference standard for LTBI. · The tuberculin skin test (TST) remains the best studied test. · IFN-γ release assays (IGRAs) reduce false-positive results related to previous exposure to BCG vaccination, and are more sensitive in candidates with chronic renal failure. · IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI. Here both tests could be performed.
Diagnosis of Active TB Infection · Neither TST nor IGRAs are recommended for diagnosing active infection. · SOT recipients may present unusual manifestations, TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin. · The availability of a rapid molecular test, such as the Xpert MTB/RIF assay, may have a major impact in the management of these patients. · Due to its high sensitivity and specifity, Xpert MTB/ RIF assay is useful in diagnosis of pulmonary and extrapulmonary TB. · Xpert MTB/ RIF assay also allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB. 1. Prevention Risk Assessment of the Transplant Candidate · A history of clinical or radiological TB and the treatment received should be assessed in all recipients. · Candidates should un dergo evaluation for LTBI with either TST or IGRA if no history of past TB. · In TST, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. · A second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion. · Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started. · Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative. Risk Assessment of Deceased and Living Donors Living donors should undergo the same evaluation as candidates, but the cutoff for TST should be 10 mm or greater. The evaluation of the deceased donor for TB
· Medical history: The history of untreated TB, and reactive IGRA or TST should be elicited.
· Assessment of risk factors for TB infection
· Assessment for radiological evidence of previous TBI.
· Active TB infection should be ruled out in donors at increased risk by obtaining samples, for example, sputum or bronchoalveolar lavage.
· Because the results of micro- biological investigation will be available after procurement, it must be ensured that all data will be forwarded to transplant teams.
· Organs from donors with known active TB infection should be discarded.
· If diagnosis of TB in the donor becomes available only after organ transplantation, therapy for TBI should be immediately started in the recipient.
· Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
· Lungs with residual tuberculous lesions should not be used for transplantation.
· A history of untreated LTBI is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered.
2. Treatment
Treatment of LTBI in Transplant Candidates and Recipients
· LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
· Those with high-risk pre-transplant TB exposure and those with history of active TB infection that was inadequately treated should be considered for therapy even if the TST or IGRA is negative.
· Chest imaging suggestive of previous untreated TB should prompt consideration for therapy.
· Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB.
· Therapy is also recommended, if the recipient is exposed to TB after transplantation.
Therapeutic Regimens· For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months with oral pyridoxine 25 to 50 mg daily with monitoring for hepatotoxicity· Alternative regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks. These regimens can be considered pre-transplant, but should be avoided post-transplant.· When possible, treatment for LTBI should be started before transplant.· If recently transplanted patients are planning to move to a highly endemic area, INH preventive therapy should be considered du ing the first post-transplant year.Treatment of Active TB Infection · Treatment should follow local guidelines for the general population.· In the context of SOT, many factors should be considered, such as the risk of hepatotoxicity related to the antituberculous treatment and drug interactions of rifampicin.· Many specialists recommend that treatment duration should be at least 9 months.Monitoring of Adverse Events Related to Therapy· Close monitoring of adverse events is highly recommended, mainly during the first 2 months of treatment.· A 3-fold increase aminotransferases accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation. Drug Interactions· Rifamycins leads to a reduction in the blood levels ta crolimus, cyclosporine, sirolimus, everolimus, and corticosteroids. · A lower blood level of these drugs is associated with higher risk of graft rejection.· Rifabutin, which has a weaker enzyme induction is an alternative for rifampin. It has been demonstrated to be as effective as rifampin for the treatment of TB in non-transplant patients.· When rifabutin is used , drug monitoring of immunosuppressive is indicated.
I admire your clarity of thought process and I quote from your write-up in italics:
Those with high-risk pre-transplant TB exposure and those with history of active TB infection that was inadequately treated should be considered for therapy even if the TST or IGRA is negative.
Yes.professor. as the probability of harbouring TB is high in these subset of patients . These tests are not 100% sensitive. Latent TB is a real concern in transplant recepients. I believe it should be treated before the transplant itself whenever possible especially in LR transplant.
Epidemiology in Latin America: In Latin America, most countries in the region are still moderately to highly endemic, with incidence remaining over 100 cases per 100 000 in Haiti, Bolivia, and Peru. Multidrug-resistant (MDR) TB, which is defined by the isolation of a causative strain of Mycobacterium tuberculosis resistant to rifampicin and isoniazid (INH), is a global challenge, and accounts < 3% of the newly diagnosed cases, the risk increases in those previously treated for TB infection. The prevalence of MDR-TB in Ecuador, Guatemala, and Peru, is in the range of 20-26%.
TB after solid organ transplantation: The incidence rate of TB markedly increases after solid organ transplantation (SOT), the risk being highest among lung recipients, and correspond to the local TB prevalence. Reactivation of the latent infection is the most common cause of post transplant TB infection, then community acquired primary infection, and rarely donor derived active disease transmission are the sources to disease.
International Travel and Posttransplant TB: Immigration, travel to high endemic area and transplant tourism increases the risk of LTBI, Humanitarian work with high-risk populations, such as prisoners and homeless people, may also be a significant risk factor, long time flights, underground and puplic transportation are risk factors for active TB infection.
DIAGNOSIS: 1- Latent tuberculosis: TST is the most recommended screening for latent TB for both donor and recipient worldwide. and IGRAs – interferon gamma release assay is widely used in the last decade with major PROS in: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis. IGRAs CONS– (1) poor negative predictive value in high risk population cannot rule out the disease, (2) higher cost and (3) the frequent occurrence of conversions and reversions of test results when serial screening is performed, which may complicate the interpretation of their results among SOT candidates.
2- Primary tuberculosis: The diagnosis of primary TB relies on the detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing. Which may take long time and increase the morbidity and mortality from a disease. Xpert MTB/RIF assay, highly specific, rapid test to start treatment, with a sensitivity of 67% in smear negative and 98% in smear positive body secretions, and allows the simultaneous detection of rifampicin resistance.
PREVENTION: – Risk Assessment of the Transplant Candidate: A history and radiological assessment and treatment for TB should be taken before transplant, until the disease is well controlled and smears are negative. Evaluation for LTBI to all transplant candidate is a must, TST for high risk candidates, TST of 5 mm or more considered positive and mandate treatment., and IGRAs for low risk candidates should be considered. Active infection is not an absolute contraindication to transplantation when urgently needed.
– Risk Assessment of Deceased and Living Donors: The TST 10 mm or more considered positive and required treatment. The evaluation of the deceased donor for TB relies on: a. Medical history. The history of untreated or insufficiently treated TB should be investigated, as well as previous reactive IGRA or TST. b. Endemic exposures. Travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the last 2 years, homeless or refugee status, incarceration and alcoholism may be associated with LTBI. c. Radiographic findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening. So, microbiological evalutation of sputum or bronchoalveolar lavage with drug susceptibility should done in deceased donors and transmitted to transplant team as soon as the result comes. Untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered.
TREATMENT: 1- Treatment of LTBI in Transplant Candidates and Recipients:
Treatment for the followings after ruling out active disease: · All transplant candidate with positive TST and IGRAs. · Those with high risk TB exposure should receive even if both TST and IGRAs are negative. · Those with exposure to TB patients post transplant. · Those with history of active TB infection that was inadequately treated, or chest X-ray findings suggestive of not well treated TB. Therapeutic Regimens: Isoniazid 300 mg + pryridoxin 25-50 mg daily for 9 months, with frequent monitoring of ALT every two weeks for 6 weeks then monthly- the preferred regimen. Rifampin 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks – can be considered before transplant but should be avoided after transplant due to drug-drug interactions. Fluoroquinolones (± ethambutol), a recent randomized study of pretransplant levofloxacin versus posttransplant INH in liver transplant recipients was stopped early because of excessive adverse events in the levofloxacin arm. Timing of Treatment: LTBI treatment should start before organ transplantation, if urgent transplant is indicated then the treatment should be held perioperatively and resumed after medically feasible, avoiding rifamycin based therapy.
For Transplanted Patients Who Travel to Endemic Areas INH prophylaxis in the first year of transplantation is indicated, No indication for BCG vaccine before travel, and it is contraindicated in transplant recipients.
2- Treatment of Active TB Infection: Treatment should follow local guidelines for the general population, 4 drug regimen INH+RIF based for 9 months. Monitoring the adverse effects of drugs biweekly for 2 months then monthly, with 3-5 times dose increment of CNI and m-TORi, doubling steroid and frequent drug level monitoring. Drug Interactions: Rifamycin is a strong enzyme inducer, decreasing the levels of immunosuppressive drugs, making them prone to rejection, enzyme induction starts within hours after the first dose of rifampin, maximum effect is reached in about 1 to 2 weeks and slowly declines over 2 weeks after stopping its use. Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin. Liver function test monitoring if ALT increases 3 times with symptoms, or 5 times normal with no symptoms, consider discontinuation of INH+RIF.
What is the level of evidence provided by this article? Level of evidence is I – recommendations and guidelines by the transplantation society.
Introduction: In Latin America, the burden of TB has reduced in the last 2 decades, but it remains a high TB endemic zone. The prevalence varies in each country. The emergence of multidrug resistant TB (MDR TB) is a challenge. It is defined by the isolation of a causative strain of Mycobacterium tuberculosis resistant to rifampicin and isoniazid (INH). The transmission of MDR TB has a significant impact on mortality.
TB after solid organ transplantation: The incidence rate of TB increases after solid organ transplantation (SOT), the risk is highest after lung transplantation. The main cause of TB after transplantation is reactivation of foci of latent TB infection (LTBI). Primary infection after exposure to a patient with active TB is also a major cause of TB after SOT. Another cause is transmission to the recipient via the donor graft.
International travel and post-transplant TB: Transplant candidates from endemic area have a higher prevalence of LTBI and are, hence, at an increased risk of developing active TB infection after SOT. Immigration may also affect the risk of donor transmission. The time spent in the endemic areas also influences the risk of TB infection. Humanitarian work with high-risk populations, such as prisoners and homeless people, may also be a significant risk factor.
Diagnosis of LTBI: The tuberculin skin test (TST) is recommended for the screening of LTBI in solid organ donor candidates/recipients and living donors. Interferon gamma release assays (IGRAs) off more advantages over TST. They avoid interpreting bias, reduce false-positive results related to exposure to BCG vaccinations, and are more sensitive in candidates with chronic renal failure and advanced cirrhosis. Unfortunately, they are more expensive.
Diagnosis of active TB infection: The diagnosis of active TB requires detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing. Neither TST or IGRAs are recommended for diagnosing active infection. SOT recipients may present with unusual clinical manifestations. Invasive diagnostic procedures are required in this population. This results in a delay in diagnosis and higher mortality. The Xpert MTB/RIF assay is highly specific and sensitive to TB infection diagnosis. It also allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB. Unfortunately, it has been associated with false-positive results in patients previously treated for TB.
Prevention: Risk assessment of the transplant candidate For the recipients, a history of clinical or radiological TB and any treatment received should be assessed. If there is no history of past TB or treatment for LTBI, then the potential recipients should undergo evaluation for LTBI with either TST or IGRA, both for patients living in high risk settings. If the tests are positive, active TB infection must be excluded before LTBI treatment is started. If active TB infection is present, the transplant should be postponed until the disease is well controlled, but it is not an absolute contraindication for the procedure.
Risk assessment of deceased and living donors Living donors should undergo the same evaluation as the potential recipients. Deceased donor evaluation relies on their medical history, endemic exposure and radiographic findings. Active TB should be ruled out in donors at increased risk. The organs with active TB infection from deceased donors should be discarded. If the diagnosis is made after the transplantation, then therapy for active TB should be initiated in the recipient.
Treatment Treatment of LTBI in transplant candidates and recipientsTreatment for LBTI is reported to be effective in preventing active disease, in transplant recipients. LTBI therapy is recommended for potential transplant recipients with:
Positive TST or IGRA who have not been previously treated
High-risk pre-transplant TB exposure
History of active TB infection that was not treated adequately
Chest imaging suggestive of previously untreated TB
A donor history of untreated or incompletely treated TB LTBI or TB.
The preferred treatment for LTBI is INH 300mg/day for 9 months, with pyridoxine 25-50mg/day. The treatment should ideally be started before the transplant if the transplant is not an emergency procedure. INH preventative therapy should be considered during the first year post-transplant for patients in high-risk areas, or traveling to high-risk areas.
Treatment of active TB infection Treatment should follow local guidelines. The optimal length of treatment is not defined, most specialists recommend at least 9 months of treatment. Adverse effects and drug levels should be monitored closely. A three-fold increase of aminotransferases with any symptoms, or a five-fold increase regardless of a symptom requires discontinuation of the anti-TB medications.
Monitoring of Adverse Events Related To Therapy: There is an increased risk of adverse events and drug to drug interactions that will need very close monitoring. Both, INH and rifampin interact with CNIs, mTOR inhibitors and glucocorticoids. Therefore, it is important, especially at the beginning of therapy for the first two to four weeks and after completing therapy, to monitor the drug levels.
I admire your debate regarding the use of TST Vs IGRA in risk assessment of those with suspected latent TB. I like the way you mitigate against bias when interpreting tests.
I like your summary, level of evidence, analysis and take home.
Tb recommendations for Solid Organ Transplant Patients and Donors
Reactivation of latent TB infection (LTBI) is likely the main cause of post-transplant TB, and DDI for TB primarily results from deceased donation. The incidence rate of TB infection is considerably raised following solid organ transplantation (SOT), with the risk being highest among lung recipients.
There are numerous risk factors for SOT recipients that include working with high-risk populations, including prisoners and the homeless, being exposed on long-distance flights, and visiting endemic regions.
Latent Tb infection diagnosis
Although there are no universally accepted diagnostic standards for LTBI, all recommendations call for tuberculin skin testing (TST) in solid organ candidates, recipients, and living donors. IFN-release assays (IGRAs), a recent development in diagnostic tools, serve as the second test. The benefits of IGRA over the tuberculin test include the avoidance of interpretation bias, the reduction of false-positive results resulting from prior exposure to nontuberculous mycobacteria or BCG vaccination, and the likelihood that they are more sensitive in candidates with advanced cirrhosis and chronic renal failure.
The use of a more specific test may lower the rate of false-positive results, so in low-risk patients, IGRAs were thought to be the only approach. On the other hand, in high-risk patients, both tests could be used, and any positive result should be taken as evidence of LTBI to maximize screening’s sensitivity.
Active TB infection diagnosis
The Xpert MTB/RIF assay is highly specific and has an estimated sensitivity of 98% and 67% in smear-positive and -negative respiratory samples, respectively. It also plays a role in the detection of rifampicin resistance. TST and IGRAs have no role in the diagnosis of active TB, but Mycobacterium tuberculosis bacilli can be confirmed by culture, and nucleic acid testing is the cornerstone of the diagnosis.
Prevention
Transplant Candidate Risk Assessment
Assess all recipients for clinical or radiological TB and therapy. TST or IGRA for LTBI evaluation if no history of TB or therapy. High-risk patients can undergo both tests, with a positive result indicating LTBI. Active TB infection should be treated before donation according to local/international protocols. Donor Risk Assessment
Organs from donors with known active TB infection should be discarded, as TSTs are difficult and time-consuming and IGRAs have not been validated in deceased donors. If active TB infection is confirmed in the donor, treatment should be started in the recipient immediately per local guidelines. History of untreated LTBI without evidence of active infection is not a contraindication to donation, but all recipients should receive preventive therapy.
Transplant Candidates and Recipients LTBI Therapy
Treatment Requirements
1- Untreated transplant candidates with positive TST or IGRA should receive LTBI.
2- Active TB infection untreated.
3- Transplant recipients whose donors have LTBI or TB should receive therapy.
Treatment options for Latent Tb infection Oral INH 300 mg/d for 9 months, with pyridoxine 25 to 50 mg daily. Alternatively, rifampicin given as 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
Recommendation for transplanted Patients Traveling to Endemic Areas INH preventative therapy should be considered in the first year post-transplant. Before visiting endemic areas, BCG vaccination is not recommended and contraindicated. Infected kidney recipients should seek medical help.
Therapy for Active Tuberculosis Typically, a 4-drug regimen is advised. The most effective first-line treatments for TB are indomethacin (INH) and rifampicin, which are typically given for nine months. The first two months of treatment are very important for close monitoring, which should be done every two weeks. If the LFT is 5 times higher than normal, medication should be stopped.
Adverse drug reactions-drug interactions Rifampicin is a powerful drug inducer that increases drug metabolism and, as a result, lowers blood levels of drugs like (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids), which can cause graft rejection. Rifabutin has the advantage over Rifampicin in that it is less of a drug inducer, but drugs should still be strictly monitored.
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors.
The incidence rate of TB infection is markedly increased after solid organ transplantation (SOT) and the risk being highest among lung recipients, reactivation of latent TB infection (LTBI) is probably the main cause of post-transplant TB and DDI for TB is mainly occurring from deceased donation.
Many risk factors for developing TB in SOT recipients such as work with high-risk populations, such as prisoners and homeless people, exposure in long-distance flights, and travelling to endemic areas. Diagnosis of LTBI.
There is no standard diagnostic criteria for LITB but all guidelines recommend The tuberculin skin test (TST) in solid organ candidates/recipients and living donors and the second test is IFN-γ release assays (IGRAs) which is a new diagnostic tools in the last decade, the advantages of it compared with TST are avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis.
So, in low-risk patients, IGRAs was considered as the sole approach, because the use of a more specific test might reduce the rate of false-positive results and on the other hand, in high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening. Diagnosis of Active TB Infection.
TST and IGRAs have no role inactive TB diagnosis but detection of M. tuberculosis bacilli by culture,and nucleic acid testing is the quintessential of the diagnosis, the Xpert MTB/RIF assay is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98%and 67%, respectively and also has a role in detection of rifampicin resistance . Prevention: Risk Assessment of the Transplant Candidate.
1- A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
2- No history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA.
3- For high-risk candidates, both tests could be performed and any positive reaction considered an evidence of LTBI.
4- Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative. Risk Assessment of Deceased and Living Donors.
Organs from donors with known active TB infection should be discarded, it is not easy and time does not allow for a TST and IGRAs have not been validated in deceased donors, and if active TB infection confirmed in the donor, immediately treatment should be started in the recipient per local guidelines, history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered and lung with residual TB should be discarded. Treatment of LTBI in Transplant Candidates and Recipients Criteria to Start Treatment. 1- LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated. 2- Those with history of active TB infection that was inadequately treated. 3- Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB. Therapeutic Regimens.
1- The preferred regimen for LTBI is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
2- Alternative regimens containing rifampicin can be considered pre-transplant, these regimens include RIF 600mg daily for 4 months or INH and rifapentine weekly for 12 weeks. Timing of Treatment.
Better to complete the treatment course before transplantation but if urgent transplant is indicated, the treatment can be held preoperatively and resumed when medically possible until completion of the originally planned course. Recommendations for Transplanted Patients Who Travel to Endemic Areas.
–INH preventive therapy should be considered during the first post-transplant year.
-BCG vaccine is contraindicated and not indicated before traveling to endemic area.
–Anyone kidney recipient with symptoms of infection should seek medical evaluation immediately. Treatment of Active TB Infection.
In most cases, a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB and usually for 9 months not least. Close monitoring is highly recommended, mainly during the first 2 months of treatment when it should be performed biweekly and if LFT is 5 folds than normal, medications should be discontinued. Drug Interactions.
Rifampicin is considered potent drug inducer which leads to increasing drugs metabolism and hence, decreasing their level in blood such as (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids) that may lead do graft rejection, and so frequent monitoring of these drugs is such important, Rifabutin has an advantage over Rifampicin that it is less drug inducer but still drugs should be strictly monitored. Level of evidence: V Narrative study .
I appreciate your debate regarding the use of TST Vs IGRA in risk assessment. I like your comment, “TST and IGRAs have not been validated in deceased donors”,
I like your summary, level of evidence, analysis and take home messages
SUMMARY Introduction
The burden of TB in the Latin has reduced in the Latin American continent in the last decades, although according to WHO classification, Bazil still remains one of the countries with the highest burden of the disease with 110,000 prevalence disease and 7700 TB death. Moreso, the national incidence varies from as low as 11 cases per 100000 in the capital city to as high as 300 per 100000 in underprivileged communities. A more challenging situation is the emergence of MDR which is known to be quite common among those previously treated with TB
TB after solid organ transplantation
The risk and the incidence of TB is higher among SOT patient, especially in lung transplant patients
TB infection can be contracted by; reactivation of primary infection, infection from the environment of donor organs especially diseased donors
Immigration from or to an endemic country after SOT can also influence the risk of contracting TB especially if staying more than 3 months in an endemic country.
Immigration of donors or organs can contribute to the incidence of TB in SOT
Other at risk are humanitarian staff that work in high-risk places like homeless homes, prisons, and minimal report documents on long haul flight
Diagnosis of Latent TB
TST
IGRA
Advantages of IGRA over TST
it avoids interpreting bias,
it reduces false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination,
probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients
Limitation of IGRA
suboptimal negative predictive value
high cost of the assays
The advice given by some specialists is to use IGRA in low-risk patients and in those with high risk for TB
Diagnosis of active TB
It relies on the detection of M. Tuberculosis in samples via tests like
Culture
Nucleic acid testing
molecular test like gene-Xpert – limitation is the detection of false positives in previously treated TB patient
Risk assessment of transplant patient-recipients
Clinical history and radiological test for TB
Use of TST and IGRA in suspected LTBI
Exclude active TB infection from transplantation
Risk assessment of transplant patient-donors and diseased donor
medical history of exposure to treatment for TB
History of diagnosis or treatment for LTBI
radiological investigation
TST, IGRA
Lungs with residual TB lesions should not be used for donation
Treatment for LTBI in transplant and recipient patient
INH 300mg/ day + pyridoxine for 9 months (close LFT check) OR
Rifampicin 600mg daily for 4 months OR
INH + Rifapentine weekly for 4 months
Transplant patient that travels to an endemic country during the first year post-KTP, should take INH as a prophylaxis
Treatment of active infection
The general local guideline of the country or region be followed based on the endemicity of TB in the area and it has been advised that the treatment should be at least 9 months. The treatment comprises the intensive phase (INH+RIF+ PYRAZINAMIDE + EHTAMBUTO), for 2 months then followed by 6-9 months of the maintenance phase of INH + RIF.
Drug interaction
The major challenge is a rifampicin drug interaction with CNIs, mTORs, and corticosteroids by reducing their trough level and this could result in allograft rejection or loss.
Other toxicities of concern are neurotoxicity, hepatotoxicity, and nephrotoxicity
There is a around 50% decrease both in the number and mortality of TBC in Latin America. TB-associated death reduced from 43000 to 22000; this data belongs to the years 1990 and 2014. According to WHO, Brazil is still one of the countries with a high endemic rate. The incidence is variable among countries. Recently, we have been in the challenge of multidrug-resistant TBv (MDR-TBC), defined as resistance to rifampicin and INH.
After solid organ transplantation, the reactivation of latent TBC seems to be the most common cause. Nosocomial or primary active infection is less. Donor-related transmission can also be seen with a transmission risk of %30.
LTBI is high in patients from high-endemic areas. Guidelines still suggest normal Tuberculin skin test, as it is in most studied. Recently IGRA is offered but still not optimal to rule out infection in patients with a high risk of latent TBC infection. Still, it has the advantage of reducing interpretation bias, and low false positive results due ton on tuberculous tbc or previous infection as well. IGRA is still not widely used by transplantation centres. Some use it in combination with TST.
For diagnosis of active tbc neither TST nor IGRA is recommended. The real challenge is suspicion which is not easy because of non-specific or symptoms that can be attributed to other reasons.
Prevention is key. All patients should be evaluated for latent infection by history and x-ray. Candidates without previous history of TBC should be screened by either TST or IGRA. An induration of more than 5 mm should be considered positive. For those with very high risk or those with suspected contact or those from endemic areas, both tests need to be performed.
Treatment of active LTBI
Those who are at a high risk of exposure and those with positive skin or IGRA tests should be treated to prevent an active infection. Usually, the preferred treatment is INH 300 mg/day (9 months) combined with vitamin B6.
Management of active TBC: should comply with the guidelines but usually is based on 4 drugs regimen. INH and rifampicin constitute the backbone of treatment. Close monitoring is essential. Interaction with rifampicin should be considered. We need to consider that the net effect is seen oardas the second week and subsides likewise after discontinuation.
I appreciate your debate regarding the use of TST Vs IGRA in active TB.
I like your summary, level of evidence, analysis and take home messages.Please use headings and sub-headings to make easier to read your write-up. Please use bold or underline to highlight headings and sub-headings.
Tuberculosis is a public health problem ,but in period from 1990 to 2014 prevalent cases declining ( from 600,000 to 342000) and mortality rate( 43000 to 22000 ) this data from latin America counteries .
Brazil remains in the group of 22 counteries with the highest tuberculos burden in the world.
MDR (multi drug resistant ) is below 3% in new TB cases.
TB after solid –organ transplantation.
The incidence of TB increases after solid organ transplantation which is higher in lung transplantation.
Reactivation latent TB is main cause of posttransplant TB, primary infection is less common and less common also in infection from donor-recipient transmission . International travel and post transplant TB
Immigration and travel to endemic area may influence in posttransplant TB.
Prisoner and homeless are risk factor. DIAGNOSIS of latent TB:
TST is still recommended for diagnosing latent TB.
IGRA is new ,and there is some advantage like : avoid interpreting bias,reduce false positive results ,
And more sensitive in CKD and cirrhotic liver.
The use of TST and IGRA differ from centre to another ,as in Europian survey :
TST alone used in 48% .
IGRA alone in 30% .
TST and IGRA simultaneously in 16%.
TST followed by IGRA in 6%. Diagnosis of active TB:
the diagnosis of active TB relies on detection of mybacterium TB bacilli by direct observation ,by culture and nucleic acid testing.
Gene expert test MTB/RIF assay is highly specific and sensitivity depend on if smear positive sensitivity 98% ,if smear negative respiratory sample 67%.
Expert assay use to rule- in extra pulmonary TB.
Expert assay use in detection of rifampicin resistance .
Limited use of expert assay is that false positive results in already treated for TB. Risk assessment of the transplant candidates :
The history of any TB treatment and radiological manifestation for all recipient must be assessed.
If no history latent TB should be assessed by TST.
IGRA alone or combination with TST .
Active TB must be exclude in any TST or IGRA positive test. Risk assessment of deceased and living donor
History of any TB ,treatment ,endemic area and any radiological findings.
In high risk donor ,sputum test must be taken.
Exclusion of the donor if had active TB.
If donor treated for 6 month later can donate . Treatment of latent TB in transplant candidates and recipient
Any positive TST or IGRA therapy is recommended .
In high risk pre transplant inspite of negative TST or IGRA therapy is recommended .
INH 300 mg/d for 9 month ,with oral 25 to 50 mg pyridoxine daily . Monitoring of adverse events related to therapy
Monitoring for hepatotoxicity ,if liver enzymes increase by 3 to 5 fold ,stop the therapy. Drug interaction
Rifamycins have an inuction effect through cytochrome P450.
Close monitoring and dose adjustment regularly is highly recommended. Level of evidence V
Summarise this article * TB incidence increases after SOT, with the highest risk in lung recipients. * TB was diagnosed in 0.9% to 5.9% of the recipients. * Reactivation of foci of latent TB infection (LTBI) is probably the main cause of post transplant TB. * Primary infection acquired in the community, and less frequently in the nosocomial environment * Transplant candidates originating from endemic areas have a higher prevalence of LTBI and increased risk of developing active TB infection * Transplant recipients from low-incidence countries may be exposed to primary infection while traveling to an endemic area. * the actual impact of such exposure in this specific population has not been assessed. * risks to increase incidence of TB infection are : immunocompetent travelers returning from endemic countries, travellers who were involved in Healthcare or academic medical exchange programs. Humanitarian work with high-risk populations. * Time spent in the endemic area ( more than 3 months) · Diagnosis of LTBI ( TST the standard ) , next is (IGRAs) * There is a marked variation across transplant centers regarding the approach for screening LTBI in candidates, with TST alone being used in 48% of the participating centers, IGRA alone in 30%, TST and IGRA simultaneously in 16% and TST followed by IGRA in 6%. Diagnosis of Active TB Infection * by detection of M. tuberculosis bacilli by direct observation, culture, and nucleic acid testing. * Neither TST nor IGRAs are recommended for diagnosing active infection. *SOT recipients may present unusual manifestations,or aysmptomatic and most of time with extra pulmonary symptoms .
SOT candidates evaluation :
*A history of clinical or radiological TB and treatment for LTBI should be assessed in all recipients. * If TST induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. * A second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion. * Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started. * If active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative. DONORS evaluation : * Living donors should undergo the same evaluation as candidates for TB with Medical history, endemic exposures, and radiographic findings, but induration of TST 10 mm or greater. * for deceased donors, TST and IGRAs should be considered * Organs from donors with active TB infection should be discarded and therapy for active infection should be immediately started. * Lungs with residual tuberculous lesions should not be used for transplantation. TREATMENT * LTBI therapy is recommended for transplant candidates with positive TST or IGRA, those with high-risk pretransplant TB exposure, and those with a history of active TB infection. * It is also recommended for transplant recipients whose donor has a history of untreated LTBI or TB, or if the recipient is exposed to TB after transplantation. * oral INH 300 mg/d for 9 months, with pyridoxine 25 to 50 mg daily. * Alternative regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks. * Treatment for LTBI should be started before transplant, and if an urgent transplant is indicated, held perioperatively and resumed when medically possible until completion of the course. * Monitoring of INH, rifampicin, and pyrazinamide is recommended due to the increased risk of hepatotoxicity. * Rifampycins have an induction effect on different drug-metabolizing enzyme systems, leading to a reduction in the blood levels of immunosuppressive drugs used after SOT.
* maintain therapeutic blood levels of calcineurin and mammalian target of rapamycin inhibitors during TB treatment.
level of evidence provided by this article Level V
Latin America has seen a decrease in the burden of tuberculosis (TB) over the last two decades, but Brazil remains in the group of 22 countries with the highest TB burden.
Most countries in the region are still moderately to highly endemic, with incidence remaining over 100 cases per 100 000.
Emergence of multidrug-resistant (MDR) TB is a global challenge, with higher prevalence in Ecuador, Guatemala, and Peru.
MDR infection among new TB cases is higher in Ecuador, Guatemala, and Peru, with an estimated prevalence of 20% to 26%.
==================================================================== TB AFTER SOLID-ORGAN TRANSPLANTATION
The incidence rate of TB after solid organ transplantation (SOT) is highest among lung recipients, with active TB infection affecting 0.9% to 5.9%.
Reactivation of latent TB infection (LTBI) is the main cause of posttransplant TB, with primary infection acquired in the community and less frequently in the nosocomial environment.
International Travel and Posttransplant TB
Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB after SOT.
Transplant recipients from low incidence countries may be exposed to primary infection while traveling to an endemic area, but the actual impact of such exposure in this specific population has not been assessed.
Time spent in the endemic area and a cumulative history longer than 3 months of travel to high-risk areas are associated with a significantly higher risk.
Humanitarian work with high risk populations may also be a significant risk factor.
The tuberculin skin test (TST) is the best studied test for LTBI, and most current guidelines recommend its use for the screening of solid organ candidates/recipients and living donors.
IFN-γ release assays (IGRAs) have emerged as new diagnostic tools, but their negative predictive value is not optimal to rule out infection in patients considered to be at high risk for LTBI.
There is marked variation across transplant centers regarding the approach for screening LTBI in candidates, with TST alone being used in 48% of the participating centers, IGRA alone in 30%, TST and IGRA simultaneously in 16% and TST followed by IGRA in 6%.
Some specialists suggest adapting the diagnostic approach per the estimated risk of being infected.
Diagnosis of Active TB Infection
The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, culture, and nucleic acid testing.
SOT recipients may present unusual manifestations, with a greater proportion of extrapulmonary involvement.
Rapid molecular tests such as the Xpert MTB/RIF assay may have a major impact in the management of these patients, as it has an estimated sensitivity insmear positive and smear negative respiratory samples of 98% and 67%, respectively.
However, false positive results have been observed among patients who had been successfully treated for TB.
The risk assessment of the Transplant Candidate should include a history of clinical or radiological TB and treatment for LTBI.
If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction.
A second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses.
Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
Transplanation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
Risk Assessment of Deceased and Living Donors
Living donors should undergo the same evaluation as deceased donors for TB, with the cutoff for TST being 10 mm or greater.
Medical history of untreated or insufficiently treated TB should be investigated, as well as previous reactive IGRA or TST.
Endemic exposures, travel to endemic areas, homeless or refugee status, incarceration and alcoholism may be associated with LTBI.
Radiographic findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes or pleural thickening.
Organs from donors with known active TB infection should be discarded, and therapy for active infection should be immediately started in the recipient.
Drug susceptibility tests should be performed on any M. tuberculosis specimen isolated from the donor, and lungs with residual tuberculous lesions should not be used for transplantation.
Administration of preventive therapy to all recipients should be considered, especially for lung recipients, but the risk of transmission is low if therapy for LTBI was completed before organ donation.
Treatment of LTBI in Transplant Candidates and Recipients Criteria to Start Treatment
Therapy for LTBI is an effective strategy for the prevention of active TB infection in transplant recipients, and is recommended for transplant candidates with positive TST or IGRA who have not been previously treated and those with high risk pretransplant TB exposure.
Therapeutic Regimens
The preferred regimen for LTBI is oral INH300 mg/d for 9 months, with pyridoxine 25-50 mg daily.
Alternative regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
Timing of Treatment
Treatment for LTBI should be started before transplant, and if urgent transplant is indicated, held perioperatively and resumed when medically possible until completion of the originally planned course, with the caveat that rifamycins are usually avoided after transplant.
Recommendations for Transplanted Patients Who Travel to Endemic Areas
Transplant recipients who travel to TB endemic areas should follow standard precautions to prevent nosocomial acquisition of infection, and those with possible TB exposure should be evaluated on return and seek medical evaluation immediately.
Treatment of Active TB Infection
Treatment of active TB infection should follow local guidelines,with a 4-drug regimen recommended in most cases.
INH and rifampicin are the most powerful first line drugs, but the optimal length of treatment in transplant recipients is not defined.
Monitoring of Adverse Events Related to Therapy
Close monitoring is recommended during the first 2 months of treatment due to increased risk of adverse events and potential drug interactions.
Concomitant use of INH, rifampicin, and pyrazinamide can lead to increased risk of hepatotoxicity, especially in liver recipients.
Drug Interactions
Rifamycins have an induction effect on different drug metabolizing enzyme systems, leading to a reduction in the blood levels of immunosuppressive drugs used after SOT.
Close monitoring and continuous dose adjustment are recommended.
Rifabutin is an alternative for rifampin, but its weaker effect on CYP3A4 makes it easier to maintain therapeutic blood levels of calcineurin and mammalian target of rapamycin inhibitors during TB treatment.
The incidence rate of TB markedly increases after SOT
In Latin America, decade, TB was diagnosed in 0.9% to 5.9% of the recipients.
International travel and post transplant T.B:
The possibility of donor transmission of TB has also been associated with transplant tourism.
Time spent in the endemic area influences the risk of TB infection.
Humanitarian work with high-risk populations, such as prisoners and homeless people, may also be a significant risk factor.
Diagnosis of latent T.B
In low-risk patients, IGRAs could be considered as the sole approach.
In high-risk patients, both IGRAs and skin test could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
Diagnosis of active T.B
It relies on the detection of M. tuberculosis bacilli by direct observation, by culture and nucleic acid testing.
SOT recipients may present unusual manifestations, with a greater proportion of extra-pulmonary involvement.
Invasive diagnostic procedures are more frequently required in this population, resulting in a delay of the proper diagnosis and higher mortality.
In this regard, the availability of a rapid molecular test, such as the Xpert MTB/RIF assay, may have a major impact in the management of these patients. This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98%and 67%, respectively.
Prevention: a- Recipient:
Candidates should undergo evaluation for LTBI with either TST or IGRA.
Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
b- Donor
Living donors should undergo the same evaluation as candidates.
Organs from donors with known active TB infection should be discarded.
The microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines.
Treatment of latent T.B:
It is recommended in:
a- Recipient with positive tests who have not previously treated.
b- Those with history of active TB infection that was inadequately treated.
c- donor with history of untreated or incompletely treated LTBI or TB,
d- if the recipient is exposed to TB after transplantation.
The preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
Time:
treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist.
If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible until completion of the originally planned course.
Recipient travelling to endemic area:
should follow standard precautions to prevent nosocomial acquisition of infection.
evaluation on return.
INH preventive therapy should be considered during the first post-transplant year.
Treatment of active T.B:
A 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB.
The optimal length of treatment of TB in transplant recipients is not defined. Many specialists recommend that treatment duration should be at least 9 months.
Monitor of adverse events:
The most common is hepatotoxicity
monitoring is highly recommended, mainly during the first 2 months of treatment when it should be performed biweekly.
Drug interaction:
Rifampicin is an inducer of cytochrome P 450 and P glycoprotein, so enhance the metabolism of IS drugs and decreases the doses of CNI, -TOR inhibitors and glucocorticoids. So the drug dose should be increased.
Summary of the article Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
1. Diagnosis:
A. Diagnosis of latent TB: There is no diagnostic reference standard for LTBI.
a) The tuberculin skin test (TST) remains the best studied test.
b) IFN-γ release assays (IGRAs)
I. offer some advantages as compared with TST:
· avoid interpreting bias.
· reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination.
· probably more sensitive in candidates with chronic renal failure and advanced cirrhosis.
II. Limitations of IGRAs:
· the negative predictive value of IGRAs is not optimal to rule out infection in patients at high risk for LTBI.
· higher cost.
· the frequent occurrence of conversions and reversions of test results.
B. Diagnosis of active TB infection:
a) The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation(culture and nucleic acid testing).
b) Neither TST nor IGRAs are recommended for diagnosing active infection.
c) Rapid molecular test(the Xpert MTB/RIF assay) is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively.
· The Xpert MTB/ RIF assay is a useful rule-in diagnostic test for extrapulmonary TB(when testing nonrespiratory samples, such as tissue biopsies and cerebrospinal fluid).
· The Xpert MTB/ RIF assay is highly predictive of MDR-TB.
· The Xpert MTB/ RIF assay has a limitation of false-positive results( have been observed among patients who had been successfully treated for TB).
2. Prevention of TB
a) Risk Assessment of the Transplant Candidate: · A history of clinical or radiological TB and the treatment received should be assessed in all recipients. · Candidates should undergo evaluation for LTBI with either TST or IGRA. · When using TST, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. · A second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion. · Candidates who have low risk for LTBI should preferably be tested solely with IGRA. · In high-risk candidates, both tests could be performed and any positive reaction considered an evidence of LTBI. · Whenever dual-test approach is used, IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses. b) Although, active infection may not be considered an absolutecontraindication to transplantation,once active TB infection is diagnosed, transplantation should be postponed. c) Risk Assessment of Deceased and Living Donors · Living donors should undergo the same evaluation, with the exception that the cutoff for TST should be 10 mm or greater. · The evaluation of the deceased donor for TB relies on: medical history, endemic exposuresand radiographic findings. · Organs from donors with known active TB infection should be discarded. · Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted. · Lungs with residual tuberculous lesions should not be used for transplantation. · A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered.
3. Treatment
a) Treatment of LTBI in Transplant Candidates and Recipients:
I. Criteria to Start Treatment
· LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
· Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive.
· Chest imaging suggestive of previous untreated TB should prompt consideration for therapy.
· Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
II. Therapeutic Regimens
· For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
· Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
· Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
III. Timing of Treatment
· treatment for LTBI should be started before transplant.
· if urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible until completion of the originally planned course, with the caveat that rifamycins are usually avoided after transplant.
IV. Recommendations for Transplanted Patients Who Travel to Endemic Areas
· INH preventive therapy should be considered during the first post-transplant year.
· There is no indication for BCG vaccine before travel, and it is contraindicated in transplant recipients.
b) Treatment of Active TB Infection
· The optimal length of treatment of TB in transplant recipients is not defined. Many specialists recommend that treatment duration should be at least 9 months.
c) Monitoring of Adverse Events Related to Therapy
· close monitoring is highly recommended, mainly during the first 2 months of treatment when it should be performed biweekly.
· Low-grade elevation of aminotransferases can be observed during the first 2 months of treatment, but a 3-fold increase accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation.
d) Drug interaction:
1) Rifamycins
· Rifamycins have an induction effect on different drug- metabolizing enzyme systems, most notably the cytochrome P450 (CYP) 3A4, which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus, cyclosporine, sirolimus, everolimus, and even corti- costeroids).
· Two- to 5-fold increments in the daily dose of cyclosporine, tacro- limus, and mammalian target of rapamycin inhibitors are generally necessary to maintain trough levels of the drug in the therapeutic range.
2) Rifabutin
· a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin.
· It has been demonstrated to be as effective as rifampin for the treatment of TB in trials conducted in nontransplant patients.
· Its weaker effect on CYP3A4 makes it easier to maintain therapeutic blood levels of calcineurin and mammalian target of rapamycin inhibitors during TB treatment.
· the same recommendation for close therapeutic drug monitorings of immunosuppressive drugs apply when rifabutin is used.
The level of evidence provided by this article:
This is a narrative reviews and expert opinions with level of evidence grade 5.
Epidemiology in Latin America ·The burden of tuberculosis (TB) has decreased significantly in Latin America (LA) countries, with the estimated absolute number of prevalent cases declining from 600,000 to 342,000 between 1990 and 2014. ·However, Brazil remains in the group of 22 countries with the highest TB burden, with 110 000 prevalent cases and 7700 TB deaths. ·It is important to be aware that national average incidence estimates may mask wide variations within a country. In Rio de Janeiro, for instance, the incidence in some underprivileged neighborhoods remains around 300 cases per 100 000. ·MDR is a global challenge, with higher prevalence in Ecuador, Guatemala, and Peru, with a significant impact on mortality. TB AFTER SOLID-ORGAN TRANSPLANTATION
·TB incidence increases after SOT, with the highest risk in lung recipients.
· LTBI is the main cause of posttransplant TB, but primary infection acquired in the community and nosocomial environment may also be a factor.
International Travel and Posttransplant TB
·Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB after SOT.
·Transplant recipients from low-incidence countries may be exposed to primary infection while traveling to an endemic area, but the actual impact of such exposure in this specific population has not been assessed.
· Among immunocompetent travelers returning from endemic countries, the estimated risk of acquisition of TB infection has generally ranged from 0.4% to 2.0%.
· Higher rates (1.8% to 4.2%) were reported among travelers who were involved in Healthcare or academic medical exchange programs.
·Time spent in the endemic area influences the risk of TB infection, with a cumulative history longer than 3 months of travel to high-incidence areas associated with a significantly higher risk. Humanitarian work with high-risk populations may also be a significant risk factor.
·Visiting friends and relatives is a known risk factor for acute diseases, but the impact of such activity on the risk of acquiring TB has not been established.
DIAGNOSIS
Diagnosis of LTBI · The tuberculin skin test (TST) is the best-studied test for LTBI, and most current guidelines recommend its use for the screening of solid organ candidates/recipients and living donors. · IFN-γ release assays (IGRAs) have emerged as new diagnostic tools, but their negative predictive value is not optimal to rule out infection in patients considered to be at high risk for LTBI. · There is a marked variation across transplant centers regarding the approach for screening LTBI in candidates, with TST alone being used in 48% of the participating centers, IGRA alone in 30%, TST and IGRA simultaneously in 16% and TST followed by IGRA in 6%. · Some specialists suggest adapting the diagnostic approach per the estimated risk of being infected. Diagnosis of Active TB Infection · The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, culture, and nucleic acid testing. SOT recipients may present unusual manifestations, with a greater proportion of extrapulmonary involvement. · The Xpert MTB/RIF assay is a useful rule-in diagnostic test for extrapulmonary TB, with an estimated sensitivity in smear-positive and smear-negative respiratory samples of 98% and 67%, respectively. · However, false-positive results have been observed among patients who had been successfully treated for TB, and it cannot fully replace the execution of conventional drug susceptibility tests. PREVENTION
Risk Assessment of the Transplant Candidate · A history of clinical or radiological TB and treatment for LTBI should be assessed in all recipients. · If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. · A second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion. · IGRA should be formed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses. Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started. · If active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
Risk Assessment of Deceased and Living Donors
·Living donors should undergo the same evaluation as candidates for TB, with a cutoff of 10 mm or greater. Medical history, endemic exposures, and radiographic findings should be taken into account.
·TST and IGRAs should be validated in deceased donors, and samples should be obtained to test for M. tuberculosis.
·Organs from donors with active TB infection should be discarded and therapy for active infection should be immediately started.
·Drug susceptibility tests should be performed on any M. tuberculosis specimen.
·Lungs with residual tuberculous lesions should not be used for transplantation.
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients Criteria to Start Treatment· LTBI therapy is recommended for transplant candidates with positive TST or IGRA, those with high-risk pretransplant TB exposure, and those with a history of active TB infection. · It is also recommended for transplant recipients whose donor has a history of untreated LTBI or TB, or if the recipient is exposed to TB after transplantation. · LTBI therapy is recommended for transplant candidates with positive TST or IGRA, those with high-risk pretransplant TB exposure, and those with a history of active TB infection. · It is also recommended for transplant recipients whose donor has a history of untreated LTBI or TB, or if the recipient is exposed to TB after transplantation.
Therapeutic Regimens· The preferred regimen for LTBI is oral INH 300 mg/d for 9 months, with pyridoxine 25 to 50 mg daily. · Alternative regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
Timing of Treatment· Treatment for LTBI should be started before transplant, and if an urgent transplant is indicated, held perioperatively and resumed when medically possible until completion of the originally planned course.
Recommendations for Transplanted Patients Who Travel to Endemic Areas
· INH preventive therapy should be considered for transplanted patients in highly endemic areas, and BCG vaccine is contraindicated in transplant recipients.
Treatment of Active TB Infection
· The optimal length of treatment of TB in transplant recipients should be at least 9 months, based on studies suggesting an association between shorter regimens and greater recurrence and mortality.
Monitoring of Adverse Events Related to Therapy· Monitoring of INH, rifampicin, and pyrazinamide is recommended due to the increased risk of hepatotoxicity.Drug Interactions· Rifamycins have an induction effect on different drug-metabolizing enzyme systems, leading to a reduction in the blood levels of immunosuppressive drugs used after SOT. · Close monitoring and continuous dose adjustment are recommended.
· Rifabutin is an alternative to rifampin, but its weaker effect on CYP3A4 makes it easier to maintain therapeutic blood levels of calcineurin and mammalian target of rapamycin inhibitors during TB treatment. ========================================================== What is the level of evidence provided by this article?
III. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors 1. Summarise this article Epidemiology
Throughout the nations of Latin America, TB continues to be a significant public health issue.
The incidence of TB increases after SOT, the highest risk among lung recipients.
TB was diagnosed in 0.9% to 5.9% of the recipients.
Reactivation of LTBI is the main cause of post-TX TB. Primary infection acquired in the community account for some cases.
Donor-recipient transmission is a minor contributor to primary infections.
The risk of TB may be impacted by immigration, travel to endemic regions, & transplant tourism.
Working with high-risk populations (convicts & the homeless can pose a potential risk.
Diagnosis of LTBI
There is no diagnostic gold standard.
Most guidelines recommend TST.
IGRAs have a few advantages over TST:
More sensitive
Exhibit a higher yield & a better correlation with clinical risk factors for LTBI in patients with CKD & liver cirrhosis.
Less false-positive results from prior non-tuberculous mycobacterial exposure or BCG vaccination. However, the NPR of IGRAs is suboptimal in patients considered to be at high risk for LTBI.
To increase the sensitivity of screening, both tests may be conisdered high-risk patients, & any positive result proves LTBI.
IGRAs could be the sole method in low-risk patients.
Diagnosis of active TB Infection in SOT recipients
Unusual manifestations are common in SOT recipients with a greater proportion of extra-pulmonary disease.
Diagnosis should be considered in recipients presenting with PUO.
Neither TST nor IGRAs are recommended.
Invasive procedures are more frequently required, resulting in a delay of diagnosis & higher mortality.
A rapid molecular test (Xpert MTB/RIF assay) may have a major impact in the management.
Advantages of Xpert MTB/RIF assay:
Highly specific & sensitive (98% & 67% in smear positive & smear negative samples).
It is a useful rule-in diagnostic test for extrapulmonary TB. It allows the detection of rifampicin resistance, which is highly predictive of MDR-TB.
Limitations of the assay:
False-positive results after successful treatement for TB.
It cannot obviate the need for standard drug susceptibility tests.
Prevention Risk assessment of the transplant candidate
A H/O TB & the treatment received should be assessed.
LTBI is assessed with either TST or IGRA if there is no H/O past TB or treatment for LTBI.
For TST, an induration of 5 mm or greater at 48 to 72 hours is considered positive.
IGRA is preferred in those with low risk for LTBI.
In high-risk candidates, both TST & IGRA could be used.
Active TB infection must be excluded in all candidates with
a positive result in any of these tests before LTBI treatment is started.
Transplantation should be delayed once active TB infection is diagnosed until the condition is adequately treated & smears are negative.However, for those who on despair need for TX, current infection is not an absolute contraindication to TX.
Risk assessment of deceased & living donors
The cutoff for TST should be 10 mm or greater.
H/O untreated or insufficiently treated TB should be assessed.
H/O previous IGRA or TST.
Travel to or residence in endemic areas.
Exposure to active TB infection (household or workplace, homeless, etc).
Radiographic evidence of TB.
Active TB should rule out in donors at increased risk by obtaining samples to test for M. tuberculosis.
Organs from donors with known active TB infection are discarded.
Organs from donors successfully for TB are accepted.
Untreated LTBI is not a contraindication to donation, but preventive therapy is indicated for all recipients (especially for lung recipients).
Treatment of LTBI in transplant candidates & recipients Therapy is recommended for:
Recipients with positive TST or IGRA who have not previously received therapy.
Recipients whose donor has a H/O untreated or incompletely treated LTBI or TB
Recipients exposed to TB after transplantation.
Therapy is considered in:
High-risk pre-TX TB exposure, even if TST or IGRA is negative.
Radiographic evidence of previous untreated TB.
Therapeutic regimens
For LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
Monitor for hepatotoxicity with at least serum ALT every
2 weeks for 6 weeks, then monthly thereafter.
Alternative regimens containing rifamycins should be avoided posttransplant because of IS drug interactions.
Timing of treatmentof LTBI
Preferably started before transplant & can often be completed while the patient is on the waitlist.
Otherwise, it can be started.perioperatively or when medically possible until completion of the course.
Treatment of active TB infection
Should follow local guidelines for the general population.
In most cases, a 4-drug regimen is recommended.
INH and rifampicin are the most powerful 1st-line drugs.
Consider the risk of hepatotoxicity & drug interactions of rifampicin in SOT.
The optimal length of treatment of TB in TX recipients
is not defined. However, many specialists recommend a duration of at least 9 months.
Drug interactions
Rifamycins can lead to a reduction in the blood levels of most IS drugs used after SOT (tacrolimus, cyclosporine, sirolimus, everolimus, & corticosteroids).
A lower blood levels invite graft rejection.
Close monitoring & continuous dose adjustment are highly recommended.
========================= 2. What is the level of evidence provided by this article?
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
Guilherme S and colleagues in this review article examines the recommendations for the management of tuberculosis for organ transplant recipients and donors.
EPIDEMIOLOGY Epidemiology in Latin America
In the last 2 decades, the burden of tuberculosis (TB) has been considerably reduced in Latin America (LA) countries. Although the estimated proportion of MDR infection among new TB cases remains below 3% in most countries of the region, higher prevalence (between 3.0% and 6.0%) has been found in Ecuador, Guatemala, and Peru. Emergence of multidrug-resistant (MDR) TB, which is defined by the isolation of a causative strain of Mycobacterium tuberculosis resistant to rifampicin and isoniazid (INH), is a global challenge. Recent reports from the latter country provide evidence of ongoing community transmission of MDR infection with significant impact on mortality. Moreover, the prevalence of MDR infection is expectedly higher among patients who were previously treated for TB. In those 3 countries, this prevalence has been estimated to range from 20% to 26%.
TB AFTER SOLID-ORGAN TRANSPLANTATION
The incidence rate of TB markedly increases after solid organ transplantation (SOT), the risk being highest among lung recipients. The proportion of patients affected by active TB infection also varies widely among transplant centers in correspondence with the local prevalence of the disease. In studies carried out in LA SOT centers in the last decade, TB was diagnosed in 0.9% to 5.9% of the recipients.
International Travel and Posttransplant TB
Transplant recipients from low-incidence countries may be exposed to primary infection while traveling to an endemic area. Among immunocompetent travelers returning from endemic countries, the estimated risk of acquisition of TB infection has generally ranged from 0.4% to 2.0%.20-22 Higher rates (1.8% to 4.2%) were reported among travelers who were involved in healthcare or academic medical exchange programs.
Transplant candidates originating from endemic areas have a higher prevalence of LTBI and are, hence are at an increased risk of developing active TB infection after SOT.
DIAGNOSIS Diagnosis of LTBI
There is no diagnostic reference standard for LTBI. Most current guidelines still recommend tuberculin skin testing for the screening of LTBI in solid organ candidates/recipients and living donor.
IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade. It has numerous advantages over tuberculin skin testing because it: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination. They are also probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients. Despite these advantages, the negative predictive value is not sufficient to rule out LTBI in high-risk patients such as those who were born to or lived in endemic countries, household contacts of a case of active TB infection, and those who work or live in high-risk settings, such as correctional facilities and homeless shelters. Other limitations of these assays include their higher cost and the frequent occurrence of conversions and reversions of test results when serial screening is performed, which may complicate the interpretation of their results among SOT candidates.
Diagnosis of Active TB Infection
The diagnosis of active TB infection relies on high index clinical suspicion and the detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing. SOT recipients may present unusual manifestations, with a greater proportion of extrapulmonary involvement. TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin. Invasive diagnostic procedures are more frequently required in this population, resulting in a delay of the proper diagnosis and higher mortality.
PREVENTION Risk Assessment of the Transplant Candidate
First step is adequate and thorough history including radiological investigations in the past. If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA. If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
Candidates who have low risk for LTBI should preferably be tested solely with IGRA. In high-risk candidates (i.e., patients originated from endemic countries, household contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), both tests could be performed, and any positive reaction considered evidence of LTBI. Whenever this dual-test approach is used, IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses.
Treatment of LTBI should be commenced only when active TB has been excluded. Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative. Despite this, active infection may not be an absolute contraindication when transplantation is urgently needed.
Risk Assessment of Deceased and Living Donors
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater. The evaluation of the deceased donor for TB relies on: thorough history, physical examination and radiological testing. Organs from donors with known active TB infection should be discarded. If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines. Drug susceptibility tests should be performed on any M. tuberculosis specimen isolated from the donor, since the detection of drug resistance may be of critical importance for guiding therapy in the recipients. Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted. Lungs with residual tuberculous lesions should not be used for transplantation. A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, especially for lung recipients.
TREATMENT Treatment of LTBI in Transplant Candidates and Recipients Criteria to Start Treatment
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated. Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated. Chest imaging suggestive of previous untreated TB should prompt consideration for therapy, especially in areas where endemic mycoses are uncommon. Treatment is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
Therapeutic Regimens
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily. Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine aminotransferase checked every 2 weeks for 6 weeks, then monthly thereafter. Alternative regimens containing rifamycins can be considered pretransplant but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks. Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
Timing of Treatment
Balancing the risk of infection and benefit of transplantation is important. It’s preferred to treat before transplantation but urgent need for transplantation might warrant treatment commencing in the perioperative period.
Recommendations for Transplanted Patients Who Travel to Endemic Areas
Those traveling to endemic regions after transplantation should use INH prophylaxis in the first post-transplant year. BCG vaccination iscontraindicated. Those with possible TB exposure should be evaluated on return, and anyone with symptoms of infection should seek medical evaluation immediately.
Treatment of Active TB Infection
Treatment should follow local guideline just like in general population. However, there is need for monitoring for drug interaction and toxicity.
I like your very sensible clinical approach as to when to treat for latent TB in a transplant recipient. I appreciate your debate regarding the uncertainty on optimal duration of therapy
Summary TB after solid organ transplantation
Incidence TB increases after SOT more so in lung recipients.
Main cause of post-transplant TB is reactivation of latent TB.
Rarely primary infection may occur in people living in endemic areas.
However in minority of cases can have donor-recipient transmission.
Diagnosis of LTBI
There is no gold standard.
TST is most studied test hence most guidelines recommend it.
IGRA has advantages over TST:
Less interpretation bias
No false positive in those with prior exposure or vaccinated
Sensitive in CKD and liver cirrhosis patients
However is disadvantages include:
Expensive
Frequent conversion and reversion of test results when serial screening is performed.
Low risk patients IGRA is recommended, while in high risk patients both TST and IGRA should be done.
Diagnosis of active TB
TST and IGRA not recommended.
Relies on detection of MTB bacilli by direct observation, culture and nucleic acid amplification test.
High index of suspicion is crucial because recipients do not present with the classical clinical presentation and there is a high proportion of extra pulmonary TB.
Xpert MTB/RIF: is highly sensitive and specific in pulmonary TB.
Can also be used as a rule in test in the diagnosis of extra pulmonary TB.
Allows for simultaneous testing for rifampicin resistance.
Its only limitation is that false positive results have been observed in patients who have been successfully treated for TB.
Risk assessment of the recipient
A through history including history of prior treatment of TB should be obtained.
In absence of prior treatment, they should be assessed for LTBI with either TST or IGRA.
TST induration of ≥ 5mm after 48 to 72 hrs is considered positive.
High risk patients should ideally have the IGRA done before the TST to avoid TST mediated boasting of the IGRA response.
Before initiation of LTBI treatment, active TB should be ruled out with a CXR, through history and physical examination and imaging of other body sites in cases of extra-pulmonary TB.
Presence of active TB is not an absolute contraindication of transplant, however treatment should be started and transplant postponed until smears are negative.
Risk assessment in donor
Similar to recipient but the TST induration should be ≥ 10mm.
Deceased donor evaluation relies on medical history, endemic exposure and radiological findings.
Deceased donors with active TB the organs should be discarded. If the information because available after transplantation then recipient should be treated for active TB promptly.
Organs from donors successfully treated for 6 months can be accepted.
History of untreated LTBI is not a contraindication of donation.
If donor had been treated for LTBI infection prior to donation then the risk of transmission is considered to be low, thus recipients can be monitored without receiving treatment.
Treatment of LTBI in recipients and donors
Should be considered in recipient or donor who have a positive TST or IGRA and have not been treated prior.
In high risk patients, treatment should be considered with or without TST or IGRA being positive and also in those with history of incomplete treatment of active TB.
Recipients receiving from a donor with history of incomplete treatment of LTBI/active TB should also receive treatment.
Preferred treatment is oral INH 300mg/ day for 9 months.
Nine months preferred over six months due to better protection.
Monitoring for serum alanine transaminase should be done every 2 weeks for the first 6 weeks then monthly after due to the risk of hepatotoxicity.
Rifamycins can be considered pre transplant and avoided post-transplant due to drug interactions.
Alternative regimens include: RIF 600mg/day for 4 months or INH and rifapentine weekly for 12 weeks.
Ideally treatment should begin before transplant and completed while on the waiting list.
However if transplant is to be done before completion of treatment then the treatment can be withheld peri-operatively and resumed when medically possible.
If recently transplanted patients plan to travel to highly endemic areas in the first year post transplant then INH preventive therapy should be given.
Vaccinations is contraindicated in recipients.
Treatment of active TB
Should follow the local guidelines.
Four drug treatment regimen is recommended.
Optimal duration is not defined, some specialist recommend 9 months duration due to studies that have suggested an association between shorter duration with high recurrence and mortality.
Monitoring of adverse events
First 2 months monitoring should be bi-weekly.
Discontinuation of treatment should be considered when there is a 3 fold increase of aminotransferase with symptoms or 5 fold increase with or without symptoms.
Drug interactions
Rifamycins are inducer of the cytochrome P 450 which leads to reduced drug levels of immunosuppressive drugs- cyclosporine, tacrolimus, sirolimus and corticosteroid.
Their sub therapeutic levels is associated with allograft rejection.
Hence close monitoring and dose adjustments is recommended.
Enzyme induction begins after few hours of the first doses, reaches maximally effect in 1-2 weeks and slowly declines 2 weeks after stopping the drug.
Rifabutin a rifamycin with weaker enzyme induction is an alternative to rifampicin.
Tuberculosis after solid organ transplantation:
The incidence of tuberculosis increased significantly after solid organ transplantation (SOT).
In studies conducted at LA SOT centers over the past decade, TB was diagnosed in 0.9% to 5.9% of beneficiaries.
Primary infection, especially in patients living in endemic areas.
Most of these cases have been documented in patients who received transplants from deceased donors with active TB infection, a condition associated with an approximately 30% risk of transmission.
Migration, international travel to endemic countries, and transplant tourism may affect the risk of TB at SOT.
Transplant recipients from low prevalence countries may be exposed to primary infection when traveling to endemic areas, but the true impact of this exposure in this specific population has not been assessed
Diagnosis
Diagnosis of LTBI:
Tuberculin) is still the best documented test. Most current guidelines still recommend its use for screening solid organ candidates/recipients and living donors for LTBI.
IFN-γ release assays (IGRA) as new diagnostic tools.
Pros:
1- Avoid interpretation bias.
2- Reduction of false positives linked to previous exposure
3- Non-tuberculous mycobacteria or BCG vaccination.
4- More sensitive to candidates with chronic renal failure and advanced cirrhosis. Limitations:
1- Higher cost
2- Conversion and inversion of test results often occurs when performing continuous screening, which can make it difficult for SOT candidates to interpret their results .
Diagnosis of active tuberculosis infection:
Detection of Mycobacterium tuberculosis by direct observation, culture and nucleic acid testing
Rapid molecular tests such as the Xpert MTB/RIF test
A limitation of this test is false positive results Prevention Transplant Candidates Human Risk Assessment:
All recipients should be evaluated for clinical or radiological history of tuberculosis and treatment received.
Applicants should be assessed for LTBI using the TST or IGRA if there is no history of treatment for TB or LTBI. If the TST is chosen as a screening test, a duration of 5 mm or more within 48 to 72 hours should be considered a positive response.
In addition, a second TST should be performed 7-10 days after the first TST to assess boost-related transitions.
Low-risk candidates for ITL would be better off taking only the IGRA test.
Among high-risk candidates (i.e., patients from endemic countries, household contacts of tuberculosis infection active and those who work or live in correctional facilities or homeless shelters), two tests may be administered, and any positive response is considered an LTBI
Applicants with a positive result on either of these tests must be ruled out for active TB infection before starting treatment for ITL. Risk assessment for deceased and living donors:
Medical history
Endemic exposures
Radiological findings
Increased risk should be excluded by obtaining specimens (e.g. Tuberculosis
Organs from donors known to have active TB infection should be eliminated.
Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all
recipients should be considered, especially for lung recipients Treatment of LTBI in Transplant Candidates and Recipients: Criteria to Start Treatment:
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated
Those with high-risk pre transplant TB exposure should be
considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated
Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation Therapeutic Regimens:
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily Nine months of therapy is preferred over 6months because of better protection
Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine amino transferase checked every
2 weeks for 6 weeks, then monthly thereafter.
Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600mg daily for 4 months or INH and rifapentine weekly for 12 weeks.51,52 Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy
The timing of LTBI treatment requires balancing risks and benefits for each patient
Transplant recipients who are traveling to TB endemic areas to provide medical or humanitarian care should follow standard precautions to prevent nosocomial
acquisition of infection.
BCG vaccination is not indicated before travel and is contraindicated in transplant recipients.
Treatment should follow local guidelines for the general population.
Monitoring for treatment-related adverse events Due to the increased risk of adverse events and potential drug interactions, close monitoring is strongly recommended, primarily during the first 2 months of treatment, which should be performed every two weeks Level 5
I like your summary, level of evidence, analysis and take home messages. I appreciate that you have explained postive points of IGRA and limitations as well.
This article is about TB infection in SOTR and donors. This is especially important because risk of TB increases after SOT, particular lung transplant recipients.
TB incidence in SOTR is usually from reactivation of latent TB. Nosocomial infection and primary infection from the environment are also possible because of the immunocompromised status of the recipient. A small percentage of cases can develop from donor transmission.
Discussion
Travel from different places such as TB endemic countries can increase the risk of TB in the recipient. Immigration impacts the risk of donor transmission.
Current guidelines recommend screening for LTBI in recipients and live donors of SOT. This is done through tuberculin skin test or TST. Another recent diagnostic tool is IFN -gamma release assay. The latter tool has advantages over TST such as avoiding interpreting bias, reduced false positive results related to prior exposure to TB or BCG vaccine. However, higher cost for performing these assays can be a deterrent in some centres, thus preventing standardization.
Recommendations include performing IGRA alone for low risk patients and both TST and IGRA for high risk patients. This is done in order to maximize the sensitivity and accuracy of screening protocols.
Diagnosis of TB infection involves detecting Mycobacterium tuberculosis bacilli directly, via culture and nucleic acid test. IGRA and TST are not recommended for the diagnosis of active TB infection in the patient.
Another aspect to consider is the extrapulmonary manifestation of TB in SOT recipients. This is often more difficult to diagnose compared to the classic presentation of TB. One recommendation is to consider TB in patients with fever of unknown origin. Availability of MTB/RIF assay can help in managing these patients because of its high specificity and sensitivity.
Limitations for this method of diagnosis include false positive results in the case of patients who have been successfully treated for TB.
Prevention and treatment strategies
Prevention of TB in the recipient involves rigorous assessment of donor, including IGRA and TST. Appropriate risk assessment profiles are also to be done to prevent donor transmission as well as primary incidence in recipient from other sources.
Treatment involves oral INH 300 mg/day for 9 months, with oral pyridoxine 25-50 mg daily. Extended period of 9 months is preferred to 6 months because it gives better protection for the patient.
Monitoring for hepatotoxicity is crucial in these patients with serum ALT being checked every 2 weeks for a period of 6 weeks, and then every month.
Alternative regimen pre-transplant include rifamycin, which should be avoided post transplant to prevent interaction with immunosuppressive drug interactions. Fluoroquinolones are recommended for LTBI therapy.
Reactivation of foci of latent TB infection (LTBI) is probably the main cause of posttransplant TB.
Primary infection acquired in the community, and less frequently in the nosocomial environment, may also account for a considerable proportion of the cases, especially among patients living in endemic areas.
A minor proportion of primary infections result from donor-recipient transmission.
Diagnosis of LTBI
There is no diagnostic reference standard for LTBI.
The tuberculin skin test (TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.
IFN-γ release assays (IGRAs) offer some advantages as compared with TST:
avoid interpreting bias,
reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination,
more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients
Diagnosis of Active TB Infection
Fever of unknown origin
rapid molecular test, such as the Xpert MTB/RIF assay
This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively
Tissue biopsies and cerebrospinal fluid, indicating that Xpert MTB/ RIF assay is a useful rule-in diagnostic test for extrapulmonary TB
Risk Assessment of the Transplant Candidate
A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA.
If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction.
In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion
In high-risk candidates (ie, patients originated from endemic countries, household contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), both tests could be performed and any positive reaction considered an evidence of LTBI
If any evidence of active infection is found in this workup, appropriate clinical specimens should be collected for microbiological confirmation of the diagnosis.
Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
Risk Assessment of Deceased and Living Donors
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
The evaluation of the deceased donor for TB relies on:
Medical history. The history of untreated or insufficiently treated TB should be investigated, as well as previous reactive IGRA or TST.
Endemic exposures within last 2 years
Radiographic findings, such as apical fibronodular le[1]sions, calcified solitary nodules, calcified lymph nodes, or pleural thickening.
Active TB infection should be ruled out in donors at increased risk by obtaining samples, for example, sputum or bronchoalveolar lavage, to test for the presence of M. tuberculosis
Organs from donors with known active TB infection should be discarded.
If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines.
Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, therefore, transplant recipients from such donors can be clinically montored without receiving LTBI ther
Treatment of LTBI in Transplant Candidates and Recipients
Criteria to Start Treatment
Therapy for LTBI is an effective strategy for the prevention of active TB infection in transplant recipients.
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated.
Chest imaging suggestive of previous untreated TB should prompt consideration for therapy, especially in areas where endemic mycoses are uncommon.
Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
Therapeutic Regimens
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
Nine months of therapy is preferred over 6 months because of better protection.
Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine aminotransferase checked every 2 weeks for 6 weeks, then monthly thereafter
Recommendations for Transplanted Patients Who Travel to Endemic Areas
If recently transplanted patients are planning to move to a highly endemic area (ie, those with prevalence ≥100/ 100000), INH preventive therapy should be considered during the first posttransplant year, especially for those planning to take part in medical or humanitarian care, given the higher risk of primary TB acquisition.
There is no indication for BCG vaccine before travel, and it is contraindicated in transplant recipient.
Treatment of Active TB Infection
4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB for atleast 9 months
Side effects: hepatotoxicity
Drug interactions:
Rifampin has the most potent enzyme induction effect.
Two-to 5-fold increments in the daily dose of cyclosporine, tacrolimus, and mammalian target of rapamycin inhibitors are generally necessary to maintain trough levels of the drug in the therapeutic range.
Thus, therapeutic drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption
Summarise this article Burden of tuberculosis (TB) has been considerably reduced in Latin America (LA) in the last two decades. Brazil remains in the group of 22 countries with the highest TB burden Marked geographical variation in incidence Marked emergence of Mycobactarium- MDR (the isolation of a causative strain of Mycobacterium)
TB after solid-organ transplantation Incidence increases after transplant with highest incidence in lung transplant recipients Main cause is reactivation of foci of latent TB infection (LTBI) Other cause can be Primary infection acquired in the community or nosocomial infection Donor derived -documented in patients who received a graft from a deceased donor with active TB infection Immigration, international travel to endemic countries may affect incidence
Diagnosis of Active TB Infection Detection of M. tuberculosis bacilli by direct observation, by culture and nucleic acid testing Xpert MTB/RIF assay, may have a major impact in the management RIF assay is a useful rule-in diagnostic test for extrapulmonary TB
Latent TB- TST and IGRA Advantages of IGRA- Avoid interpreting bias Reduce false-positive results More sensitive in candidates with chronic renal failure and advanced cirrhosis Higher yield Better correlation with clinical risk factors for LTBI However the negative predictive value of IGRAs is not optimal Low-risk patients- IGRAs High risk-Both
PREVENTION
Risk Assessment of the Transplant Candidate No history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA TST- induration of 5 mm or greater at 48 to 72 hours should be considered a positive Perform second TST should be performed 7 to 10 days after the first TST Low risk for LTBI should preferably be tested solely with IGRA High Risk – Both test Active TB infection must be excluded in all candidates- Detailed history, Chest radiographs, Other imaging in case suspected extrapulmonary TB. Active infection- transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative
Risk Assessment of Deceased and Living Donors Cutoff for TST should be 10 mm or greater. Medical history of of untreated or insufficiently treated TB/ previous reactive IGRA or TST Endemic exposures Radiographic findings- apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening. Active TB infection should be ruled out in donors at increased risk Organs from donors with known active TB infection should be discarded If diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted
Treatment of LTBI in Transplant Candidates and Recipients Start treatment if positive TST or IGRA who have not been previously treated High-risk pretransplant TB exposure Chest imaging suggestive of previous untreated TB History of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation
Treatment of Active TB Infection 4-drug regimen is recommended- 2 month intensive phase Treatment duration should be at least 9 months Close monitoring is highly recommended, mainly during the first 2 months of treatment- Bi weekly
Rifampicin induces cytochrome P450 and reduces the levels of tacrolimus, cyclosporine, sirolimus, everolimus, and corticosteroids This can potentially lead to higher risk of rejection
Therapeutic drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption
Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction- efficacy similar to Rifampicin
TB burden reduced in Latin America(LA). to half from 1090 to 2014 with reduction of TB associated death.
Brazil is in the 22 countries with highest TB burden in the world.
Wide variation in estimated TB incidence in LA.
MDR infection among new TB cases <30% in most LA countries.
But TB prevalence in Ecuador, Guatemala & peru ~20-26%.
TB after SOT:
The risk is highest among lung transplant.
In LA, TB diagnosed in 0.9-5.9% of SOT recipients.
Reactivation is the most common source of infection
Organ derived transmission(deceased donor with active TB) can reach 30% of TB infection.
Immigration, international travel to endemic areas increase risk of TB after SOT.
Immunocompetent person from low endemic area travel to endemic country, the risk of acquired TB reach 0.4-2% which count substantial proportion of new infection in low endemic countries.
Longer time spent in endemic area (>3months) associated with higher to acquired TB infection.
Diagnosis of LTBI:
TST still recommended by guidelines in pre transplant screening.
IGRA had some advantage on TST:
avoid interpreting bias.
reduce false +ve result.
higher sensitivity.
Limitation of IGRA:
not optimal to rule out infection in high risk LTBI.
higher cost.
frequent occurrence of conversion & reversion of test result.
In low risk patients IGRA could be the sole approach & in high risk patients both TST &IGRA considered in screening of LTBI.
Diagnosis of active TB:
Diagnosis depend on detection of MBT by direct observation, culture r NAT.
TB infection should be suspected in any patient with fever of unknown origin.
Molecular test e.g. X-pert have high specificity & estimated sensitivity in smear +ve 98% & smear negative 67%, it also effective in diagnosis of extra pulmonary TB.
X-pert can also detect MDR-TB.
Limitation of X-pert is false +ve result in successful treated TB patients.
Risk assessment in transplant candidates:
If TST used, induration 5mm or more at 48-72 hours considered positive.
Low risk patients can be screened by IGRA.
High risk patients screened with both IGRA & TST & ant positive result considered an evidence of LTBI.
Active TB should be excluded before treatment of LTBI.
Risk assessment of deceased & live donors:
Live donor undergo same evaluation as transplant candidates, but cutoff of TST should be 10mm or more.
Deceased donor evaluation include:
Medical history of untreated or insufficiently treated TB, previous reactive IGRA or TST.
Endemic exposure: travel or residence in endemic area, exposure to active TB within 2 years, homeless or refugee status, incarceration & alcoholism
Radiology finding e.g. apical fibronodular lesion, calcifies solitary nodules, calcified LN or pleural thickening.
There is no time for IGRA & TST in deceased donors.
If diagnosis of TB established after transplantation starting of treatment should be start immediately.
Organs from donors with history of TB & successful treatment for 6 months can be accepted for donation.
Untreated LTBI is not contraindicated for transplantation, but the recipient should receive prevention therapy.
Treatment of TB in candidates & recipients:
LTBI should be treated if:
TST or IGRA positive
High risk pre-transplant TB exposure (positive or negative TST & IGRA)
This narrative review addresses the epidemiology of mycobacterial tuberculosis( TB ) from the Latin American region with the challenges of the rise of MDR -resistant TB strains with increased clustering of new cases in certain countries with prevalence reported between3.0% and 6.0%) have been found in Ecuador, Guatemala, and Peru with the continuous spread of MDR TB in the community level even more than 20% according to the recent data with increased mortality rate and its higher among those with previous TB treatment MDR TB infection defined as failure to respond to an anti-TB regimen including ( INH, REFAMPCIN )after two months of starting therapy with an overall prevalence of < 3 % but can go even higher in endemic areas.
TB AFTER SOLID-ORGAN TRANSPLANTATION
· TB after SOT is more prevalent compared to the general population and also the incidence varies according to the local epidemiology with higher reports from endemic areas, higher rate after lung transplantation
· Reactivation of latent TB infection (LTBI) is the most common source of infection after SOT
· A small percentage of primary infections result from donor-recipient transmission, especially DD sources with active TB and to less extent LTBI in the donor.
·International Travel and Posttransplant TB
·Immigration, as per US data children born to parents from the endemic area are at high risk of active TB, also donor source of TB In Spain, the prevalence of active TB infection was obviously increased in deceased donors who originated from a high-incidence country in eastern Europe.
· Travel to endemic states, and the duration spent usually > 3 months also impacts the risk of getting a TB infection
· Commercial transplantation may impact the risk of TB after SOT.
· Transplant recipients from endemic areas have more risk of LTBI with an increased risk of active TB post-transplantation
· Type of work like Humanitarian work with high-risk populations, such as prisoners and homeless people, may also be an important risk factor
· Use of public transportation or long travel time in the endemic area is also considered a risk factor for TB exposure Diagnosis of TB and its challenges Diagnosis of LTBI
There is variation among SOT centers in screening for LTBI, with more prevalence use of TST alone at 48%, and IGRA alone at 30% while the combination of IGRA, and TST is around 16%.
1. Tuberculin skin test (TST) is still considered for screening of LTBI for SOT recipients and donors as per most guidelines
2. IFN-γ release assays (IGRAs) have been used more recently for LTBI screening with more sensitivity compared to TST and suitable for CKD and liver cirrhosis candidates screen with less interpretation bias and less false positive results from previous exposure or BCG vaccination however despite its better yield and better correlation with clinical risk still the negative predictive value(NPV) of IGRAs is not ideal to rule out infection in high-risk candidates for LTBI, The limitation of the IGRA test is more cost and there is variation in interpretation among SOT candidates mandate serial testing
3. Among those with low risk it’s preferred to go for the IGRA test and in candidates from high-risk areas it’s preferred to do both TST, and IGRA together to increase the sensitivity
of screening. Diagnosis of active TB
1. Both TST and IGRA are not used for the diagnosis of active TB
2. The diagnosis of active TB depends on the isolation of M. tuberculosis bacilli by direct examination. Either by culture or rapid molecular tests like Xpert MTB/RIF assay which is more specific, especially in extrapulmonary TB and MDR – TB diagnosis with high predictive value, the only concern with this test is that false-positive results have been observed in patients who had been effectively treated for TB
3. more invasive testing like tissue biopsy and histology, one of the diagnostics challenges after SOT is due to atypical presentation and nonspecific symptoms, especially with extrapulmonary TB or disseminated infection which leads to a delay in diagnosis and initiation of treatment in the appropriate time and carries high morbidity and mortality rate. Prevention Risk assessment for transplant recipients
Full history of previous exposure or sick contact previous history of TB and treatment course, previous history of LBTI epidemiological risk, and social background
Candidates from low-risk areas can be screened for LTBI by either TST or IGRA test only while those from the high endemic areas can do both TST and IGRA testing
TST with an induration of 5 mm or more at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to
10 days after the first TST to evaluate a boosted-related skin conversion
Any suspected case of Active TB should go for comprehensive history and examination, CXR in case of PTB, or other organs images in case of extra-renal manifestation including invasive tissue biopsy
DD risk assessment . Living donors should follow the same protocol of recipient risk assessment but for LTBI the TST cutoff value for a positive test is> 10mm.
.The evaluation of DD for TB 1. Will be very important to focus on a history of active TB or treatment from previous exposure, previous positive IGRA or TST, sick contact 2. Endemic contact risk, travel history to an endemic area, duration and exposure to active TB in the workplace or households within the last 2 years 3. social history including homeless, alcohol addiction, refugee status (LTBI risk). 4. X-RAY findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening 5. Both TST and IGRA tests not validated for DD screen and in high clinical suspicion for active TB in DD samples like sputum and BAL fluid for microbiology testing for MTB should be sent and usually need time for confirmation so the OPT should effectively communicate and track the results for the transplantation team 6. Organs from donors with known active TB infection should be discarded (absolute contraindication for SOT). 7. The organs from DD with previous active TB and completed 6 months of anti-TB still can be used as DD but lungs with remaining focus of infection should be discarded, donors with LTBI still can be used but with starting the recipients on prophylaxis course according to local protocol.
TREATMENT Criteria for Treatment of LTBI in Transplant Candidate and Recipient
1. All donors and recipients with positive TST or IGRA test should be treated for LTBI, including those from high-risk endemic areas should be treated for, possible LTBI regardless of the TST or IGRA test in order to reduce the risk of active TB after transplantation
2. Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation. Therapeutic regimens LTBI preferred to use INH 300 mg/day for 9 months per oral in combination with B6 25-50mg OD, 9 months duration gives better prevention from active TB, and needs close monitoring for hepatotoxicity with LFT monitoring every two weeks for the first 6 weeks then monthly.
rifampicin regimen RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks preferred use pre-transplant not after TX to avoid drug interaction with CNI
1.Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy stopped based on evidence from RCT due to toxic side effects with levofloxacin arm
preferred to get the treatment course before transplantation but in case of an urgent need for transplantation then still can consider starting the treatment but avoid rifampicin due to drug interaction.
BCG is contraindicated for organ transplantation candidates
Treatment of active TB
Should follow up the same local protocol for the treatment of active TB in the general population taking into consideration the risk of hepatotoxicity, drug safety, and interactions with immunosuppression like rifampicin with CNI,m TOR inhibitors, steroids inhibitory effect as its enzyme inducer (P450 (CYP) 3A4), and need higher doses 3-5 time increase in tacrolimus or cyclosporine dose with frequent monitoring ( sometimes given TID dose ) also important to early identification of MDR – TB cases but Rifabutin, a rifamycin have weaker induction effect of CYP3A4 with similar sterilization efficacy as rifampicin and can be tolerated as an alternative with close monitoring of CNI, EVEROLIMUS or sirolimus level
Hepatotoxicity with INH, Pyrazinamide needs frequent monitoring with LFT level every week in the first two months, 5 fold increase in ALT is an indication to stop the treatment.
A 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB. At least for 9 months in most recommendations as shorter courses are associated with higher relapse rates and mortality.
this is for the next journal (Latent tuberculosis infection and renal transplantation – Diagnosis and management) because I have a problem in submitting the answer
Summarise this article
Some facts
The prevalence of active TB is significantly higher in SOT than general populationIt is estimated that around 1.7 billion people are suffering from latent TB worldwide10 % of patients with latent TB can develop active TB during their lifetime, if they are immunosuppressed Active TB in renal transplant recipients is associated with increased morbidity and mortality and one third of cases can lose the graftMode of transmission
Activation of latent TB (the most common)Acquiring the disease from the graft (donor derived)Acquiring new infection through air born transmission (not common, rapidly progressing to military TB)Diagnosis of latent TB
Recipients with latent TB are at high risk of conversion to active TB after transplantation, on the other hand, if the donor has latent TB and did not receive treatment it carry a risk of transmission to the recipientSo all recipients and donors should both be undergo careful evaluation of the risk, history, examination and CXR, together with test for latent TBIn general, all transplant recipients and donors with latent TB should be received2 test are used to detect latent TB, tuberculin skin test (TST) and IGRA (Quantiferon, T-SPOT), both are usually negative in immunosuppressed patients due to their dependence on the host immune response which is impaired in these sets of patientsIn SOT candidates with ESRD (renal transplant candidate), it is preferred to use IGRA over TST due to its higher sensitivity in these sets of patientsAll transplant recipients and donors should have thorough history taking and CXRRenal transplant recipients should have no symptoms, CXR should be normal and no evidence of exra-pulmonary TB in order to settle the diagnosis of latent TBIf radiology is suspicious for TB (apical fibronodular lesions, calcified solitary nodule, calcified lymph nodes, or pleural thickening) thorough evaluation including microbiological assessment is indicated to exclude TB as a causeIf TB diagnosed in the recipient transplantation should be delayed till complete treatment of TBProtocol for treatment of latent TB
INH for 6-9 months (the preferred regimen)Rifampin for 3-4 months INH+ rifapentine for 3 monthsINH + rifampin for 3 monthsPatient should be monitored for liver enzymes and bilirubin when using INH
oral pyridoxine 50 mg given daily with INH decrease the incidence of peripheral neuropathy
What is the level of evidence provided by this article?
The prevalence of active TB is significantly higher in SOT than general population; around 20-74 times higher than general population. It differ according to geographic area, it ranges from 0.3–6.4%, in developed countries and in up to 15% in endemic regions and is associated with high incidence of morbidity and mortality among kidney transplant recipients
MDR TB is defined as the isolation of Mycobacterium tuberculosis resistant to rifampicin and INH, in Ecuador, Guatemala, and Peruwhich it was estimated to be 3-6% in newly diagnosed patients and 20-26% in patients with prior history of TB treatment.
Mode of transmission
Activation of latent TB (the most common)
Acquiring the disease from the graft (donor derived), usually from deceased donor with unrecognized active TB, the transmission risk was around 30%, risk factors includes homeless patients, prisoners and travelling from endemic area
Acquiring new infection through air born transmission (not common)
Diagnosis of latent TB
Recipients with latent TB are at high risk of conversion to active TB after transplantation, on the other hand, if the donor has latent TB and did not receive treatment it carry a risk of transmission to the recipient
So all recipients and donors should both be undergo careful evaluation of the risk, history, examination and CXR, together with test for latent TB
In general, all transplant recipients and donors should be evaluated for the presence of latent TB and once detected treatment should be received
2 test are used to detect latent TB, tuberculin skin test (TST) and IGRA, both are usually negative in immunosuppressed patients due to their dependence on the host immune response which is impaired in these sets of patients
Patient and donor should have no symptoms, CXR should be normal and no evidence of exra-pulmonary TB in order to settle the diagnosis of latent TB
Which test to use?
In low risk transplant recipients, it is it is preferred to use IGRA over TST due to its higher sensitivity in these sets of patients
In low risk donor, either of both tests can be used, with the preference of IGRA in patients with previous vaccination
In high risk transplant recipients and donor (patient who are living in country with high TB prevalence , contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), it is better to do both tests to maximize sensitivity, at that time IGRA should be done either at the same time of before TST to avoid TST-mediated IGRA response.
All transplant recipients and donors should have thorough history taking and CXR
Interpretation of the result
If TST is negative the test should be repeated after 7-10 days to detect posted effect
If IGRA is negative treatment is considered only in high risk transplant recipients
If the TST is positive (Induration ≥5 mm in recipient or > 10 mm in donor), there is a history of positive TST or IGRA is positive, the patients is considered to have latent TB provided that the CXR is normal and the patient is asymptomatic
If radiology is suspicious for TB (apical fibronodular lesions, calcified solitary nodule, calcified lymph nodes, or pleural thickening) thorough evaluation including microbiological assessment is indicated to exclude TB as a cause
If TB diagnosed in the recipient transplantation should be delayed till complete treatment of TB
If TB is diagnosed in the donor donation should be postponed till successful treatment is given for at least 6 months
Indications of treatment of latent TB in transplant recipient and donor
Positive TST (> 5mm in recipient, > 10 mm in donor) or a positive IGRA
History of positive TST or pervious history of TB
Negative TST and/or IGRA in a patient with close contact to an active TB case
If the donor has latent TB and did not receive treatment (treat the recipient), but if the donor received treatment there is no need to treat the recipient
Protocol for treatment of latent TB
The preferred regimen in renal transplant candidate is the use of INH in a dose of 5 mg/kg (maximum dose 300 mg) together with oral pyridoxine 50 mg daily for 6-9 months (9 months is preferred).
Rifampin in a dose of 600 mg for 4 months
INH+ weekly rifapentine for 3 months
Ideally, regimen should be started before transplantation, but if it started after transplantation, Rifampicin containing regimen should be avoided
Patient should be monitored for liver enzymes and bilirubin at baseline, every 2 weeks for 6 weeks then monthly, if there is 3 fold rise of liver enzymes with symptoms or 5 fold rise without symptoms , INH should be stopped
Recommendations for Transplanted Patients Who Travel to Endemic Areas
If renal transplant recipient wants to travel in the first year post transplant to an endemic area with prevalence ≥100/100000, they should follow standard precautions to prevent TB infection and they should receive INH preventive therapy.
BCG is contraindicated in transplantation
The diagnosis is challenging (needs high index of suspicion) due to the following
Atypical clinical presentation is more common in immunocompromsied compared to immunocompetent patients
High proportion of cases presents with extra pulmonary or disseminated TB (much higher than immunocompetent hosts)
Tuberculin test and IGRA are usually negative and should not be used for the diagnosis
Sputum smear for TB is usually negative despite active TB.
PCR from specimen is highly accurate and sensitive but can be falsely positive in patients who had successful treatment of TB
It is uncommon for the transplant recipients to have the classic picture of TB
To reach diagnosis invasive procedure is usually required including bronchoscopy and BAL or lung biopsy which may delay the diagnosis
The treatment of TB in SOT is challenging due to the following
Drug-drug interaction between rifampicin (the cornstone of TB treatment) and immunosuppressive medications used in transplantation
Loss of host immune response to TB due to the use of immunosuppressive drugs
Toxicity of anti-TB medications most commonly hepatotoxicity
Protocols used in treatment of TB
4-drug regimen of Rifampicin+ INH+ ethambutol + pyrazinamide for 2 months, followed by a 2-drug regimen of Rifampicin + INH for 7 months
Once rifampin is used, it is recommended to increase the dose of CNI or rapamycin 2-5 folds, with close follow up of serum level especially in the first 2 weeks after treatment
Rifabutiun can be used instead of rifampicin due to its lesser effect on cytochrome p450, so minimal drug-drug interactions but experience is little when using this drug in transplantation, although it seems effective in HIV TB patients.
What is the level of evidence provided by this article?
This is a narrative review (level V of evidence) for tuberculosis-related care in solid organ transplant patients (donor and recipient).
Epidemiology
South America has several cases of tuberculosis per year, with Brazil being the largest with 110,000 cases of prevalence with areas reaching 300 cases per 100,000 inhabitants. The emergence of multidrug-resistant strains is also a concern.
Tuberculosis after solid organ transplantation
It is more worrisome in patients who have received lung transplants, with the reactivation of latent disease being the main cause of infection.
Immigration, travel to endemic countries, medical tourism, and humanitarian work can be risk factors.
Diagnosis 1. LTBI
TST and IGRA are the most used methods, the latter being more specific and without the interference of the vaccine context and pre-exposure.
IGRA seems to be better for screening low-risk patients, while for those who are exposed to risk factors, the most appropriate is the joint use of TST and IGRA.
2. Active tuberculosis
Detection of mycobacteria either by culture or by molecular methods. Transplanted patients are at higher risk for extrapulmonary disease.
Molecular methods may give false positives after previous treatment for tuberculosis.
Prevention
Clinical history and radiological investigation added to a screening test should be performed on all candidates. Active disease is an exclusion factor for organ donation.
In deceased donors, it makes adequate screening tests are impossible, and samples are collected by bronchoalveolar lavage in addition to radiological findings. After six months of successful treatment, you should move on to the transplant queue. Lungs with sequelae should not be considered.
Treatment 1. LTBI
Isoniazid 300mg for nine months
Rifampicin 600mg for four months
or weekly combinations of Rifapentine and Isoniazid for 12 weeks.
2. Active tuberculosis
Classic scheme RHZE for 6 to 9 months. It is important to monitor for side effects, particularly liver damage. Drug interactions, especially with regard to rifampicin, should be considered and immunosuppressants measured frequently.
o Most countries in Latin America are moderately to highly endemic TB infectiono Brazil is in the group of 22 countries with the highest TB burden in the world (110 000 prevalent cases and 7700 TB deaths)
o Higher prevalence of multidrug-resistant (MDR) (between 3.0% and 6.0%) found in Ecuador, Guatemala, and Peru
Epidemiology in Latin America: TB after solid organ transplantation
o The incidence rate of TB infection markedly increases after SOT, with the highest among lung recipients
o Diagnosed in 0.9%-5.9% of the recipients according to a study
o Reactivation of LTBI is the main cause of posttransplant TB (other causes are primary infection and donor-recipient transmission)
o Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB after SOT
o Transplant candidates from endemic areas have a higher prevalence of LTBI and increase risk of active TB infection after SOT
o Time spent in the endemic area influences the risk of TB infection (longer than 3 months of travel to high-incidence areas is associated with a significantly higher risk)
o Transplant recipients from low-incidence countries may be exposed to primary infection while traveling to an endemic area Diagnosis Diagnosis of LTBI: 1. Tuberculin skin test (TST) 2. IFN-γ release assays (IGRAs)
Advantages of IGRAs:
1. Avoid interpreting bias
2. Reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination
3. More sensitive in candidates with CRF and advanced cirrhosis
Limitations of IGRAs:
1. The NPV of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI
2. Higher cost
3. Frequent occurrence of conversions and reversions of test results when serial screening is performed (may complicate the interpretation of their results among SOT candidates)
o In low-risk patients: do only IGRAs, because the use of a more specific test might reduce the rate of false-positive results and, consequently, the number of patients who will unnecessarily be exposed to LTBI therapy
o In high-risk patients: do both tests (IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses), and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening
Diagnosis of active TB:
o Detection of M. tuberculosis bacilli by direct observation, culture, and NAT
o Active infection IN SOT recipients may present with unusual manifestations, with a greater proportion of extrapulmonary involvement
o Diagnosis should be considered in any patient presenting with fever of unknown origin
o Xpert MTB/RIF assay: a rapid molecular test. It is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively. Useful rule-in diagnostic test for extrapulmonary TB (tissue biopsies and cerebrospinal fluid). It allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB. Limitations are false-positive and cannot fully replace the execution of conventional drug susceptibility tests
Prevention Risk assessment of the transplant candidate:
o Clinical or radiological history of TB and prior treatment in all recipients
o Do LTBI with TST or IGRA if no history of past TB or treatment for LTBI
o TST: induration of 5 mm or greater at 48-72 hours is a positive test. A second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion
o Active TB infection must be excluded in all candidates with a positive LTBI before treatment
o If active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative
Risk assessment of deceased and living donors:
Evaluation is the same for living donors but the cutoff for TST in donors should be 10 mm or more
The evaluation of the deceased donor for TB:
1. Clinical history of untreated or insufficiently treated TB should be investigated and any previous reactive IGRA or TST
2. Endemic exposures: travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the last 2 years, homeless or refugee status, incarceration and alcoholism
3. Radiology: apical fibronodular lesions calcified solitary nodules, calcified lymph nodes, or pleural thickening
4. Active TB infection should be ruled out in donors at increased risk by obtaining samples (sputum or bronchoalveolar lavage) for M. tuberculosis.
Treatment Treatment of LTBI in transplant candidates and recipient:
Criteria to Start Treatmento First rule out active TB infection
o Therapy is recommended for transplant candidates with positive TST or IGRA and not treated previously
o High-risk pretransplant TB exposure should be treated even if the TST or IGRA is not positive, and also those with history of active TB infection that was inadequately treated
Therapy for transplant recipients:
1. Donor has a history of untreated or incompletely treated LTBI or TB
2. If the recipient is exposed to TB after transplantation
Therapeutic Regimenso Oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily is the preferred regimen
o Monitor for hepatotoxicity with at least serum ALT checked every 2 weeks for 6 weeks, then monthly thereafter
o Alternative regimens containing rifamycins (RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks) can be considered pretransplant (should be avoided posttransplant because of immunosuppressive drug interactions)
Timing of Treatmento Balancing risks and benefits
o Treatment for should be started before transplant if possible, and can often be completed while the patient is on the waitlist
o If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible
Recommendations for Transplanted Patients Who Travel to Endemic Areaso For recently transplanted patients planning to move to a highly endemic area (prevalence ≥100/100 000), INH preventive therapy should be considered during the first posttransplant year
o Follow standard precautions to prevent nosocomial acquisition of infection
o Possible TB exposure should be evaluated immediately on return
Treatment of active TB infection:
o Follow local guidelines (4-drug regimen)
o INH and rifampicin are the most powerful first-line drugs
o Consider the risk of hepatotoxicity related to the antituberculous treatment and drug interactions of rifampicin IN SOT
o The duration of treatment of TB in transplant recipients is not defined (may be at least 9 months)
Monitoring of Adverse Events Related to Therapyo Close monitoring during the first 2 months of treatment (biweekly)
o Low-grade elevation of aminotransferases can be observed during the first 2 months of treatment, but a 3-fold increase with symptoms or a 5-fold increase regardless of symptoms requires discontinuation
Drug Interactionso Rifamycins have intract with cytochrome P450 (CYP) 3A4, which lead to a reduction in the blood levels of most immunosuppressive drugs (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids)
o Rifampin has the most potent enzyme induction effect
o Enzyme induction start within hours after the first dose of rifampin but the maximum effect is reached in about 1-2 weeks and slowly declines over 2 weeks after stopping its use
o Drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption
o Rifampicin is not contraindicated in SOT recipients
o Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin (as effective as rifampin for the treatment of TB in trials conducted in nontransplant patients.)
What is the level of evidence provided by this article?
Level V (narrative review)
Name of the study: Tuberculosis Recommendations for Solid Organ
Transplant Recipients and Donors Year of the study: February 2018 journal: transplant journal the level of evidence: narrative review with evidence V. TB AFTER SOLID-ORGAN TRANSPLANTATION Causes
1. Reactivation of foci of latent TB infection (LTBI)
2. Primary infection acquired in the community
3. donor-recipient transmission. DIAGNOSIS Diagnosis of LTBI: There is no diagnostic reference standard for LTBI.
Definition of latent TB is persistent immunological response to TB antigen with no evidence of active disease Immunological response can be diagnosed either by
· The tuberculin skin test (TST) remains the best studied test and still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.
· IFN-γ release assays (IGRAs):
1. Advantages: compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and more sensitive in candidates with chronic renal failure and advanced cirrhosis.
2. disadvantages: negative predictive value of IGRAs is not optimal to rule out
infection in patients considered to be at high risk for LTBI. Diagnosis of Active TB Infection
persistent immunological response with evidence of active infection based on clinical,radiological and laboratory investigations like detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing. Molecular test, such as the Xpert MTB/RIF assay, may have a major impact in the management of these patients. This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%.
Clinical presentation in SOT recipients may present as unusual manifestations, with a greater proportion of extrapulmonary involvement that’s why TB should be considered in patients presenting with fever of unknown origin. Risk Assessment of the Transplant Candidate(recipient)
· screening is needed with either TST or IGRA. the screening strategy may be adapted per the patient’s characteristics. both tests could be performed and any positive reaction considered an evidence of LTBI.
· Active TB infection transplantation should be postponed until the disease is well controlled
with adequate treatment and smears are negative. Nevertheless, active infection may not be considered an absolute contraindication to transplantation for candidates who urgently need it. Risk Assessment of Deceased and Living Donors
· Living donors: screening and diagnosis same like recipient.
· deceased donor for TB relies on: Medical history, Endemic exposures and Radiographic findings. Time does not allow for a TST and IGRAs have not been validated in deceased donors.
We can classify donors into 3 main categories:
1. Organs from donors with known active TB infection should be discarded but If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines. Drug susceptibility tests should be performed on any M. tuberculosis specimen isolated from the donor, since the detection of drug resistance may be of critical importance for guiding therapy in the recipients.
2. Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
3. A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, the risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, therefore,
transplant recipients from such donors can be clinically monitored without receiving LTBI therapy. TREATMENT
· Treatment of LTBI in Transplant Candidates and Recipients Criteria to Start Treatment
all recipient with LTBI who have not been previously treated should be treated.
· Active infection should be excluded Therapeutic Regimens
· oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.Nine months of therapy is preferred over 6 months because of better protection.
· Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions.
· Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy. However, a recent randomized study of pretransplant levofloxacin versus posttransplant INH in liver transplant recipients was stopped early because of excessive adverse events in the levofloxacin arm. Timing of Treatment
treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist. If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible until completion of the originally planned course, with the caveat that rifamycins are usually avoided after transplant. Recommendations for Transplanted Patients Who Travel to Endemic Areas
· INH preventive therapy should be considered during the first posttransplant year
· BCG vaccine is contraindicated in transplant recipients.
· Transplant recipients should follow standard precautions to prevent nosocomial acquisition of infection. On return symptoms of infection should seek medical evaluation immediately.
Treatment of Active TB Infection
Treatment should follow local guidelines for the general population. The optimal length of treatment of TB in transplant recipients is not defined. Many specialists recommend that treatment
duration should be at least 9 months with close monitoring of Adverse Events Related to Therapy and drug Interactions.
I like your summary, level of evidence, analysis and take home messages. What is your suggestion regarding communication gap between availability of newer diagnostic tests and promptness of action?
Thanks Prof Ajay GeneXpert will make revolution regarding rapid detection of TB in just couple of hours solving the problem regarding routine culture which may take 2 months average to get the results.
– Summary Epidemiology
In the last 2 decades, the absolute numbers of tuberculosis (TB) infection and mortality has decreased in Latin America (LA) countries but TB still represents a public health burden in this area.
In Brazil, the estimated average national incidence in 2015,varied between cities and even in the same city .
Multidrug-resistant (MDR) TB, resistant to rifampicin and isoniazid (INH) is a global problem particularly for cases treated previously with anti TB drugs. TB after SOT
TB risk is higher after SOT specially after lung transplantation.
SOT centers in LA during the last decade, TB infection was in 0.9% to 5.9% of the recipients caused mainly by reactivation by latent TB foci ,primary infection and nosocomial infection is less common.
Recipients mostly acquire infection from deceased donor with active TB ,infection rate from donor with latent TB foci is not assessed yet . International Travel and Posttransplant TB
International travel to endemic areas ,immigration and transplant tourism can increase the risk of TB after SOT.
Recipients from endemic areas are highly liable to reactivation of latent TB infection LTBI after transplant.
The estimated risk of acquiring TB infection among immunocompetent travellers returning from endemic countries, ranged from 0.4% to 2.0% but higher rates (1.8% to 4.2%) was noticed among travellers who were working in health care .
The duration spent in endemic area and duration exposure is a risk factor as those involved in humanitarian works . Diagnosis of LTBI
Guidelines recommend using Tuberculin skin test (TST) for screening of LTBI in solid organ candidates/recipients and living donors.
IFN-γ release assays (IGRAs)compared to TST has less bias, less false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and is more sensitive in candidates with chronic renal failure and advanced cirrhosis.
IGRAs is not the best test to exclude cases at high risk of LTBI.
The limitations of IGRAs are it’s high cost , having reversions and conversions when used serially.
Therefore screening approach is variable between centers .
It was suggested in low risk cases IGRA can be used and for high risk both IGRA and TST can be used.
Diagnosis of active TB
Is done by culture and nucleic acid testing ,it’s diagnosis is based on clinical suspicion and in SOT it can have extrapulmonary manifestations. Invasive methods are needing for diagnosis which can delay it.
Rapid molecular test, as the Xpert MTB/RIF assay is highly specific with variable sensitivity for respiratory and non respiratory specimens , it can aid in the management of these patients and it is highly predictive of rifampicin resistant -TB on the other hand it can give false-positive results among patients successfully treated for TB. Prevention
If candidates has no past TB history or LTBI treatment then either TST or IGRA need to be used for LTBI assessment.
TST test can be done twice to assess boosted related skin conversion.
Screening method has to be individualised for each case.
Active TB infection have to be excluded in cases with a positive TST or IGRA result before LTBI treatment is started.
Transplantation need to be postponed for candidates with active TB till treated and well cured
Less active TB might not necessitate delay of transplantation if urgently indicated. Risk assessment of deceased and living donors
Living donors have the same evaluation as recipients except for TST ,it has to be 10 mm or more
For deceased donors evaluation depends on medical history , travelling to endemic areas and radiological imaging.
Active TB has to be excluded by sputum testing or BAL testing for Mycobacterium tuberculosis .
Organs from donors with active TB are contraindicated to be used , if active TB is discovered after transplant ,urgent therapy has to be started also drug susceptibility need to be tested.
Donors with a history of TB treated well for at least 6 months can be included in donation.
Untreated LTBI history without active infection can be a donor candidate but preventive therapy to all recipients should be applied. Treatment of LTBI in Transplant candidates and recipients
LTBI has to be treated to avoid TB infection.
Transplant candidates with positive TST or IGRA without previous therapy have to be treated
High-risk cases of pretransplant TB exposure , those with history of active TB infection that
was inadequately treated and those with radiological suggestive findings have to be treated too.
Recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation also needs treatment. For treatment of LTBI
The preferred regimen is oral INH 300 mg/d with oral pyridoxine 25 to 50 mg daily for 9 months with liver function tests follow up for hepatotoxicity every 2 weeks for 6 weeks then monthly.
Another regimen is rifampicin 600 mg daily for 4 months or INH and rifapentine weekly for 12 week but rifampicin interacts with immunosuppressives.
for LTBI therapy, Fluoroquinolones (± ethambutol) have been proposed.
LTBI treatment need to be started before transplant, and completed while the patient is on the waitlist. If urgent transplant treatment can be held perioperatively and continued when applicable
till the course is finished.
INH preventive therapy during the first posttransplant year must be considered for recipients travelling to endemic areas particularly participating in medical care.
Active TB treatment is the same as general population 4 drug regimen for 9 months minimum with close monitoring for hepatoxicity and drug interaction.
Rifamycin as an enzyme inducer lowers immunosuppressives ‘ level increasing rejection risk.
Rifabutin, has a weaker enzyme induction activity so can be used as an alternative to rifampicin meanwhile needs close monitoring.
During solid organ transplantation (SOT), lung patients had the greatest risk of TB. Transplant facilities’ active TB infection rates vary according to local disease incidence. In the recent decade, LA SOT clinics identified 0.9% to 5.9% of patients with TB.
Posttransplant TB likely results from LTBI reactivation. In endemic locations, community-acquired primary infections may account for a significant number of infections. Donor-recipient transmission causes fewer initial infections.
LTBI diagnosis:
LTBI diagnosis has no standard. Most current recommendations propose screening solid organ candidates, recipients, and live donors for LTBI using the tuberculin skin test (TST), the best-studied test. IFN-release assays (IGRAs) are emerging diagnostic techniques.
They have benefits over TST: they avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and may be more sensitive in candidates with chronic renal failure and advanced cirrhosis due to their higher yield and better correlation with clinical risk factors for LTBI. Despite their better yield, IGRAs’ negative predictive value is not optimal to rule out infection in patients at high risk for LTBI, including those born to or living in endemic countries, household contacts of active TB cases, and those who work or live in high-risk settings like correctional facilities and homeless shelters.
These assays’ greater cost and numerous test result conversions and reversions during repeated screening may make SOT candidate interpretation difficult. Because of TST and IGRA restrictions, transplant hospitals examine candidates for LTBI differently.
Diagnosing Active TB
Direct observation, culture, and nucleic acid testing for M. tuberculosis bacilli determine active TB infection. TST and IGRA are not indicated for active infection diagnosis.
Clinical suspicion of a current infection is the hardest. SOT recipients may have more extrapulmonary involvement. Patients with unexplained fever should be evaluated for TB.
This group requires more invasive diagnostic procedures, delaying diagnosis and increasing death.
The Xpert MTB/RIF assay, a fast molecular diagnostic, may improve patient treatment. This test has a 98% sensitivity in smear-positive respiratory samples and 67% sensitivity in smear-negative samples.
Donor Risk Assessment:
Live donors should be evaluated like candidates, but their TST should be 10 mm or above.
• Medical history Untreated TB and reactive IGRA or TST should be explored.
Endemic exposures. Travel to or residency in endemic regions, active TB infection in the family or workplace within 2 years, homeless or refugee status, imprisonment, and drinking may be linked to LTBI. With LA’s dropping TB incidence, current TB prevalence estimates may not adequately represent prior exposure risk in these nations.
• Radiographic features including apical fibronodular lesions, calcified isolated nodules, lymph nodes, or pleural thickening.
LTBI treatment :
prevents active TB infection in transplant patients. Untreated transplant candidates with positive TST or IGRA should get LTBI treatment.
High-risk pretransplant TB exposure and poorly treated active TB infection need medication even if the TST or IGRA is negative. In places without endemic mycoses, chest imaging suggests that untreated TB warrants treatment. Transplant patients exposed to TB after transplantation or whose donors have untreated or incompletely treated LTBI or TB should get therapy. First, rule out active TB.
Active TB Treatment:
Local population guidelines should guide treatment. Each population’s medication resistance should determine the intensive phase regimen’s drug count. A 4-drug regimen is usually advised. INH and rifampicin are the best first-line TB medicines. Rifampicin medication interactions and antitubercular therapy hepatotoxicity should be evaluated in SOT.
TB therapy in transplant patients has no recommended duration. Based on a few studies linking shorter regimens to higher recurrence and death, many physicians advocate at least 9 months of therapy.
Treatment Adverse Events Monitoring:
Close monitoring, especially biweekly in the first two months, is advised because of the increased risk of adverse events and medication interactions. INH, rifampicin, and pyrazinamide induce hepatotoxicity, particularly in liver recipients. 60 During the first two months of therapy, aminotransferases may rise slowly, but a 3-fold increase with any symptom or a 5-fold increase without symptoms warrants termination.
What is the level of evidence provided by this article?
Summary of the Article TB after SOT TB has a higher incidence after transplantation, which varies among centers and according to the local prevalence of the disease. The incidence rate in Latin America varies from 0.6 to 5.6% of the recipients. Source of the infection
Reactivation of latent TB in the Recipients.
De Novo disease.
DD-TB.
Generally, immigrants and travelers from the endemic area are associated with a higher risk of post-KT TB.
Diagnosis of LTBI
No diagnostic standard.
TST is the best-studied test and is recommended by most guidelines in screening the disease.
IGRAs over some advantages; avoid interpreting bias, and reduce false +ve results, but have a lower predictive value to rule out latent infection.
In a low-risk patient, IGRAs can be used alone for their high specificity.
In a high-risk patient, both TST and IGRA should be used and any +ve result should be considered.
Diagnosis of active TB
Clinical suspicion should take place in diagnosing post-transplant TB as it presents with an atypical manifestation and extrapulmonary disease.
Diagnosis based on culture, clinical suspicion, and fever of unknown cause, fever persistent after a proper antibiotic protocol.
Rapid molecular test Xpert MTB/RIF is more sensitive and specific and helps in diagnosing rifampicin resistance.
The limitation of the test Xpert MTB/RIF is that of its false +ve result which can be detected in a treated TB.
Prevention Risk assessment of recipients
Radiograph screening for all recipients.
TST or IGRAs for LTBI.
For TST, an induration of 5 mm or more after 48 to 72 hours is considered as +ve, repeated after 7 to 10 days to evaluate a boosted-related skin test.
Both tests should be performed on high-risk candidates.
Active TB infection should be excluded in any +ve results, and transplantation must be postponed if active TB is confirmed.
Risk assessment of deceased and living donors
A living donor should be assessed as a recipient, unless for TST induration which should be greater than 10 mm.
Deceased donors, should be evaluated based on the following
Medical history.
Endemic exposure.
Radiographic finding.
Communication between centers.
Organs from active TB should be discarded.
Donors with treated TB can donate after 6 months after successful treatment.
History of untreated latent TB should not be excluded, but preventive measures should be ensured.
Treatment Treatment of LTBI in recipients and donors Criteria to start treatment
Positive TST or IGRA results.
High-risk TB exposure, even if TST or IGRA -ve.
Positive chest x-ray findings for untreated TB.
TB therapy for recipients receiving organs from donors with untreated LTBI or TB.
For LTBI it’s first to exclude active TB infection.
Therapeutic regiment
For LTBI, INH 300 mg/d for 9 months plus oral pyridoxine 25-50 mg /d.
Monitor for hepatotoxicity, with serum ALT every 2 weeks for 6 weeks, then monthly.
The alternative regiment includes Rif 600 mg/d for 4 months (monitor immunosuppressant trough level) or INH/RIf weekly for 12 weeks.
Flouroquinilones +/- ethambutol for LTBI.
Timing;
Pretransplant in elected surgery or while on a waiting list.
Perioperatively in urgent surgery.
Transplant recipients who travel to an endemic area
Preventive therapy (INH) during the first transplant year.
No indication for the BCG vaccine and its a contraindicated in transplant recipients.
Summary of the Article TB after SOT TB has a higher incidence after transplantation, which varies among centers and according to the local prevalence of the disease. The incidence rate in Latin America varies from 0.6 to 5.6% of the recipients. Source of the infection
Reactivation of latent TB in the Recipients.
De Novo disease.
DD-TB.
Generally, immigrants and travelers from the endemic area are associated with a higher risk of post-KT TB.
Diagnosis of LTBI
No diagnostic standard.
TST is the best-studied test and is recommended by most guidelines in screening the disease.
IGRAs over some advantages; avoid interpreting bias, and reduce false +ve results, but have a lower predictive value to rule out latent infection.
In a low-risk patient, IGRAs can be used alone for their high specificity.
In a high-risk patient, both TST and IGRA should be used and any +ve result should be considered.
Diagnosis of active TB
Clinical suspicion should take place in diagnosing post-transplant TB as it presents with an atypical manifestation and extrapulmonary disease.
Diagnosis based on culture, clinical suspicion, and fever of unknown cause, fever persistent after a proper antibiotic protocol.
Rapid molecular test Xpert MTB/RIF is more sensitive and specific and helps in diagnosing rifampicin resistance.
The limitation of the test Xpert MTB/RIF is that of its false +ve result which can be detected in a treated TB.
Prevention Risk assessment of recipients
Radiograph screening for all recipients.
TST or IGRAs for LTBI.
For TST, an induration of 5 mm or more after 48 to 72 hours is considered as +ve, repeated after 7 to 10 days to evaluate a boosted-related skin test.
Both tests should be performed on high-risk candidates.
Active TB infection should be excluded in any +ve results, and transplantation must be postponed if active TB is confirmed.
Risk assessment of deceased and living donors
A living donor should be assessed as a recipient, unless for TST induration which should be greater than 10 mm.
Deceased donors, should be evaluated based on the following
Medical history.
Endemic exposure.
Radiographic finding.
Communication between centers.
Organs from active TB should be discarded.
Donors with treated TB can donate after 6 months after successful treatment.
History of untreated latent TB should not be excluded, but preventive measures should be ensured.
Treatment Treatment of LTBI in recipients and donors Criteria to start treatment
Positive TST or IGRA results.
High-risk TB exposure, even if TST or IGRA -ve.
Positive chest x-ray findings for untreated TB.
TB therapy for recipients receiving organs from donors with untreated LTBI or TB.
For LTBI it’s first to exclude active TB infection.
Therapeutic regiment
For LTBI, INH 300 mg/d for 9 months plus oral pyridoxine 25-50 mg /d.
Monitor for hepatotoxicity, with serum ALT every 2 weeks for 6 weeks, then monthly.
The alternative regiment includes Rif 600 mg/d for 4 months (monitor immunosuppressant trough level) or INH/RIf weekly for 12 weeks.
Flouroquinilones +/- ethambutol for LTBI.
Timing;
Pretransplant in elected surgery or while on a waiting list.
Perioperatively in urgent surgery.
Transplant recipients who travel to an endemic area
Preventive therapy (INH) during the first transplant year.
No indication for the BCG vaccine and its a contraindicated in transplant recipients.
Tuberculosis Recommendations for SOT Recipients and Donors
Summary
· Diagnosis of latent TB in recipients and potential donors:
o Tuberculin skin test (TST) remains the most studied test.
o TST (induration ≥ 5 mm at 48 to 72 hours is considered positive). In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
o IGRA has better sensitivity and many advantages over TST.
o IGRA advantages: it avoids interpreting bias of TST, reduce false +ve results related to previous exposure to nontuberculous mycobacteria or BCG vaccine, and are probably more sensitive in candidates with CKD and advanced cirrhosis.
o IGRA disadvantages: suboptimal -ve predictive value (not exclude latent infection in high risk individuals as endemic areas).
o Mostly, in high risk (endemic areas, household contacts of active TB infection, homeless shelters) we use both tests to increase sensitivity.
o Whenever dual-test approach is used, IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses (false +ve result).
o Any case diagnosed with latent TB, active TB disease must be excluded by clinical symptoms, CXR and other body imaging) as treatment varies between both latent and active TB (regarding dose and duration).
o Active TB in recipient must be fully treated prior to transplantation (until clinical and bacteriological cure, negative smear. While, in latent TB we can start and continue therapy even after transplantation. So, TB is not absolute CI to transplantation.
o Latent TB in potential living donor is the same by TST and IGRA, but TST cut off is ≥ 10 mm.
o TB in deceased donor is excluded by excluding hx of prior TB ttt, prior +ve TST or IGRA, exposure to TB cases, travel or residency in endemic area, radiographic findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening.
o Organs from active TB in deceased donor must be discarded, while those who were successfully treated for at least 6 months, can donate.
o Deceased donor with hx of untreated latent TB, start immediate prophylactic therapy with transplantation.
o If diagnosis is made after organ retrieval, start immediate therapy for TB.
· Diagnosis of active TB in recipients and potential donors:
o High index of suspicion due to atypical and extrapulmonary manifestations.
o Early diagnosis and treatment are essential for early ttt and prevent graft loss and mortality.
o Detection of MTB in sputum, or need invasive bronchosciopy and BAL to do special stain (ZN) or culture on L J or rapid culture on BACTEC system.
o Rapid molecular test, such as the Xpert MTB/RIF assay.
§ Additionally, performance of gene Xpert is also observed when testing non respiratory samples, such as tissue biopsies and cerebrospinal fluid, indicating that it is a useful rule-in diagnostic test for extrapulmonary TB.
§ Also, it helps to detect both rifampin and multi drug resistant TB (so earlier than conventional culture).
§ But it can give false positive results in already treated cases.
· Treatment of latent TB in recipients:
o Treatment should be completed prior to transplantation, but if urgent indication of transplantation (no line for dialysis for example), we can complete course post-transplant with better avoidance of rifampin.
o INH + vit B6 for 6-9 months.
o Oral rifampin for 4 months (but better avoided post-transplant, to minimize drug-drug interaction.
· Precautions for recipients travelling to endemic areas:
o JUST avoid exposure while BCG vaccine is CI in transplant recipients.
· Treatment of active TB in recipients:
o Start immediately after diagnosis.
o Consider epidemiological criteria of the disease and drug resistant strains.
o Duration of therapy ranges from 6-24 months, at least 6 months,
o 2 Regimens:
1. Intensive therapy for 2 months with 4 drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) followed by continuation phase of 2 drugs (isoniazid and rifampicin) for 4 months.
o Rifampin is enzyme inducer and lower trough level of CNI and mTORi so increase their dose 3-5 folds and double dose of steroids to avoid risk of rejection.
o After stoppage of rifampin, decrease dose according to the trough level is essential.
o Rifabutin is an alternative, less enzyme inducer but not well-studied in transplant cases. While fluoroquinolones are another safe and effective alternative in transplant cases.
2. Intensive phase of 2-month of 3 drugs (should contain isoniazid, ethambutol and pyrazinamide or levofloxacin), followed by a continuation phase of 12–18 months with 2 drugs (isoniazid and ethambutol or pyrazinamide). Longer period of treatment is recommended.
a. Monitoring of adverse effects as hepatotoxicity.
b. Hepatotoxicity is The most common adverse event associated with anti-TB therapy; therefore, liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter
Do you think IGRA has a better specificity and therefore higher LR ratio? What is your comment on this statement of mine. You may or may not agree with me.
Thanks dear professor,
Yes, I think it has higher specificity than TST as it is not affected by BCG vaccine or presence in high endemic area in addition, it has better sensitivity in immunocompromised patients as CKD, ESKD and transplant recipients.
Epidemiology in latin America
In the last 2 decades, the burden of tuberculosis(TB) has been considerably reduced in Latin Anerican countries.
The estimated proportion of MDR infection among new TB cases remains below 3% in most countries of the region, higher prevalence has been found in Ecuador, Guatemala, and Peru.
3.0% and 6.0%) has been found in Ecuador, Guatemala, and Peru
Recent reports from the latter country provide evidence of ongoing community transmission of MDR infection with significant impact on mortality.
The prevalence of MDR infection is expectedly higher among patients who were previously treated for TB
In those 3 countries, this prevalence has been estimated to range from 20% to 26%.
Most of these cases were documented in patients who received a graft from a deceased donor with active TB infection, a situation that has been associated with a risk of transmission of approximately 30%.13,14 it is probable that donors with untreated LTBI may be a source of TB transmission, the influence of donor LTBI on the risk of posttransplant TB is undetermined yet.
International travel and post transplant TB
Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB after.
Transplant candidates originating from endemic areas have a higher prevalence of LTBI and are, at Received 2 July 2017.
Funded by a technical cooperation agreement between the Pan American health organization(PAHO) and the Ministry of Health of Brazil Recommendations for management of endemic
Diseases and Travel Medicine in Solid-Organ Transplant Recipients and Donors:Latin America supplement.
In Spain, the prevalence of active TB infection was markedly increased in deceased donors who originated from a high-incidence country in eastern Europe.
Transplant recipients from low-incidence countries may be exposed to primary infection while traveling to an endemic area, but the actual impact of such exposure in this specific population has not been assessed.
Such figures are lower than those reported for other diseases, such as dengue fever and malaria, they are not negligible, and it is possible that travel-related acquisition may account for a substantial proportion of new infections among people living in low-incidence countries.
The use of public transportation in a high-incidence area in Peru was an independent risk factor for active TB infection.
Visiting friends and relatives is a known risk factor for acute diseases, such as traveler’s diarrhea, but the impact, if any, of such activity on the risk of acquiring TB has not been established.
Diagnosis of LTBI
There is no diagnostic reference standard for LTBI. The tuberculin skin test (TST) remains the best studied test and, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors. IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade.
IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade
They offer some advantages as compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients.
In high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
Diagnosis of active TB infection
The diagnosis of active TB infection relies on the detection of M-tuberculosis bacilli by direct observation, by culture, FIGURE 1.
The availability of a rapid molecular test, such as the Xpert MTB/RIF assay, may have a major impact in the management of these patients.
This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of.
It allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB
It may have a critical role for providing the timely start of MDR-TB treatment while results of conventional culture and drug susceptibility tests are pending.
It is noteworthy that it cannot fully replace the execution of conventional drug susceptibility tests
Risk assessment of the transplant candidate
A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
In high-risk candidates, both tests could be performed and any positive reaction considered an evidence of LTBI.
Whenever this dual-test approach is used, IGRA should be performed before or concurrently with TST placement to avoid.
Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
This evaluation includes checking the presence of symptoms and signs suggestive of TB, performing a chest radiograph and, in cases with extrapulmonary manifestations, imaging of other body sites.
Active infection may not be considered an absolute contraindication to transplantation for candidates who urgently need it. Risk assessment of deceased and living donors
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
Travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the last 2 years, homeless or refugee status, incarceration and alcoholism may be associated with LTBI.
In this regard, it is important to notice that, given the declining trend of TB incidence in LA current estimates of TB prevalence may not accurately reflect the actual risk of past exposure in these countries.
If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines.
The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, transplant recipients from such donors can be clinically monitored without receiving LTBI therapy
Criteria to start treatment
Therapy for LTBI is an effective strategy for the prevention of active TB infection in transplant recipients, TBI therapy is recommended for transplant candidates with positive.
Therapy for LTBI is an effective strategy for the prevention of active TB infection in transplant recipients.
LTBI therapy is recommended for transplant candidates with positive.
Transplant journal.com considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated.
Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
In considering treatment for LTBI, it is imperative to first rule out active TB infection
Therapeutic regimens
300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily. Nine months of therapy is preferred over 6 months because of better protection.
Nine months of therapy is preferred over 6 months because of better protection.
Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine aminotransferase checked every.
Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions.
These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for.
Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
A recent randomized study of pretransplant levofloxacin versus posttransplant.
INH in liver transplant recipients was stopped early because of excessive adverse events in the levofloxacin arm. Timing of treatment
The timing of LTBI treatment requires balancing risks and benefits for each patient.
Treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist.
If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible until completion of the originally planned course, with the caveat that rifamycins are usually avoided after transplant.
It can be challenging to treat liver transplant candidates before transplant.
In several small studies, INH has been shown to be safe in those with compensated cirrhosis awaiting transplant with careful monitoring, some experts do prefer waiting until after transplant to begin INH once liver function has been normalized
Recommendation for transplanted patients who travel endemic area
If recently transplanted patients are planning to move to a highly endemic area
If recently transplanted patients are planning to move to a highly endemic area, INH preventive therapy should be considered during the first posttransplant year, especially for those planning to take part in medical or humanitarian care, given the higher risk of primary TB acquisition.
Transplant recipients who are traveling to TB endemic areas to provide medical or humanitarian care should follow standard precautions to prevent nosocomial acquisition of infection.
There is no indication for BCG vaccine before travel, and it is contraindicated in transplant recipients.
Those with possible TB exposure should be evaluated on return, and anyone with symptoms of infection should seek medical evaluation immediately
Treatmenmt of active TB infection
Treatment should follow local guidelines for the general population.
The number of drugs used in the intensive phase regimen should be defined per the prevalence of drug resistance in each population.
INH and rifampicin are the most powerful first-line drugs against TB.
In the context of SOT, many factors should be carefully considered, such as the risk of hepatotoxicity related to the antituberculous treatment and drug interactions of rifampicin.
The optimal length of treatment of TB in transplant recipients is not defined.
Many specialists recommend that treatment duration should be at least 9 months, based on the results of a few studies that have suggested an association between shorter regimens and greater recurrence and mortality.
Monitoring of adverse events related to therapy
Due to the increased risk of adverse events and potential drug interactions, close monitoring is highly recommended, mainly during the first 2 months of treatment when it should be performed biweekly.
Concomitant use of INH, rifampicin, and pyrazinamide is associated with an increased risk of hepatotoxicity, especially in liver recipients.
Low-grade elevation of aminotransferases can be observed during the first.
2 months of treatment, but a 3-fold increase accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation
Findings
The estimated proportion of MDR infection among new TB cases remains below 3% in most countries of the region, higher prevalence
Drug interaction
Rifamycins have an induction effect on different drugmetabolizing enzyme systems, most notably the cytochrome.
Twoto 5-fold increments in the daily dose of cyclosporine, tacrolimus, and mammaliantarget of rapamycin inhibitors are generally necessary to maintain trough levels of the drug in the therapeutic range.
Therapeutic drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption.
Despite these drug interactions, rifampicin is not contraindicated in SOT recipients.
Its weaker effect on CYP3A4 makes it easier to maintain therapeutic blood levels of calcineurin and mammalian target of rapamycin inhibitors during.
Close therapeutic drug monitorings of these immunosuppressive drugs apply when rifabutin is used
1-Summarise this article; TB after SOT;
-The incidence rate of TB markedly increases after solid organ transplantation (SOT),
-The risk being highest among lung recipients.
-Reactivation of foci of latent TB infection (LTBI) is probably the main cause of post-transplant TB.
-Patients who received a graft from a deceased donor with active TB infection, are associated with a risk of transmission of approximately 30%.
-The possibility of donor transmission of TB has also been associated with transplant tourism. Diagnosis of LTBI;
-There is no diagnostic reference standard for LTBI.
-Most current guidelines still recommend using tuberculin skin test (TST) for the screening of LTBI in solid organ candidates/recipients and living donors.
-IFN-γ release assays (IGRAs) offer some advantages as compared with TST:
*Reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination,
*More sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a better correlation with clinical risk factors for LTBI in these patients.
-Other limitations of these assays include:
*Their higher cost
*The frequent occurrence of conversions and reversions of test results when serial screening is performed, which may complicate the interpretation of their results among SOT candidates. Diagnosis of Active TB Infection;
-The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing.
-Neither TST nor IGRAs are recommended for diagnosing active infection.
-It also allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB.
-Thus, it may have a critical role for providing the timely start of MDR-TB treatment while results of conventional culture and drug susceptibility tests are pending Prevention; Risk Assessment of the Transplant Candidate;
-In high-risk candidates (ie, patients originated from endemic countries, household contacts of active TB infection) both tests (TST& IGRAs) could be performed and any positive reaction considered an evidence of LTBI.
-Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
-Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative. Risk Assessment of Deceased and Living Donors;
-Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
-Time does not allow for a TST and IGRAs have not been validated in deceased donors.
-Organs from donors with known active TB infection should be discarded.
-If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines.
-Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
-Lungs with residual tuberculous lesions should not be used for transplantation.
-A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, especially for lung recipients.
-The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, therefore, transplant recipients from such donors can be clinically monitored without receiving LTBI therapy. Treatment; Treatment of LTBI in Transplant Candidates and Recipients;
-LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
-Those with high-risk pre-transplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated.
-Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation. Therapeutic Regimens;
-For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
-Nine months of therapy is preferred over 6 months because of better protection.
-If recently transplanted patients are planning to move to a highly endemic area (ie, those with prevalence ≥100/ 100000), INH preventive therapy should be considered during the first post-transplant year.
-There is no indication for BCG vaccine before travel, and it is contraindicated in transplant recipients. Treatment of Active TB Infection;
-The number of drugs used in the intensive phase regimen should be defined per the prevalence of drug resistance in each population.
-In most cases, a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB.
-The optimal length of treatment of TB in transplant recipients is not defined.
-Many specialists recommend that treatment duration should be at least 9 months, based on the results of a few studies that have suggested an association between shorter regimens and greater recurrence and mortality. Monitoring of Adverse Events Related to Therapy;
-Due to the increased risk of adverse events and potential drug interactions, close monitoring is highly recommended, mainly during the first 2 months of treatment when it should be performed biweekly.
-Low-grade elevation of aminotransferases can be observed during the first 2 months of treatment, but a 3-fold increase accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation.
-Rifamycins have an induction effect on different drug metabolizing enzyme systems , which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids).
-A lower blood level of these drugs is associated with higher risk of graft rejection.
-Therefore, close monitoring and continuous dose adjustment are highly recommended. 2-What is the level of evidence provided by this article?
-This article is narrative review (LOE 5).
We would do drug monitoring 3 times a week, rather than 2 times a week as per your suggestion, once drugs that do interfere with cytochrome enzymes have been commenced. MMF would need to be discontinued for 6 weeks when treating active tuberculosis in a transplant recipient. Please do not forget to recommence once the patient gets better.
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors DOI: 10.1097/TP.0000000000002014
Incidence: The incidence rate of TB markedly increases after transplantation and highest in lung tx. incidence in LA ranges from 1-6%. Reactivation of foci of latent TB infection (LTBI) is probably the main cause of posttransplant TB. It is more common in recipients from endemic areas or if they live more than 3 months in endemic areas.
Diagnosis of LTBI
The tuberculin skin test (TST) or IFN-γ release assays (IGRAs), there is variation in its use. Low risk: IGRA High risk: use both.
Diagnosis of Active TB Infection
1- Detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing. 2- Xpert MTB/RIF assay is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively. It also allows the simultaneous detection of rifampicin resistance.
PREVENTION
A) Risk Assessment of the Transplant Candidate
History of clinical or radiological TB and the treatment received should be assessed in all recipients.
If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA.
If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion
low risk for LTBI should preferably be tested solely with IGRA.
In high-risk candidates (ie, patients originated from endemic countries, household contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), both tests could be performed and any positive reaction considered an evidence of LTBI. Whenever this dual-test approach is used, IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses.
B) Risk Assessment of Deceased and Living Donors
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
The evaluation of the deceased donor for TB relies on: Medical history, Endemic exposures within the last 2 years, homeless or refugee status, incarceration and alcoholism may be associated with LTBI and Radiographic findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated
Oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
Other regimen pre-transplant: RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
Recommendations for Transplanted Patients Who Travel to Endemic Areas If recently transplanted patients are planning to move to a highly endemic area (ie, those with prevalence ≥100/ 100000), INH preventive therapy should be considered during the first post transplant year
There is no indication for BCG vaccine before travel, and it is contraindicated in transplant recipients
Treatment of Active TB Infection should follow local guidelines for the general population with 4 drug regimens.
Drug Interactions Rifamycins induce cytochrome P450 which lead to a reduction in the blood levels of most immunosuppressive drugs. Two to five fold increase in the dose is generally necessary to maintain trough levels of the drug. Therapeutic drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption.
***************
Level of evidence: Narrative review written 2017.
Funded by the Pan American Health organization (PAHO) and the Ministry of Health of Brazil.
It is important before it is use to look for higher level of evidence/ recent guidance.
Epidemiology in Latin America -TB is a public health problem worldwide. -Most countries in Latin America are moderately to highly endemic, with incidence remaining over 100 cases per 100 000 -In the last 2 decades, the prevalence and number of TB associated death decreased significantly by 50 % -Significant variations in the incidence based on notification.
–MDR infection is a global challenge, its prevalence of MDR is expectedly higher among patients in some Latin American countries. TB after SOT . -The risk is increased among SOT, being highest among lung recipients. – LA SOT centers, TB was diagnosed in 0.9% to 5.9% of the recipients, with some variations due to local prevalence – Most of the cases resulted from reactivation of latent TB, Also, primary TB infection reported in people live in endemic areas, minority acquired from donor transmission especially donors with untreated LTBI. International Travel and Posttransplant TB – Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB after SOT (the risk of donor transmission, and Travel-acquired infection) – Time spent in the endemic area influences the risk of TB infection – Humanitarian work with high-risk populations, – The use of public transportation in a high-incidence area and long distant flight. Diagnosis of LTBI – There is no diagnostic reference standard for LTBI. – Most current guidelines still recommend using tuberculin skin test TST for screening of LTBI in SOT. – IFN-γ release assays (IGRAs); offersome advantages as compared with TST but has some limitations. -IGRA is more sensitive and correlate better with clinical risk factor for LTBI. – Despite the NPP of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI – Variation in screening protocols for LTBI. – Some suggests; in low-risk patients to use IGRAs alone, in high-risk patients, both IGRA and TST used to maximize the sensitivity of screening. Diagnosis of Active TB Infection -It relies on the detection of M. tuberculosis bacilli by direct observation, by culture and nucleic acid testing. -Neither TST nor IGRAs are recommended for diagnosing active infection. – The diagnosis usually delayed in SOT, as they present with atypical manifestations, extrapulmonary involvement and frequent requirement to invasive diagnostic procedure. – Rapid molecular test (Xpert MTB/RIF assay): – It is highly specific and sensitivity – It is a useful rule-in diagnostic test for extrapulmonary TB. – Allows detection of rifampicin resistance, which is highly predictive of MDR-TB. – Limitations: false-positive results in successfully treated for TB and cannot replace conventional drug susceptibility tests.
Risk Assessment of the Transplant Candidate – A history of clinical or radiological TB and the treatment received should be assessed in all recipients. – Screening for LTBI; If there is no history of past TB or treatment for LTBI either TST or IGRA – Induration of > 5 mm is considered a positive reaction. – Low risk Candidates for LTBI tested solely with IGRA. – High-risk candidates both tests performed. –IGRA should be done before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses. – Active TB infection must be excluded in all candidates ( symptoms, radiologically). – Active infection should delay the transplantation till candidate is treated. Risk Assessment of Deceased and Living Donors – They undergo the same evaluation as candidates, with the exception that the cutoff for TST should be > 10 mm. – Reviewing medical history, exposure history and radiographic findings. – Organs from donors with known active TB infection should be discarded. – If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy should be immediately started . – Drug susceptibility tests should be performed on any M. tuberculosis specimen – Untreated LTBI without evidence of active infection is not a contraindication to donation, and preventive therapy to all recipients should be considered. -Donors with completed treatment for LTBI, recipients will require clinical monitoring without therapy. TREATMENT Treatment of LTBI in Transplant Candidates and Recipients
Indication : – Rule out active TB infection first. -Transplant candidates with positive TST or IGRA who have not been previously treated. – High-risk pre-transplant TB exposure even if the TST or IGRA is not positive. – History of active TB infection that was inadequately treated. – Chest imaging suggestive of previous untreated TB. – Donor has a history of untreated or incompletely treated LTBI or TB. -Recipient exposure to TB after transplantation. Therapeutic Regimens -Oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily. – Monitored for hepatotoxicity q 2 weeks for 6 weeks, then monthly. – Alternative regimens can be considered pre-transplant only RIF 600mg daily for 4 months or INH and rifapentine weekly for 12 weeks. Timing of Treatment -Should be started before transplant – If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible Travel to Endemic Areas – INH preventive therapy should be considered during the first posttransplant year. – There is no indication for BCG vaccine before travel, and it is contraindicated in transplant recipients. Treatment of Active TB Infection – Follow local guidelines for the general population. – 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB. – Treatment duration should be at least 9 months – Careful consideration to drug interaction and hepatotoxicity. – Treatment should be discontinued if ; 5-fold increase in liver enzymes regardless of symptomatology or 3-fold increase accompanied by any symptom. Drug Interactions -Rifamycins is cytochrome inducer that reduce the level of most immunosuppressive drugs used. – close monitoring dose adjustment are highly recommended to reduce the risk of rejection. – Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin. – Rifampicin is not contraindicated in SOT recipients. Level of Evidence: Level 5 narrative review
I like your summary, level of evidence, and analysis.
What is your comment in regards to the utility of TST nor IGRAs as a screening test or in diagnosing active infection.”
– Neither TST nor IGRAs are recommended for diagnosing active infection as both test may be falsely negative in active TB and immunocompromised patients, as these test assess the immune response of the body to MTB. -For LTBI either TST or IGRA can be used depend on the availability and the result should be interrupted with cautions. Both test can be negative in immunocompromised individuals. TST can be falsely positive if BCG vaccination received. IGRAsresult will not be affected by prior BCG vaccination, and it is more sensitive and correlate better with clinical risk factor for LTBI.
Summary of Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors by Guilherme Santoro-Lopes
TB AFTER SOLID-ORGAN TRANSPLANTATION
TB was diagnosed in 0.9% to 5.9% of the recipients.
The incidence rate of TB markedly increases after solid organ transplantation (SOT), the risk being highest among lung recipients.
Reactivation of foci of latent TB infection (LTBI) is probably the main cause of posttransplant TB. Primary infection acquired in the community, and less frequently in the nosocomial environment.
A minor proportion of primary infections result from donor-recipient transmission. Most of these cases were documented in patients who received a graft from a deceased donor with active TB infection, a situation that has been associated with a risk of transmission of approximately 30%.
DIAGNOSIS
Diagnosis of LTBI: There is no diagnostic reference standard for LTBI.
· The tuberculin skin test (TST) remains the best studied test. Most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.
· 2 IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade. They offer some advantages as compared with TST:
Ø Advantages:
§ Avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination,
§ Sensitive in candidates with chronic renal failure and advanced cirrhosis.
Ø Disadvantages:
§ The negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI, which includes those who were born to or lived in endemic countries, household contacts of a case of active TB infection, and those who work or live in high-risk settings, such as prisons and homeless shelters.
§ Higher cost
§ Frequent occurrence of conversions and reversions of test results when serial screening is performed.
In low-risk patients, IGRAs could be considered as the sole approach.
In the high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
Diagnosis of Active TB Infection:
· Neither TST nor IGRAs are recommended for diagnosing active infection.
· The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing.
· Invasive diagnostic procedures are more frequently required in this population, resulting in a delay of the proper diagnosis and higher mortality.
· Rapid molecular test, such as the Xpert MTB/RIF assay, may have a major impact in the management of these patients. This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively. It also allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB. One limitation of this assay is that false-positive results have been observed among patients who had been successfully treated for TB.
PREVENTION
Risk Assessment of the Transplant Candidate
· A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
· If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA. If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction.
· In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
· Candidates who have low risk for LTBI should preferably be tested solely with IGRA.
· In high-risk candidates (ie, patients originated from endemic countries, household contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), both tests could be performed, and any positive reaction considered evidence of LTBI.
Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
If any evidence of active infection is found in workup, appropriate clinical specimens should be collected for microbiological confirmation of the diagnosis.
Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative. Nevertheless, active infection may not be considered an absolute contraindication to transplantation for candidates who urgently need it.
Risk Assessment of Deceased and Living Donors
Living donors should undergo the same evaluation as candidates, with the exception that the cut-off for TST should be 10 mm or greater.
The evaluation of the deceased donor for TB relies on:
• Medical history. The history of untreated TB should be investigated, as well as previous reactive IGRA or TST. Endemic exposures. Travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the last 2 years, homeless or refugee status, incarceration and alcoholism may be associated with LTBI.
• Radiographic findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening.
Active TB infection should be ruled out in donors at increased risk by obtaining samples, for example, sputum or bronchoalveolar lavage, to test for the presence of M. tuberculosis. Because the results of microbiological investigation will more often be available after procurement, it must be ensured that all data will be forwarded to transplant teams as soon as possible to enable appropriate actions. Organs from donors with known active TB infection should be discarded.
If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines. Drug susceptibility tests should be performed.
Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
Lungs with residual tuberculous lesions should not be used for transplantation.
A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, especially for lung recipients.
The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, therefore, transplant recipients from such donors can be clinically monitored without receiving LTBI therapy.
TREATMENT Treatment of LTBI in Transplant Candidates and Recipients
Criteria to Start Treatment Therapy for LTBI
LTBI therapy is recommended for:
· Transplant candidates with positive TST or IGRA who have not been previously treated.
· Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive,
· Those with history of active TB infection that was inadequately treated.
· Chest imaging suggestive of previous untreated TB should prompt consideration for therapy, especially in areas where endemic mycoses are uncommon.
· Transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB.
· If the recipient is exposed to TB after transplantation.
Therapeutic Regimens For treatment of LTBI:
· The preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily. Nine months of therapy is preferred over 6 months because of better protection. Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine aminotransferase checked every 2 weeks for 6 weeks, then monthly thereafter.
· Alternative regimens containing rifamycins can be considered pre-transplant but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
· Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
Timing of Treatment
· When possible, treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist.
· If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible until completion of the originally planned course, with the caveat that rifamycins are usually avoided after transplant.
Recommendations for Transplanted Patients Who Travel to Endemic Areas
· If recently transplanted patients are planning to move to a highly endemic area, INH preventive therapy should be considered during the first posttransplant year.
· Transplant recipients who are traveling to TB endemic areas to provide medical or humanitarian care should follow standard precautions to prevent nosocomial acquisition of infection.
· Those with possible TB exposure should be evaluated on return, and anyone with symptoms of infection should seek medical evaluation immediately.
Treatment of Active TB Infection
Treatment should follow local guidelines for the general population.
The number of drugs used in the intensive phase regimen should be defined per the prevalence of drug resistance in each population. Nevertheless, in most cases, a 4-drug regimen is recommended.
· INH and rifampicin are the most powerful first-line drugs against TB.
· The optimal length of treatment of TB in transplant recipients is not defined. Many specialists recommend that treatment duration should be at least 9 months.
Monitoring of Adverse Events Related to Therapy
· Close monitoring is highly recommended, mainly during the first 2 months of treatment when it should be performed biweekly.
· Low-grade elevation of aminotransferases can be observed during the first 2 months of treatment, but a 3-fold increase accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation.
Drug Interactions
Rifamycins have an induction effect on different drug metabolizing enzyme systems, most notably the cytochrome P450 (CYP) 3A4, which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids). A lower blood level of these drugs is associated with higher risk of graft rejection. Therefore, close monitoring and continuous dose adjustment are highly recommended.
Therapeutic drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption.
Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin. Nonetheless, the same recommendation for close therapeutic drug monitoring of these immunosuppressive drugs apply when rifabutin is used.
I like your very detailed summary, level of evidence, and analysis. Why do you state that, “Neither TST nor IGRAs are recommended for diagnosing active infection.”
Do you think you would like to use a test or battery of tests with good likelihood ratio of >10, rather than those with high predictive value, of diagnosing TB in an immuno-suppressed patients?
Although it remained a major pubic health problem, the prevalence has reduced by ~50% in latent America. Development of multi-drug resistant TB (MDR) is another challenge with prevalence mostly below 3%.
TB after solid-organ transplantation
The diagnosis was made in ~0.9% to 5%
Transmission mainly by latent infection reactivation and less commonly donor drive (deceased donor)
Risk factors
Immigration & traveling to endemic areas
Means of traveling may be a risk e.g., long distance flight or public transportation
Time spent in endemic areas e.g., > 3 months
Deceased donor
Humanitarian work with high risk population e.g., homeless, or prisoners
Diagnosis
1.Latent TB
No gold standard diagnostic test
Interferon gama release assays (IGRAs) may have advantage over the older tuberculin skin test (TST) but poor negative predictive value to rule out LTBI
In general consider IGRAs for low risk patient and both IGRAs & TST for high risk patient
2.Active tuberculosis
Detection of bacilli by direct observation, culture, & nucleic acid testing but the problem is suspicion of the diagnosis because of atypical presentation, and diverse clinical manifestation. All these may lead to late diagnosis and increase mortality
The rapid molecular test or Xpert MTB/RIF may be useful(specific & sensitive) and it has the advantage of detecting rifampicin resistant which may predict the diagnosis of MDR-TB. The only problem is false positive in patient previously treated for TB
Prevention
1.Risk assessment of the transplant candidate
Clinical history
Radiological Assessments
Evaluation for LTBI by IGRAs for low risk & both IGRAs & TST for high risk (cut off for TST is 5 mm and should be repeated after one week)
Exclude active TB before treatment of LTBI
Active TB is relative contra-indication to transplantation, depending on the patient profile the transplant may be hold or it may proceed
2.Risk assessment of the deceased and living donors
The living donor is evaluated the same way as the recipient except that the cut off for TST is 10 mm
The evaluation of the deceased donor depend on;
Medical history including previous IGRA,TST
Endemic exposure e.g living in endemic areas or travelling into it
Radiolographic changes e,g nodules, calcified nodes or pleural thickening
Rules of deceased donation;
*Donor organ with active TB should be discarded
*If the diagnosis of donor TB is established after transplantation, the recipient should be treat immediately according to the local guidelines
*MDR TB testing should be carried on all donor microbiological specimens
*Organs from donor treated for TB for at least 6 months can be accepted for transplantation
*Untreated LTBI without evidence of active infection is not contraindication to donation, but preventive therapy should be given to all recipients
*In a case of treated LTBI, the risk of transmission is low and therefore, all recipients for such donors should only be monitored without any treatments
Treatment
1.Latent infection(LTBI)
Exclude active TB
INH 300 mg daily plus pyridoxine 25 to 50 mg for 9 months
Pre transplant can get rifamycin based regimen
Monitor LFTs
The best time to treat is before transplantation
Consider INH preventive therapy for those who are traveling to endemic area =>100/ 100,000
2.Active TB
According to local guidelines
4 drug regimen is recommended
INH + Rifampicin are the most strong first-line
Keep an eye on hepatotoxicity & drug -drug interactions (rifampicin is a potent enzyme inducer, rifabutin may be weaker and effective for treatment of TB)
I like your summary, level of evidence, analysis and take home messages. How would you envisage doing the following and I quote your suggestion, “MDR TB testing should be carried on all donor microbiological specimens.” If we wait for this report, we would miss those cadaveric donors. What kind of screening program would you suggest that all those clinicians (stakeholders) can be informed well in time?
The idea is failure to diagnose MDR may have serious implications on the recipients
You may not need , but any tests on donor specimens should be followed up, reported and effectively communicated to the transplant team as early as possible
This article discusses tuberculosis (TB) in SOTR and donors. This is particularly important because the risk of tuberculosis increases after SOT, notably for lung transplant recipients.
The incidence of tuberculosis in SOTR typically results from the reactivation of latent TB. Due to the recipient’s immunocompromised state, both nosocomial and primary infections from the environment are also conceivable. A limited percentage of cases can be transmitted by donors.
Discussion
A recipient’s risk of contracting tuberculosis (TB) may be increased by travel from endemic TB countries. Immigration influences the risk of donor-transmitted diseases.
Current guidelines advise screening for LTBI in both SOT recipients and living donors. This is accomplished with the tuberculin skin test, or TST. The IFN-gamma release assay is a contemporary diagnostic instrument. The latter instrument has advantages over the TST, such as avoiding interpretation bias and reducing false-positive results associated with prior TB or BCG vaccination exposure. In some centers, the higher cost of conducting these assays can be a deterrent, preventing standardization.
Recommendations include administering IGRA alone to patients at low risk and both TST and IGRA to patients at high risk. In order to maximize the sensitivity and accuracy of screening protocols, this is performed.
TB infection is diagnosed by directly detecting Mycobacterium tuberculosis bacilli through culture and nucleic acid testing. IGRA and TST are not recommended for the patient’s active TB infection diagnosis.
The extrapulmonary manifestation of tuberculosis in SOT recipients is an additional factor to consider. This is typically more difficult to diagnose than the classic presentation of tuberculosis. One recommendation is to consider tuberculosis in patients with an unexplained fever. Due to its high specificity and sensitivity, the availability of an MTB/RIF assay can aid in the management of these patients.
False-positive results in patients who have been successfully treated for tuberculosis are among the limitations of this method of diagnosis.
Preventive and therapeutic measures
Prevention of tuberculosis in the recipient requires a thorough evaluation of the donor, including IGRA and TST. Additionally, appropriate risk assessment profiles must be created to prevent both donor transmission and primary incidence in the recipient from other sources.
Oral INH 300 mg per day for nine months, along with oral pyridoxine 25–50 mg per day An extended period of nine months is preferred to six months because it provides greater patient protection.
Monitoring for hepatotoxicity is essential in these patients, with serum ALT being measured every two weeks for the first six weeks and then every month thereafter.
Alternative regimens Pre-transplant medications include rifamycin, which should be avoided post-transplant to prevent drug-drug interactions. Fluoroquinolones are recommended for the treatment of LTBI.
Level of evidence 5
TB after solid organ transplantation
The incidence of TB increased among SOT recipients, the highest incidence in lung transplant recipients.
Reactivation of latent TB infection is the main cause of post-transplant TB. Primary infection which is acquired in the community is responsible for a considerable proportion of the cases especially in endemic areas, a minor portion of primary infections may result from donor-recipient transmission especially in cases of deceased donor with active TB infection or donor with untreated latent TB
International travel and post-transplant TB
International travel to endemic areas may affect the risk of TB after SOT.
Transplant recipients originating from endemic areas have a higher prevelance of LTBI so they are at an increased risk of developing active TB infection after SOT.
Transplant recipients from low incidence countries may exposed to primary infection while traveling to endemic areal. Long time spent in the endemic area , work with high risk population as prisoners increase risk of infection.
Diagnosis of latent TB infection
Tuberculin skin test is the best test for screening of LTBI in solid organ transplant recipients and donors.
IGRAs is a new diagnostic tool that offers some advantages over tuberculin test ( avoid interpretating bias, reduce false positive results related to previous exposure to non tuberculous mycobacterium or BCG vaccination and more sensitive in patients with advanced cirrhosis and CKD patients. But the negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI.
So in low risk patient,IGRAs could be the sole approach
In high risk patient both test should be performed and one of them positive is satisfactory
Diagnosis of TB infection
By detection of organism by direct observation, by culture, by nucleic acid testing.
Risk assessment of transplant recipients
History of clinical or radiological TB, history of treatment
If there is no history , test for LTBI by TST ( induration 5 mm or greater after 48 hous considered positive, IGRAs
Risk assessment of donor
As recipients but the induration more than 10 mm considered positive
Treatment
Treatment of transplant candidates with positive TST or IGRAs is recommended.
Those with high pretransplant TB exposure should be considered even if the screening test are negative
Those with history of inadequate treatment of active TB
Recipients of donor who are inadequately treated
For treatment of LTBI, the preferred regimen is oral INH for 9 months along with oral pyridoxine
The patient should be monitored for hepatoxicity
If recently transplant recipients are planning to move to high endemic area ,INH preventive treatment should be considered
Treatment of active TB
INH and Rifampcin are most powerful first line drug for 9 months ,hepatoxicity should be considered and drug interactions of Rifampcin
Level of evidence 5
There is no diagnostic standard test for LTBI and the tuberculin skin test remains the best studied test. The current guidelines recommend its use for the screening of LTBI in solid organ transplantation
IFN-γ release assays (IGRAs) can avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients.But the negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI. It has higher cost and the frequent occurrence of conversions and reversions of test results when serial screening is performed, which may complicate the interpretation of their results among SOT candidates. In low-risk patients, IGRAs could be considered as the sole approach. In high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture and nucleic acid testing. Neither TST nor IGRAs are recommended for diagnosing active infection. TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin. The Xpert MTB/RIF assay, is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively. Xpert MTB/ RIF assay is a useful rule-in diagnostic test for extrapulmonary TB. It also allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB. One limitation of this assay is that false-positive results have been observed among patients who had been successfully treated for TB and it cannot fully replace the execution of conventional drug susceptibility tests.
Prevention is through risk assessment using history of clinical or radiological TB and the treatment received. If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA. If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion. Candidates who have low risk for LTBI should preferably be tested solely with IGRA. In high-risk candidates (ie, patients originated from endemic countries, household contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), both tests could be performed and any positive reaction considered an evidence of LTBI. Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started. This evaluation includes checking the presence of symptoms and signs suggestive of TB, performing a chest radiograph and, in cases with extrapulmonary manifestations, imaging of other body sites. If any evidence of active infection is found in this workup, appropriate clinical specimens should be collected for microbiological confirmation of the diagnosis. Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
Risk assessment of deceased and living donors living donors should undergo the same evaluation with the exception that the cutoff for TST should be 10 mm or greater. Organs from donors with known active TB infection should be discarded. If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines. Drug susceptibility tests should be performed on any M. tuberculosis specimen isolated from the donor, since the detection of drug resistance may be of critical importance for guiding therapy in the recipients. Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted. Lungs with residual tuberculous lesions should not be used for transplantation. A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, especially for lung recipients. The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, therefore, transplant recipients from such donors can be clinically monitored without receiving LTBI therapy.
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated. the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily. Nine months of therapy is preferred over 6 months because of better protection. Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine aminotransferase checked every 2 weeks for 6 weeks, then monthly thereafter. Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks. Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy. When possible, treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist. If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible until completion of the originally planned course, with the caveat that rifamycins are usually avoided after transplant. If recently transplanted patients are planning to move to a highly endemic area (ie, those with prevalence ≥100/ 100000), INH preventive therapy should be considered during the first posttransplant year, especially for those planning to take part in medical or humanitarian care, given the higher risk of primary TB acquisition. There is no indication for BCG vaccine before travel, and it is contraindicated in transplant recipients.
Treatment of active TB infection should follow local guidelines for the general population.in most cases, a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB for at least 9 months. close monitoring is highly recommended, mainly during the first 2 months of treatment when it should be performed biweekly.
Rifampin has the most potent enzyme induction effect. Two to 5-fold increments in the daily dose of cyclosporine, tacrolimus, and mammalian target of rapamycin inhibitors are generally necessary to maintain trough levels of the drug in the therapeutic range. Although enzyme induction start within hours after the first dose of rifampin, maximum effect is reached in about 1 to 2 weeks and slowly declines over 2 weeks after stopping its use.
level of evidence is V
This is a narrative review of level 5 evidence regarding :
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors.
The incidence rate of TB infection is increased after solid organ transplantation SOT.
-Guidelines recommend that in low-risk patients IFN-γ release assays (IGRAs ) should be considered as the preferred method.
Active TB Infection culture, and nucleic acid testing , Xpert MTB/RIF assay is highly specific
Treatment of in Transplant Candidates and Recipients:
– The preferred regimen for LTBI is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
– Alternative regimens containing rifampicin can be considered pre-transplant, these regimens include RIF 600mg daily for 4 months or INH and rifapentine weekly for 12 weeks( Rifabutin has an advantage over Rifampicin that it is less drug inducer but still drugs should be monitored)
1- Summarise this article.
The estimated absolute number of prevalent cases in the latin countries are declined from approximately 600000 to 342000 between years 1990 and 2014, with a parallel reduction in the
number of TB-associated deaths from 43000 to 22. Nevertheless, TB remains a relevant public health problem in this region.
Emergence of multidrug-resistant (MDR) TB, which is a resistance to rifampicin and isoniazid (INH), is a global challenge. It is about 3% in most countries of this region.
TB AFTER SOLID-ORGAN TRANSPLANTATION
The incidence of TB increases after transplantation (SOT), the risk is highest in
lung transplantation.
In one study, TB incidence is 0.9% to 5.9% of the recipients.
Reactivation of latent TB infection is the main cause of post-transplant TB.
International Travel and Post-transplant TB:
Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB after transplantation.
Transplant candidates originating from endemic areas have a higher prevalence of LTBI and are, hence, at an increased risk of developing active TB infection after SOT.
DIAGNOSIS:
Diagnosis of LTBI:
There is no diagnostic reference standard for LTBI. The tuberculin skin test (TST) remains the best studied test. IFN release assays (IGRAs) have emerged as new diagnostic tools in the last decade.
However, despite their better yield, thenegative predictive value of IGRAs is not optimal to rule out infection.
Diagnosis of Active TB Infection:
The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing. Neither TST nor IGRAs are recommended for diagnosing active infection.
PREVENTION:
Risk Assessment of the Transplant Candidate
A history of clinical or radiological TB and the treatment received should be assessed in all recipients. If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TSTor IGRA.
the screening strategy may be adapted per the patient’s characteristics. Candi
dates who have low risk for LTBI should preferably be tested solely with IGRA. In high-risk candidates , both tests could be performed and any positive reaction considered an evidence of LTBI.
Active TB infectionmust be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
Risk Assessment of Deceased and Living Donors:
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
The evaluation of the deceased donor for TB relies on:
1- Medical history.
2- Endemic exposures.
3- Radiographic findings.
Time does not allow for a TST and IGRAs have not been validated in deceased donors. Active TB infection should be ruled out in donors at increased risk by obtaining samples, for example, sputum or bronchoalveolar lavage, to test for the presence of M. tuberculosis.
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients
Criteria to Start Treatment:
Therapy for LTBI is an effective strategy for the prevention of active TB infection in transplant recipients.
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated. Chest imaging suggestive of previous untreated TB should prompt consideration for therapy.
Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
In considering treatment for LTBI, it is imperative to first rule out active TB infection.
Therapeutic Regimens:
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
Nine months of therapy is preferred over 6months because of better protection.
Alternative regimens containing rifamycins can be considered pre-transplant, but should be avoided post-transplant because of immunosuppressive drug interactions. These regimens include RIF 600mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
Treatment of Active TB Infection:
Treatment should follow local guidelines for the general population. A 4-drug regimen is recommended.
INH and rifampicin are the most powerful first-line drugs against TB.
In renal transplantation , the hepatotoxicity related to the antituberculous
treatment and drug interactions of rifampicin should be kept in mind .
The optimal length of treatment of TB in transplant recipients is not defined. Many specialists recommend that treatment duration should be at least 9 months,
2- What is the level of evidence provided by this article?
The level is five.
Summarise this article
TB AFTER SOLID-ORGAN TRANSPLANTATION-
The incidence rate of TB markedly increases after solid organ transplantation (SOT)5 the risk being highest among lung recipients.Reactivation of foci of latent TB infection (LTBI) is probably the main cause of posttransplant TB. Primary infection acquired in the community, and less frequently in the nosocomial environment, may also account for a considerable proportion of the cases, especially among patients living in endemic areas.A minor proportion of primary infections result from donor-recipient transmission. Most of these cases were documented in patients who received a graft from a deceased donor with active TB infection, a situation that has been associated with a risk of transmission of approximately 30%
Diagnosis of LTBI
The tuberculin skin test (TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.2 IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade. They offer some advantages as compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis. Negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI.Thus, in low-risk patients, IGRAs could be considered as the sole approach, because the use of a more specific test might reduce the rate of false-positive results and, consequently, the number of patients who will unnecessarily be exposed to LTBI therapy. On the other hand, in high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
Diagnosis of Active TB Infection
The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture.and nucleic acid testing. Neither TST nor IGRAs are recommended for diagnosing active infection.In this regard, the availability of a rapid molecular test, such as the Xpert MTB/RIF assay, may have a major impact in the management of these patients. This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively. A similar performance has been observed when testing nonrespiratory samples, such as tissue biopsies and cerebrospinal fluid, indicating that Xpert MTB/ RIF assay is a useful rule-in diagnostic test for extrapulmonary TB.It also allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB. One limitation of this assay is that false-positive results have been observed among patients who had been successfully treated for TB.
Risk Assessment of the Transplant Candidate
If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA. If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion. . Whenever this dual-test approach is used, IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses.Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
Risk Assessment of Deceased and Living Donors
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
The evaluation of the deceased donor for TB relies on:Medical history,Endemic exposures-Travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the last 2 years and Radiographic findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening.Active TB infection should be ruled out in donors at increased risk by obtaining samples, for example, sputum or bronchoalveolar lavage, to test for the presence of M. tuberculosis. Because the results of microbiological investigation will more often be available after procurement, it must be ensured that all data will be forwarded to transplant teams as soon as possible to enable appropriate actions.Organs from donors with known active TB infection should be discarded.
Treatment of LTBI in Transplant Candidates and Recipients
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated .Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated. Chest imaging suggestive of previous untreated TB should prompt consideration for therapy, especially in areas where endemic mycoses are uncommon.Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.In considering treatment for LTBI, it is imperative to first rule out active TB infection.For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
Treatment of Active TB Infection
, In most cases, a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB. The optimal length of treatment of TB in transplant recipients is not defined. Many specialists recommend that treatment duration should be at least 9 months, based on the results of a few studies that have suggested an association between shorter regimens and greater recurrence and mortality
What is the level of evidence provided by this article?
Level 5
In the last 2 decades, the burden of tuberculosis (TB) has been considerably reduced in Latin America (LA) countries. The estimated absolute number of prevalent cases in the re- gion declined from approximately 600000 to 342000 be- tween years 1990 and 2014, with a parallel reduction in the number of TB-associated deaths from 43000 to 22000.1 Nevertheless, TB remains a relevant public health problem in this region. Per World Health Organization estimates for 2014,2 Brazil remains in the group of 22 countries with the highest TB burden in the world, with 110 000 prevalent cases and 7700 TB deaths.
TBAFTERSOLID-ORGANTRANSPLANTATION The incidence rate of TB markedly increases after solid organ transplantation (SOT), the risk being highest among lung recipients.4 The proportion of patients affected by active TB infection also varies widely among transplant centers in correspondence with the local prevalence of the disease. In studies carried out in LA SOT centers in the last decade, TB was diagnosed in 0.9% to 5.9% of the recipients.
DIAGNOSIS Diagnosis of LTBI Thereis nodiagnostic reference standard for LTBI. Thetuberculin skin test (TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors. IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade. They offer some advantages as compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients.
Diagnosis of Active TB Infection The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture and nucleic acid testing. Neither TST nor IGRAs are recommended for diagnosing active infection. Probably the most challenging situation lies on the clinical suspicion of active infection. SOT recipients may present unusual manifestations, with a greater proportion of extrapulmonary involvement. TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin. Invasive diagnostic procedures are more frequently required in this population, resulting in a delayofthe properdiagnosis and higher mortality.
Risk Assessment of the Transplant Candidate Ahistory of clinical or radiological TB and the treatment received should be assessed in all recipients. If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TSTor IGRA. IfTSTis selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
TREATMENT Treatment of LTBI in Transplant Candidates and Recipients Criteria to Start Treatment Therapy for LTBIisaneffective strategy for the prevention of active TB infection in transplant recipients.49,50 LTBI therapy is recommended for transplant candidates with positive TST or IGRAwho have not been previously treated. Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated.
Level 5
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
Guilherme S and colleagues in this review article examines the recommendations for the management of tuberculosis for organ transplant recipients and donors.
EPIDEMIOLOGY
Epidemiology in Latin America
In the last 2 decades, the burden of tuberculosis (TB) has been considerably reduced in Latin America (LA) countries. Although the estimated proportion of MDR infection among new TB cases remains below 3% in most countries of the region, higher prevalence (between 3.0% and 6.0%) has been found in Ecuador, Guatemala, and Peru. Emergence of multidrug-resistant (MDR) TB, which is defined by the isolation of a causative strain of Mycobacterium tuberculosis resistant to rifampicin and isoniazid (INH), is a global challenge. Recent reports from the latter country provide evidence of ongoing community transmission of MDR infection with significant impact on mortality. Moreover, the prevalence of MDR infection is expectedly higher among patients who were previously treated for TB. In those 3 countries, this prevalence has been estimated to range from 20% to 26%.
TB AFTER SOLID-ORGAN TRANSPLANTATION
The incidence rate of TB markedly increases after solid organ transplantation (SOT), the risk being highest among lung recipients. The proportion of patients affected by active TB infection also varies widely among transplant centers in correspondence with the local prevalence of the disease. In studies carried out in LA SOT centers in the last decade, TB was diagnosed in 0.9% to 5.9% of the recipients.
International Travel and Posttransplant TB
Transplant recipients from low-incidence countries may be exposed to primary infection while traveling to an endemic area. Among immunocompetent travelers returning from endemic countries, the estimated risk of acquisition of TB infection has generally ranged from 0.4% to 2.0%.20-22 Higher rates (1.8% to 4.2%) were reported among travelers who were involved in healthcare or academic medical exchange programs.
Transplant candidates originating from endemic areas have a higher prevalence of LTBI and are, hence are at an increased risk of developing active TB infection after SOT.
DIAGNOSIS
Diagnosis of LTBI
There is no diagnostic reference standard for LTBI. Most current guidelines still recommend tuberculin skin testing for the screening of LTBI in solid organ candidates/recipients and living donor.
IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade. It has numerous advantages over tuberculin skin testing because it: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination. They are also probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients. Despite these advantages, the negative predictive value is not sufficient to rule out LTBI in high-risk patients such as those who were born to or lived in endemic countries, household contacts of a case of active TB infection, and those who work or live in high-risk settings, such as correctional facilities and homeless shelters. Other limitations of these assays include their higher cost and the frequent occurrence of conversions and reversions of test results when serial screening is performed, which may complicate the interpretation of their results among SOT candidates.
Diagnosis of Active TB Infection
The diagnosis of active TB infection relies on high index clinical suspicion and the detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing. SOT recipients may present unusual manifestations, with a greater proportion of extrapulmonary involvement. TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin. Invasive diagnostic procedures are more frequently required in this population, resulting in a delay of the proper diagnosis and higher mortality.
PREVENTION
Risk Assessment of the Transplant Candidate
First step is adequate and thorough history including radiological investigations in the past. If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA. If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
Candidates who have low risk for LTBI should preferably be tested solely with IGRA. In high-risk candidates (i.e., patients originated from endemic countries, household contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), both tests could be performed, and any positive reaction considered evidence of LTBI. Whenever this dual-test approach is used, IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses.
Treatment of LTBI should be commenced only when active TB has been excluded. Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative. Despite this, active infection may not be an absolute contraindication when transplantation is urgently needed.
Risk Assessment of Deceased and Living Donors
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater. The evaluation of the deceased donor for TB relies on: thorough history, physical examination and radiological testing. Organs from donors with known active TB infection should be discarded. If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines. Drug susceptibility tests should be performed on any M. tuberculosis specimen isolated from the donor, since the detection of drug resistance may be of critical importance for guiding therapy in the recipients. Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted. Lungs with residual tuberculous lesions should not be used for transplantation. A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, especially for lung recipients.
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients
Criteria to Start Treatment
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated. Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated. Chest imaging suggestive of previous untreated TB should prompt consideration for therapy, especially in areas where endemic mycoses are uncommon. Treatment is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
Therapeutic Regimens
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily. Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine aminotransferase checked every 2 weeks for 6 weeks, then monthly thereafter. Alternative regimens containing rifamycins can be considered pretransplant but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks. Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
Timing of Treatment
Balancing the risk of infection and benefit of transplantation is important. It’s preferred to treat before transplantation but urgent need for transplantation might warrant treatment commencing in the perioperative period.
Recommendations for Transplanted Patients Who Travel to Endemic Areas
Those traveling to endemic regions after transplantation should use INH prophylaxis in the first post-transplant year. BCG vaccination is contraindicated. Those with possible TB exposure should be evaluated on return, and anyone with symptoms of infection should seek medical evaluation immediately.
Treatment of Active TB Infection
Treatment should follow local guideline just like in general population. However, there is need for monitoring for drug interaction and toxicity.
Level V
Summary
Introduction:
TB is a public health problem . The burden of TB has reduced in the Latin American continent in the last few decades. However, according to WHO classification, Brazil remains one of the countries with highest burden of the disease with 110,000 prevalence for disease and 7700 for TB death. The national incidence varies from as low as 11 cases per 100000 in the capital city to as high as 300 per 100000 in lower socio-economic communities. A more challenging issue is the emergence of MDR which is known to be common in those previously treated with TB. Reactivation of latent TB is the main cause of post-transplant TB, primary infection and infection from donor-recipient transmission are less common.
Latent TB diagnosis:
TST is recommended for diagnosing latent TB but IGRA is new and has some advantages; avoidance of interpreting bias, less false positive results and more sensitive in CKD and liver cirrhosis.
TST alone used in 48% ; IGRA alone in 30% .
TST with IGRA in 16%.
TST then IGRA in 6% cases.
Active TB diagnosis:
-Risk assessment of transplant patient-recipients:
. Active TB infection to be excluded from transplantation.
-Risk assessment of transplant patient-donors and diseased donor:
-Treatment for LTBI in transplant & recipient:
-Treatment of active infection:
Based on the general local guidelines has been advised that the treatment should not less than 9 months. The treatment includes intensive phase (INH plus RIF plus PYRAZINAMIDE plus EHTAMBUTO), for 2 months, followed by 6 to 9 months of maintenance phase of INH plus RIF.
-Monitoring of adverse events:
· Hepatotoxicity ,if liver enzymes increase by 3 – 5 fold ,therapy to be stopped..
· Rifampicin drug -drug interaction with CNIs, mTORs& corticosteroids by reducing trough level and may result in allograft rejection and/or loss.
Level of evidence: V.
1. Summarise this article
Epidemiology of tuberculosis (TB): TB burden in Latin America although reducing, is still high with Brazil, having the highest burden of TB in the world. Variable prevalence in different geographical areas is seen; multi-drug resistant strain (MDR-TB) especially in previously treated patients, is emerging at high prevalence (20-26%).
TB after solid organ transplantation (SOT): Incidence of TB post-SOT is increased from 0.9% to 5.9% in LA countries, highest after lung transplant. The main cause of post-transplant TB is reactivation of latent TB infection (LTBI), but it could be due to a primary infection or a donor-derived infection.
International travel and post-transplant TB: Travel to TB endemic regions can increase risk of exposure to TB (0.4-2%); increases to 1.8-4.2% in healthcare workers. Prospective recipients and donors from TB endemic regions have high prevalence of LTBI. A higher risk has been seen with cumulative history of travel to high-incidence area for more than 3 months. Public transportation has also been shown to be a risk factor for TB transmission.
Diagnosis of LTBI: There is no standard diagnostic test for LTBI. Tuberculin skin test (TST) and interferon gamma release assay (IGRA) are used for screening. IGRA increased sensitivity in CKD, CLD, reduced false positives without interpretation bias, but its negative predictive value is not optimal (can’t rule out LTBI in high-risk patients). In low-risk patients, IGRA alone can be used. In high-risk patients, both TST and IGRA should be used – any positive result should be taken as evidence of LTBI.
Diagnosis of Active TB requires either microscopic observation, culture, or nucleic acid testing (NAAT). As patients may have atypical presentation, high index of suspicion is required. Rapid molecular test (Gene X-pert / TB-Gold) is highly specific with good sensitivity (98% in smear positive and 67% in smear negative) in respiratory samples as well as non-respiratory samples (extrapulmonary TB). It also helps detection of rifampicin resistance. False-positive results are seen in patients previously treated for TB.
Risk assessment of transplant candidate:
· Detail evaluation of prospective transplant recipients should include clinical history, radiological findings and treatment received.
· In absence of clinical history – LTBI evaluation in form of TST (>5mm induration at 48-72 hours) or IGRA should be done. A second TST after 7-10 days of first TST should be done to assess boosted-related skin conversion.
· It is preferable to use IGRA alone for low-risk candidates, and combination of IGRA (performed first) and TST for high-risk candidates.
· Active TB evaluation involves checking symptoms and signs, imaging, and microbiological tests.
· Transplantation should be postponed till an active TB is fully treated.
Risk assessment of donors:
· Living donors should be evaluated like the recipient, with TST cut off >10mm induration at 48-72 hours.
· Deceased donor evaluation includes medical history, history of exposure to TB patient, and radiological findings, and ruling out active TB by taking samples for M. tuberculosis testing.
· Donors with known active TB should be declined.
· Donors with history of TB successfully treated for 6 months can be accepted.
· Donor with untreated LTBI can be accepted with preventive therapy administration to the recipient, especially lung recipient.
Treatment:
LTBI in transplant candidates and post-transplant recipients should be treated, if
· positive TST or IGRA, and not received ATT before
· High-risk pre-transplant exposure
· history of inadequately treated active TB
· chest imaging showing previous untreated TB
· exposed to TB after transplant
· donor had any history of untreated, incompletely treated LTBI or TB.
Treatment of LTBI involves INH (+pyridoxine) for 9 months, or INH + Rifampicin weekly once for 3months or Rifampicin alone daily for 4 months.
Whenever possible LTBI should be treated pre-transplant, with preferably combined regimen. Isoniazid preventive therapy should be given to those travelling to endemic areas, and they should be evaluated on their return, if symptomatic.
Treatment of active TB infection should follow local TB guidelines according to sensitivity – involves intensive phase of 4 drugs regimen, and drugs (preferably Rifampicin + INH); total duration of therapy for at least 9 months in transplant recipients.
Monitoring of liver enzymes every 2weekly x 6 weeks, then monthly thereafter. Hepatotoxicity – 5 times rise of liver enzymes or 3 times rise with symptoms, warrants stopping of ATT.
Drug interactions with rifampicin in transplant recipients is important due to effect on CYP3A4, requiring increase in doses of calcineurin inhibitors, mTOR inhibitors, and steroids. Rifabutin, with limited enzyme induction, can be used in place of rifampicin.
2. What is the level of evidence provided by this article?
Level of evidence: level 5 – Narrative review.
TB AFTER SOT
●The incidence rate of TB markedly increases after (SOT),
● It may corresponde with the local prevalence of the disease.
● In studies in LA SOT centers in the last decade, TB was diagnosed in 0.9% to 5.9% of the recipients.
● Reactivation of foci of (LTBI) is probably the main cause of posttransplant TB.
● A minor proportion of primary infections result from donor-recipient transmission.
●Most of these cases were in patients who received a graft from deceased donor with active TB infection
● a risk of transmission of approximately 30%.
the influence of donor LTBI on the risk of posttransplant TB is undetermined yet.
DIAGNOSIS
There’s nodiagnostic reference standard for LTBI.
■(TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.
■(IGRAs) have emerged as new diagnostic tools in the last decade.
advantages
♡avoid interpreting bias,
♡ reduce false-positive
♡more sensitive in candidates with chronic renal failure and advanced cirrhosis,
◇ the negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high riskf or LTBI
Per a recent European survey,
•TST alone was used in 48%
•IGRA alone in 30%,
•TSTand IGRA simultaneously in 16%
• TST followed by IGRA in 6%.
●In low-risk patients, IGRAs could be considered as the sole approach,
.
● In high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening
Diagnosis of Active TB Infection
○the detection by direct observation, by culture, and nucleic acid testing.
○Neither TST nor IGRAs are recommended for diagnosing active infection.
○The availability of a rapid molecular test, such as the Xpert MTB/RIF assay, may have a major impact in the management
the Xpert MTB/RIF assay
□It is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98%and67%,respectively.
□Testing non respiratory samples, such as tissue biopsies and cerebrospinal fluid, is a useful rule-in diagnostic test for extrapulmonary TB.
□It also allows the simultaneous detection of MDR-TB.
□ One limitation of this assay is that false-positive results have been observed among patients who had been successfully treated for TB.
PREVENTION
Risk Assessment of the Transplant Candidate
●A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
●If negative ==> undergo evaluation for LTBI with either TSTor IGRA.
●If TST , an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction.
●a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
□Candidates low risk for LTBI should preferably be tested solely with IGRA.
□in high-risk candidates
both tests could be performed and any positive reaction considered an evidence of LTBI.
IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses.
□Active TB infection
transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
active infection may not be considered an absolute contraindication to transplantation for candidates who urgently need it.
Risk Assessment of Deceased and Living Donors
Living donors should undergo the same evaluation as candidates
the cut off for TST should be 10 mm or greater.
• Radiographic findings
* apical fibronodular lesions,
*calcified solitary nodules,
* calcified lymph nodes,
* pleural thickening.
* Time does not allow for a TST and IGRAs have not been validated in deceased donors.
●Active TB infection should be ruled out in donors ( sputum or bronchoalveolar lavage).
● Therapy for active infection should be immediately started in the recipient per local guidelines.
●Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
● Lungs with residual tuberculous lesions should not be used for transplantation.
● A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, .
●The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients
■ LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
■Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive.
■Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
Therapeutic Regimens For treatment of LTBI
●The preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mgdaily.
(ALT checked every 2 weeks for 6 weeks, then monthly thereafter. )
●Alternative regimens rifamycins, but should be avoided posttransplant because of immunosuppressive drug interactions.
These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
● Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
Timing of Treatment
○treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist.
○ If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible until completion of the originally planned course
Recommendations for Transplanted Patients Who Travel to Endemic Areas
(ie, those with prevalence ≥100/ 100000), INH preventive therapy should be considered during the first posttransplant year,
There is no indication for BCGvaccine before travel, and it is contraindicated in transplant recipients.
Treatment of Active TB Infection
●Treatment should follow local guidelines for the general population.
●in most cases, a 4-drug regimen is recommended.
●INH and rifampicin are the most powerful first-line drugs against TB.
●In the context of SOT, many factors should be carefully considered, such as the risk of hepatotoxicity and drug interactions of rifampicin.
●treatment duration should be at least 9 months,
Monitoring of Adverse Events Related to Therapy
Low-grade elevation of aminotransferases can be observed during the first 2 months of treatment, but a 3-fold increase accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation.
Drug Interactions
Rifamycins (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids).
■A lower blood level of these drugs is associated with higher risk of graft rejection.
■Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin
■It has been demonstrated to be as effective as rifampin for the treatment of TB
Nonetheless, the same recommendation for close therapeutic drug monitorings of these immunosuppressive drugs apply when rifabutin is used.
TB AFTER SOLID-ORGAN TRANSPLANTATION
The main reason for increase in incidence of Tuberculosis post transplantation is reactivation of foci of latent TB infection (LTBI), Other risk factors are immigration, travel to endemic countries, medical tourism, and humanitarian work .
DIAGNOSIS
Diagnosis of LTBI: No gold standard test available for diagnosis of LTBI-TST and IGRA assays are available test and both have their own pitfalls and limitations but IGRA is better compared to TST.IGRA assays should be done alone in low-risk patients, however ,in high risk cases-both tests should be done and if any one of them is positive ,then it should be considered as a case of LTBI.
Diagnosis of Active TB Infection:
Confirmed diagnosis is done by microscopy, culture and nucleic acid testing of M. tuberculosis bacilli. Xpert MTB/RIF assay has a very good specificity and almost 98% sensitivity for smear positive and 67% 67% for smear negative respiratory samples. It has also good sensitivity for non-respiratory samples.
PREVENTION
Risk Assessment of the Transplant Candidate
Active T.B must be ruled out by taking detailed history and doing examination ,then X-ray chest ,other imaging studies like CT scan Abdomen as per needed and microbiological examination before labeling the patient as LTBI. Transplantation should be withheld till the patient is asymptomatic and smear is negative.
Risk Assessment of Deceased and Living Donors
Living Donors:
Same assessment as normal candidates-just the TT value should be 10mm or greater than 10mm.
Deceased Donors:
LTBI is difficult to diagnose in the,however,for active T.B, sputum or bronchoalveolar lavage for microbiological diagnosis should be done.
Active TB infection donors,and with residual tuberculosis should be discarded.
Donors with past treated history of TB for at least 6 months can be considered.
Patients with untreated LTBI should not be discarded and in such cases preventive therapy to all recipients should be done
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients
Criteria to Start Treatment
1-Transplant candidates with positive TST or IGRA
2-high-risk pre-transplant TB exposure(history of active TB infection that was inadequately treated)
3- Chest imaging suggestive of previous untreated TB
1- transplant recipients having donor with untreated or incompletely treated LTBI or TB
2- Exposure of T.B to recipient.
Therapeutic Regimens
1- oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily (preferred regimen)
2- RIF 600 mg daily for 4 months or
3- INH and rifapentine weekly for 12 weeks
Timing of Treatment
LTBI treatment should be started before transplant.
Treatment should be wiheld perioperatively and resumed when medically possible if transplant is planned immediately.
Recommendations for Transplanted Patients Who Travel to Endemic Areas
INH should be started in such cases.
Treatment of Active TB Infection
Treatment should be according to national guidelines .Generally a 4-drug regimen is preferred and continued for at least 09 months.But should be cautious of the drug-drug interaction especially with Rifamycins for which close monitoring and continuous dose adjustment is required. Rifampicin belongs to rifamycins group and is a potent inducer that’s why 2-5 fold increments in the daily dose of cyclosporine, tacrolimus, and mammalian target of rapamycin inhibitors are generally required to keep drug level in the range.
Monitoring of Adverse Events Related to Therapy
Side effects related to drug should be kept in mind and monitoring in the first 02 months should be done closely. Hepatotoxicity is usually observed with INH, rifampicin, and pyrazinamide.Drugs should be discontinued where there is 3 fold rise in ALT with asymptomatic patient and 5 fold rise in symptomatic patient.
Level of evidence: V narrative review .
The incidence rate of TB increases markedly after transplantation…. the current article describes the TB incidence rates in Brazil and Latin America…Brazil is one of the 22 countries in the world as per WHO to have a high burden of tuberculosis…. The risk of TB after Solid organ transplantation is highest in lung transplant recipients…. The proportion of patients with active TB may vary with each transplant center…In studies carried out in LA the incidence of 0.5-5% of all the recipients…
Reactivation of Latent TB seems the most common cause of pulmonary TB after transplant….Primary infection in those living in endemic areas are very common.. .Among transplant patients donor recipient transmission is quite rare….The risk of transmission of TB from a donor who has Latent TB, the transmission rate is quite high as upto 30%… but large scale studies are needed to ascertain the donor derived LTBI in TB transmission…..
International travel to endemic countries and Transplant tourism favor more incidence of TB in SOT recipients…. Transplant patients who are endemic for TB are at increased risk of course… Travel for more than 3 months from a low endemic to high endemic areas increases the contact exposure time and has been shown to be a risk factor for post Transplant TB…Immigrant children post transplant have shown increased risk of Post Transplant TB especially whose parents have migrated to US from an endemic region….In general the long air travel exposure, occupational health hazards for TB like health care personnel, working with prisoners and old age home persons increases the risk of TB in general and the same applies to post renal transplant patients too…Spain has reported high incidence of LTBI in those donors whose cadavers have migrated from countries in Eastern Europe…
Diagnosis of Latent TB infection: There is no standard recommendations, however the tuberculin skin test is the widely used and recommended in all solid organ transplant recipients… TST requires an intradermal injection….Interferon gamma release assay (IGRA) has been used in the place of TST in many centers… The advantages are better precision and yield, avoids bias in interpretation, avoids false positives in BCG vaccinated individuals and those with, infect and those with primary infection…. But this test is expensive and no international standardized assay are available for the same…the negative predictive value of IGRA is not optimal enough to diagnose the latent TB infection… Due to above variations in TST and IGRA various transplant centers use various protocols… In those low risk individuals TST was sufficient and in high risk individuals both IGRA and TST were done to improve the sensitivity and specificity…
Diagnosis of Active TB infection: this relies on detection of TB by AFB stain, Culture or NAT. Neither IGRA or TST can diagnose active infection.. The most challenging situation is when there is clinical suspicion of TB..It can present as pyrexia of unknown origin and can have pleural effusion or ascites… the availability of RIF/Xpert MTB as a diagnostic tool improves the sensitivity and specificity of the TB diagnosis…. the rifampicin resistance can also defined in this test… the utilization of the this is maximum in CSF and pleural fluid….One limitation of the test is the presence of false positive in those already treated for TB….
Risk assessment for transplant candidate: If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation with TST or IGRA… TST >5mm after 48-72 hours is positive for LTBI…in addition a second TST should be performed after 7-10 days after the first TST to evaluate for boosted related skin conversion….
In those with low risk of TB, patients maybe tested with IGRA itself…. In those with high risk (in those residing in endemic areas, household contacts, prisoners and shelterless people) recommendation is to do both TST and IGRA and any positive reaction on either is considered LTBI… when following this dual approach the IGRA should be done first to avoid TST mediated immune boosting response to IGRA… Active TB should always be ruled out by history and physical examination…Sputum examination should be done and CT scan of the chest should be done to rule out cavity consolidation…
Risk assessment of living and deceased donors:
Living donors should be assessed by TST in endemic areas except that the cut off for TST is greater than 10mm… In deceased donor also needs physical examination and history of past exposure to TB…TST and IGRA are not used in cadaveric donors as the results may not be available…. Organs from donors with active TB infection must be discarded.. those organs from patients whom TB is treated for more than 6 months can be used… In the rare case the transplant happens treatment has to happen immediately and care should be take to avoid drug interaction of immunosuppressive and Rifampicin….Special mention for lungs with residual TB sjhould not be used for transplantation…. Any history of treated LTBI in the donors should be enquired and the risk of transmission is less from these donors…
Treatment of LTBI: It is recommended in all transplant patients with positive TST or IGRA in those who have not been treated…. those with high risk pre transplant exposure to TB should be treated even if TST or IGRA is negative…. Treatment for LTBI is recommended in those from whom donors have been treated with partial TB or not completed TB treatment… in consideration of Active TB should be ruled out before starting treatment for active TB…
Treatment is 9 months of INH 300mg/day with pyridoxine 25 to 50 mg /day…9 months are preferred to 6 months for therapy… Other agents like Rifampicin are also used but immunosuppressive drug interaction remains a problem… Rifapentine and INH, levofloxacin have been used but not validated across many studies… The timing of the treatment is to start as early as possible… for patients on the waiting list treatment can be started before transplant and continued later after transplant…
BCG vaccination is contraindicated in renal transplant recipients… those transplant patient who desire to travel to endemic area need INH prophylaxis’s for 9 months
Treatment for active TB infection should be done based on the local/national guidelines for TB…. Rifampicin is an enzyme inducer and will reduce the level of steroid and tacrolimus exposure and it may lead to rejection of the graft… Hepatotoxicity needs to be monitored while on TB treatment
1. Summarise this article
The incidence rate of TB increases markedly after solid organ transplantation (SOT),4,5 with the highest risk among lung recipients. The proportion of patients affected by active TB infection also varies widely between transplant centers in correspondence with the local prevalence of the disease. In the last 2 decades, the burden of tuberculosis (TB) has been considerably reduced in Latin America (LA) countries. It is important to be aware that national average incidence estimates may mask wide variations within a country and marked variation may sometimes occur even within the same city.
Reactivation of foci of latent TB infection (LTBI) is probably the main cause of posttransplant TB. Primary infection acquired in the community, and less frequently in the nosocomial environment, may also account for a considerable proportion of the cases, especially among patients living in endemic areas. A minor proportion of primary infections result from donor-recipient transmission.12 Most of these cases were documented in patients who received a graft from a deceased donor with active TB infection, a situation that has been associated with a risk of transmission of approximately 30%.
Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB after SOT. Transplant candidates originating from endemic areas have a higher prevalence of LTBI and are, hence, at an increased risk of developing active TB infection after SOT and transplant recipients from low-incidence countries may be exposed to primary infection while traveling to an endemic area, but the actual impact of such exposure in this specific population has not been assessed. And the time spent in the endemic area influences the risk of TB infection. A cumulative history longer than 3 months of travel to high-incidence areas is associated with a significantly higher risk. Humanitarian work with high-risk populations, such as prisoners and homeless people, may also be a significant risk factor. The impact of other possible types of exposure is not well defined.
Diagnosis of LTBI
There is no diagnostic reference standard for LTBI. The tuberculin skin test (TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.
IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade. They offer some advantages as compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients.
However, despite their better yield, the negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI, which includes those who were born to or lived in endemic countries, household contacts of a case of active TB infection, and those who work or live in high-risk settings, such as correctional facilities and homeless shelters.
Diagnosis of TB ative infection
The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing. Neither TST nor IGRAs are recommended for diagnosing active infection. Probably the most challenging situation lies on the clinical suspicion of active infection. SOT recipients may present unusual manifestations, with a greater proportion of extrapulmonary involvement. TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin.
PREVENTION
Risk Assessment of the Transplant Candidate
A history of clinical or radiological TB and the treatment received should be assessed in all recipients. If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA. Candidates who have low risk for LTBI should preferably be tested solely with IGRA. In high-risk candidates (ie, patients originated from endemic countries, household contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), both tests could be performed and any positive reaction considered an evidence of LTBI. Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
Risk Assessment of Deceased and Living Donors
Deceased donors should have their assessment based on epidemiological risk (medical history and endemic exposures) and chest X-ray, while living donors should undergo TST, but with a cutoff point of 10mm.
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated. Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated. Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily. Nine months of therapy is preferred over 6 months because of better protection. Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
Treatment of Active TB Infection
The optimal length of treatment of TB in transplant recipients is not defined. Many specialists recommend that treatment duration should be at least 9 months, based on the results of a few studies that have suggested an association between shorter regimens and greater recurrence and mortality. The number of drugs used in the intensive phase regimen should be defined per the prevalence of drug resistance in each population. Nevertheless, in most cases, a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB.
Rifamycins have an induction effect on different drugmetabolizing enzyme systems, most notably the cytochrome P450 (CYP) 3A4, which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids). A lower blood level of these drugs is associated with higher risk of graft rejection. Therefore, close monitoring and continuous dose adjustment are highly recommended.
2. What is the level of evidence provided by this article?
This is a narrative review – level 05.
TB AFTER SOT
●The incidence rate of TB markedly increases after (SOT),
● It may corresponde with the local prevalence of the disease.
● In studies in LA SOT centers in the last decade, TB was diagnosed in 0.9% to 5.9% of the recipients.
● Reactivation of foci of (LTBI) is probably the main cause of posttransplant TB.
● A minor proportion of primary infections result from donor-recipient transmission.
●Most of these cases were in patients who received a graft from deceased donor with active TB infection
● a risk of transmission of approximately 30%.
the influence of donor LTBI on the risk of posttransplant TB is undetermined yet.
DIAGNOSIS
There’s nodiagnostic reference standard for LTBI.
■(TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.
■(IGRAs) have emerged as new diagnostic tools in the last decade.
advantages
♡avoid interpreting bias,
♡ reduce false-positive
♡more sensitive in candidates with chronic renal failure and advanced cirrhosis,
◇ the negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high riskf or LTBI
Per a recent European survey,
•TST alone was used in 48%
•IGRA alone in 30%,
•TSTand IGRA simultaneously in 16%
• TST followed by IGRA in 6%.
●In low-risk patients, IGRAs could be considered as the sole approach,
.
● In high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening
Diagnosis of Active TB Infection
○the detection by direct observation, by culture, and nucleic acid testing.
○Neither TST nor IGRAs are recommended for diagnosing active infection.
○The availability of a rapid molecular test, such as the Xpert MTB/RIF assay, may have a major impact in the management
the Xpert MTB/RIF assay
□It is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98%and67%,respectively.
□Testing non respiratory samples, such as tissue biopsies and cerebrospinal fluid, is a useful rule-in diagnostic test for extrapulmonary TB.
□It also allows the simultaneous detection of MDR-TB.
□ One limitation of this assay is that false-positive results have been observed among patients who had been successfully treated for TB.
PREVENTION
Risk Assessment of the Transplant Candidate
●A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
●If negative ==> undergo evaluation for LTBI with either TSTor IGRA.
●If TST , an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction.
●a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
□Candidates low risk for LTBI should preferably be tested solely with IGRA.
□in high-risk candidates
both tests could be performed and any positive reaction considered an evidence of LTBI.
IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses.
□Active TB infection
transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
active infection may not be considered an absolute contraindication to transplantation for candidates who urgently need it.
Risk Assessment of Deceased and Living Donors
Living donors should undergo the same evaluation as candidates
the cut off for TST should be 10 mm or greater.
• Radiographic findings
* apical fibronodular lesions,
*calcified solitary nodules,
* calcified lymph nodes,
* pleural thickening.
* Time does not allow for a TST and IGRAs have not been validated in deceased donors.
●Active TB infection should be ruled out in donors ( sputum or bronchoalveolar lavage).
● Therapy for active infection should be immediately started in the recipient per local guidelines.
●Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
● Lungs with residual tuberculous lesions should not be used for transplantation.
● A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, .
●The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients
■ LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
■Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive.
■Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
Therapeutic Regimens For treatment of LTBI
●The preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mgdaily.
(ALT checked every 2 weeks for 6 weeks, then monthly thereafter. )
●Alternative regimens rifamycins, but should be avoided posttransplant because of immunosuppressive drug interactions.
These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
● Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
Timing of Treatment
○treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist.
○ If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible until completion of the originally planned course
Recommendations for Transplanted Patients Who Travel to Endemic Areas
(ie, those with prevalence ≥100/ 100000), INH preventive therapy should be considered during the first posttransplant year,
There is no indication for BCGvaccine before travel, and it is contraindicated in transplant recipients.
Treatment of Active TB Infection
●Treatment should follow local guidelines for the general population.
●in most cases, a 4-drug regimen is recommended.
●INH and rifampicin are the most powerful first-line drugs against TB.
●In the context of SOT, many factors should be carefully considered, such as the risk of hepatotoxicity and drug interactions of rifampicin.
●treatment duration should be at least 9 months,
Monitoring of Adverse Events Related to Therapy
Low-grade elevation of aminotransferases can be observed during the first 2 months of treatment, but a 3-fold increase accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation.
Drug Interactions
Rifamycins (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids).
■A lower blood level of these drugs is associated with higher risk of graft rejection.
■Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin
■It has been demonstrated to be as effective as rifampin for the treatment of TB
Nonetheless, the same recommendation for close therapeutic drug monitorings of these immunosuppressive drugs apply when rifabutin is used.
Level of evidence (v)
1. Summarise this article
Epidemiology of tuberculosis (TB) in Latin America (LA): TB burden in LA countries, despite considerable reduction, is still significant with Brazil having the highest burden of TB in the world. Marked variation in different geographical areas is seen with increased emergence of multi-drug resistant TB (MDR-TB) especially in patients previously treated for TB having prevalence as high as 20% to 26%.
TB post solid organ transplantation (SOT): TB incidence post-SOT increases markedly, with range from 0.9% to 5.9% in LA countries, being highest in lung recipients. The main cause of post-transplant TB is reactivation of latent TB infection (LTBI), but it could be due to a primary infection or a donor-derived infection.
International travel and post-transplant TB: Travel to TB endemic regions can increase risk of TB (0.4% to 2%, increasing to 1.8% to 4.2% in those involved in healthcare). Prospective recipients and donors from TB endemic regions have high prevalence of LTBI. A higher risk has been seen with cumulative history of travel to high-incidence area for more than 3 months. Public transportation has also been shown to be a risk factor for TB transmission.
Diagnosis of LTBI: There is no diagnostic standard for LTBI. Tuberculin skin test (TST) and interferon gamma release assays (IGRAs) are used for LTBI screening. IGRAs do not have interpretation bias, have reduced false positives and increased sensitivity in chronic kidney disease and chronic live disease, but their negative predictive value is not optimal to rule out LTBI in patients considered high-risk. So, in low-rsik patients, IGRA alone can be used, while in high-risk patients, it is prudent to use both TST and IGRA and any positive result should be taken as evidence of LTBI.
Diagnosis of active TB: It requires either microscopic observation, culture, or nucleic acid testing (NAAT). As patients may have atypical presentation, high index of suspicion is required. Rapid molecular test (Xpert MTB/RIF) is highly specific with good sensitivity (98% in smear positive and 67% in smear negative) in respiratory samples. It can be utilized for extrapulmonary TB (by using on non-respiratory samples). It also helps detection of rifampicin resistance simultaneously, although false-positive results are seen in patients previously treated for TB.
Risk assessment of the transplant candidate: All prospective transplant receipts should undergo evaluation including history of clinical or radiological TB and any treatment received. If no history, LTBI evaluation in form of TST (>5mm induration at 48-72 hours) or IGRA should be done. A second TST after 7-10 days of first TST should be done to assess boosted-related skin conversion. It is preferable to use IGRA alone for low-risk candidates, and combination of IGRA (performed first) and TST for high-risk candidates. Active T valuation involves checking signs and symptoms, imaging, and microbiological tests. Transplantation should be postponed till an active TB is treated except in those who require transplant urgently.
Risk assessment of donors: Living donors should be evaluated like the recipient with TST cutoff >10mm induration at 48-72 hours. Deceased donor evaluation includes medical history, history of endemic exposure, and radiological findings, and ruling out active TB by taking samples for M. tuberculosis testing. Donors with known active TB should be declined. Donors with history of TB successfully treated for 6 months can be transplanted. Donor with untreated LTBI can be accepted with preventive therapy administration to the recipient, especially lung recipient.
Treatment: Treatment of LTBI in transplant candidates and recipients should be started if they have positive TST or IGRA (and have not been treated previously), in those with high-risk pre-transplant exposure, with history of inadequately treated active TB, with chest imaging showing previous untreated TB, if exposed to TB after transplant, or if the donor had any history of untreated, incompletely treated LTBI or TB. The treatment of LTBI involves isoniazid with pyridoxine for 9 months, or weekly isoniazid and rifampicin for 12 weeks, or rifampicin alone for 4 months. Whenever possible, LTBI should be treated pre-transplant. Isoniazid preventive therapy should be given to those travelling to endemic areas, and they should be evaluated on their return, if symptomatic. Treatment of active TB infection involves 4 drug regimen for at least 9 months in transplant recipients, with biweekly monitoring of liver enzymes in first 2 months. 3 times rise with symptoms, and 5 times rise of liver enzymes without symptoms would warrant discontinuation of medication. Drug interactions with rifampicin in transplant recipients is important due to effect on CYP3A4, requiring increase in doses of calcineurin inhibitors, mTOR inhibitors, and steroids. Rifabutin, with limited enzyme induction, can be used in place of rifampicin.
2. What is the level of evidence provided by this article?
Level of evidence: level 5 – Narrative review.
The incidence rate of TB markedly increases after solid organ transplantation (SOT),4,5 the risk being highest among lung recipients.
Reactivation of foci of latent TB infection (LTBI) is probably the main cause of posttransplant TB.
Diagnosis of LTBI There is no diagnostic reference standard for LTBI. The tuberculin skin test (TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors. IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade. They offer some advantages as compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients.
Diagnosis of Active TB Infection The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture,and nucleic acid testing. Neither TST nor IGRAs are recommended for diagnosing active infection
PREVENTION
Risk Assessment of the Transplant Candidate: A history of clinical or radiological TB and the treatment received should be assessed in all recipients. If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA. If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
Risk Assessment of Deceased and Living Donors:
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
The evaluation of the deceased donor for TB relies on: • Medical history and previous reactive IGRA or TST. • Endemic exposures. Travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the last 2 years, homeless or refugee status, incarceration and alcoholism may be associated with LTBI. In this regard, • Radiographic findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening.
TREATMENT :
Treatment of LTBI in Transplant Candidates and Recipients:
Criteria to Start Treatment Therapy for LTBI is an effective strategy for the prevention of active TB infection in transplant recipients.LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated. Chest imaging suggestive of previous untreated TB should prompt consideration for therapy, especially in endemic area.
Therapeutic Regimens For treatment of LTBI:
the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily. Nine months of therapy is preferred over 6 months because of better protection. Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine aminotransferase checked every 2 weeks for 6 weeks, then monthly thereafter. Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.51,52 Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
Treatment of Active TB Infection : in most cases, a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB. In the context of SOT, many factors should be carefully considered, such as the risk of hepatotoxicity related to the antituberculous treatment and drug interactions of rifampicin.The optimal length of treatment of TB in transplant recipients is not defined. Many specialists recommend that treatment duration should be at least 9 month
This is a narrative review, with level 5
background
Although TB prevalence is reducing it is a major health problem in Latin America
TB was diagnosed in 0.9% -5.9% of recipients
TRAVEL/ MIGRATION history is important
Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB
more than 3 months of cumulative travel to endemic are is high risk for LTBI
Children of parents from endemic area are high risk for LTBI ,which is a concern in pediatric SOT
DIAGNOSIS
IRGA are better than TST
more sensitive and unbiased in ESRD patients
low risk patient s- IGRA is preferred
high risk – TST OR IGRA can be done , any positive result is suggestive of LTBI
ACTIVE TB
Documentation of M Tubercle bacillus my smear and culture is time taking
GEBE X PERT/ RIF is more specific and time saving
given rifampicin resistance to diagnose MDR TB
risk stratification in all recipients
both tests are done
TST SHOULD NOT BE DONE BEFORE IGRA
ACTIVE TB is ruled out before starting treating for LTBI
DONOR SCREENING
LIVE = TST MORE THAN 10 MM
DECEASED DONORS
medical history
endemic exposure/ homeless / incarcerated / alcoholic
radiology and microbiology
TST – can t be done due to time constrains
IGRA – NOT VALIDATED
TREATMENT FO LTBI
recipient with TST AND IGRA positive
also high risk with negative results
ORAL INH 300 MG/DAY FOR 9 MONTHS IN POST TRANSPLANT SETTING
INH AND RIFAMPETIN FOR 3 MONTH OR ONLY RIFAMPICIN 4 MONTH IN PRE TRANSPLANT SETTING
POST TRANSPLANT CARE
NO BCG vaccine
travel to endemic are – INH preventive therapy
TREATMENT OF ACTIVE TB
4 DRUS
9 MONTHS
FOLLOW NATIONAL GUIDLINES
5X ELEVATION OF LIVER ENZYMS – DISCONTINUE
RIFAMPICIN CAN REDUCE THE LEVEL OF CNI OR STEROID so drug level require monitoring
Refabutin is an alternative with less effect on drugs
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
EPIDEMIOLOGY
Epidemiology in Latin America
· The incidence of TB is declining in Latin America, also the mortality from TB, but Brazil remains one of 22 countries with the highest TB burden in the world
· Estimated multidrug-resistant (MDR) TB is below 3%, it is > 3% in Ecuador, Guatemala, and Peru.
TB AFTER SOLID-ORGAN TRANSPLANTATION
· The risk of TB increased post solid organ transplant, which is highest in lung recipients.
· The main cause of posttransplant TB is reactivation of latent TB
· Primary infection acquired from the community is common, mainly in patients living in endemic areas.
· primary infections from donor-recipient transmission may occur, mainly from a deceased donor with active TB infection
International Travel and Posttransplant TB
· Transplant candidates from endemic areas have a higher prevalence of LTBI and have higher risk of developing active TB infection after SOT.
· In Spain, the prevalence of active TB infection was markedly increased in deceased donors who originated from a high-incidence country in eastern Europe.
· Travelling to endemic areas increased risk of TB, also prisoners and homeless people.
· the use of public transportation in a high-incidence area in Peru was an independent risk factor for active TB infection.
DIAGNOSIS
· The tuberculin skin test is still used for the screening of LTBI in solid organ candidates/recipients and living donors
· Advantages of IFN-γ release assays (IGRAs) over TST: 1) avoid interpreting bias, 2) reduce false-positive results 3) probably more sensitive in candidates with chronic renal failure and advanced cirrhosis
· IGRAs should be used for low-risk patients, but in high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI
Diagnosis of Active TB Infection
· Invasive diagnostic procedures are mostly needed but it delays the proper diagnosis
· Rapid molecular test, such as the Xpert MTB/RIF assay is highly specific and sensitive
· It can also detect rifampicin resistance, with its prediction of MDR-TB and early treatment for MDR-TB until the culture result is available.
· This assay may have false positive results, and cannot replace other drug susceptibility tests.
PREVENTION
Risk Assessment of the Transplant Candidate
· If the candidates have no history of past TB or treatment for LTBI, they should be evaluated for LTBI with either TST or IGRA.
· Candidates who have low risk for LTBI should preferably be tested solely with IGRA.
· In high-risk candidates, both tests could be performed and any positive reaction considered suggestive of LTBI.
· Active TB infection must be excluded in all candidates with a positive result before starting treatment for LTBI.
· Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
· But if transplant is needed urgently, active infection will not be an absolute contraindication to transplantation
Risk Assessment of Deceased and Living Donors
· The evaluation of the deceased donor for TB relies on: Medical history, Endemic exposures, and Radiographic findings.
· Active TB infection should be ruled out in donors at increased risk by obtaining sputum or bronchoalveolar lavage,
· Results of microbiological investigation should be forwarded to transplant teams as soon as possible, to take action if it was positive for TB.
· Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
· Lungs with residual TB lesions should not be used for transplantation.
· A history of untreated LTBI without active infection is not a contraindication to donation, but all recipients should be given drugs for prevention, especially for lung recipients.
Treatment of LTBI in Transplant Candidates and Recipients
· LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated
· Candidates with high-risk pretransplant TB exposure should be treated even if the TST or IGRA is not positive, also those with history of active TB infection and not treated adequately.
· Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
Therapeutic Regimens
· The preferred regimen for LTBI is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
· Nine months of therapy is preferred over 6 months because of better protection.
· Transplant candidates and recipients on INH should be monitored for hepatotoxicity with liver enzymes be checked every 2 weeks for 6 weeks, then monthly thereafter.
· Rifamycins regimen can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions.
· A recent study of pretransplant levofloxacin versus posttransplant INH in liver transplant recipients was stopped early because of excessive adverse events in the levofloxacin arm
Timing of Treatment
· When possible, treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist.
· If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible, with the avoidance of rifamycins after transplant.
Recommendations for Transplanted Patients Who Travel to Endemic Areas
· If recently transplanted patients are planning to move to a highly endemic area, INH preventive therapy should be considered during the first posttransplant year.
· There is no indication for BCG vaccine before travel, and it is contraindicated in transplant recipients
Treatment of Active TB Infection
· In most cases, a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB
· Many specialists recommend that treatment duration should be at least 9 months
Monitoring of Adverse Events Related to Therapy
· Biweekly monitoring for drugs interaction should be done during the first 2 months of treatment.
· Low-grade elevation of aminotransferases can be observed during the first 2 months of treatment, but a 3-fold increase accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation
Drug Interactions
· Rifamycins are drug inducer of cytochrome P450 which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT
· Rifampin has the most potent enzyme induction effect, so daily dose of cyclosporine, tacrolimus, and mTORi are generally necessary to maintain trough levels of the drug in the therapeutic range
· Rifabutin, is an alternative for rifampin, and can be as effective as rifampin for the treatment of TB
This is a narrative review, with level 5
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
TB AFTER SOLID-ORGAN TRANSPLANTATION
The incidence rate of TB markedly increases after solid organ transplantation (SOT), the risk being highest among lung recipients. The proportion of patients affected by active TB infection also varies widely among transplant centers in correspondence with the local prevalence of the disease.
Reactivation of foci of latent TB infection (LTBI) is probably the main cause of posttransplant TB.
DIAGNOSIS
Diagnosis of LTBI
There is no diagnostic reference standard for LTBI. The tuberculin skin test (TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.
IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade. They offer some advantages as compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients.
Per a recent European survey, TST alone was used in 48% of the participating centers, IGRA alone in 30%, TST and IGRA simultaneously in 16% and TST followed by IGRA in 6%.
low-risk patients, IGRAs could be considered as the sole approach, because the use of a more specific test might reduce the rate of false-positive results and, consequently, the number of patients who will unnecessarily be exposed to LTBI therapy. On the other hand, in high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
Diagnosis of Active TB Infection
Neither TST nor IGRAs are recommended for diagnosing active infection.
TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin.
the Xpert MTB/RIF assay, may have a major impact in the management of these patients. This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively.
One limitation of this assay is that false-positive results have been observed among patients who had been successfully treated for TB.
PREVENTION
Risk Assessment of the Transplant Candidate
A history of clinical or radiological TB and the treatment received should be assessed in all recipients. If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TSTor IGRA. If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction.
Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started. This evaluation includes checking the presence of symptoms and signs suggestive of TB, performing a chest radiograph and, in cases with extrapulmonary manifestations, imaging of other body sites. If any evidence of active infection is found in this workup, appropriate clinical specimens should be collected for microbiological confirmation of the diagnosis. Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative. Nevertheless, active infection may not be considered an absolute contraindication to transplantation for candidates who urgently need it.
Risk Assessment of Deceased and Living Donors
evaluation of the deceased donor for TB relies on:
• Medical history. The history of untreated or insufficiently treated TB should be investigated, as well as previous reactive IGRA or TST.
• Endemic exposures.
Radiographic
Organs from donors with known active TB infection should be discarded. If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines.
Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, especially for lung recipients. The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, therefore, transplant recipients from such donors can be clinically monitored without receiving LTBI therapy.
Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation. In considering treatment for LTBI, it is imperative to first rule out active TB infection
Therapeutic Regimens
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
Nine months of therapy is preferred over 6 months because of better protection. Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine aminotransferase checked every 2 weeks for 6 weeks, then monthly thereafter. Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks. Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy. However, a recent randomized study of pretransplant levofloxacin versus posttransplant INH in liver transplant recipients was stopped early because of excessive adverse events in the levofloxacin arm.
Nevertheless, in most cases, a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB. In the context of SOT, many factors should be carefully considered, such as the risk of hepatotoxicity related to the antituberculous treatment and drug interactions of rifampicin.
The optimal length of treatment of TB in transplant recipients is not defined. Many specialists recommend that treatment duration should be at least 9 months
Drug Interactions
Rifamycins have an induction effect on different drugmetabolizing enzyme systems, most notably the cytochrome P450 (CYP) 3A4, which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids). A lower blood level of these drugs is associated with higher risk of graft rejection.
Twoto 5-fold increments in the daily dose of cyclosporine, tacrolimus, and mammalian target of rapamycin inhibitors are generally necessary to maintain trough levels of the drug in the therapeutic range. Although enzyme induction start within hours after the first dose of rifampin, maximum effect is reached in about 1 to 2 weeks and slowly declines over 2 weeks after stopping its use. Thus, therapeutic drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption. Despite these drug interactions, rifampicin is not contraindicated in SOT recipients.
Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin. It has been demonstrated to be as effective as rifampin for the treatment of TB in trials conducted in nontransplant patients.
level of evidence V
● The risk is highest among lung recipients
● TB was diagnosed in 0.9% to 5.9% of the recipients
● Reactivation of foci of latent TB infection is the main cause of posttransplant TB.
● Primary infection especially among patients living in endemic area and in graft from a deceased donor
● Transplant candidates originating from endemic areas have a higher prevalence of LTBI are at an increased risk of developing active TB infection after SOT.
● Immigration impact the risk of donor transmission.
● Risk factors for active TB infection:
☆ A cumulative history longer than 3 months of travel to high-incidence areas
☆ Prisoners and homeless people
☆ Use of public transportation in a high-incidence area in Peru
☆ Visiting friends and relatives and traveler’s diarrhea
Diagnosis of LTBI
● TST is the best studied test in SO candidates/recipients and living donors
● IGRAs is a new diagnostic tools
● Advantages of IGRA compared to TST:
☆ Avoid interpreting bias
☆ Reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination
☆ More sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield
and a better correlation with clinical risk factors for LTBI in these patients.
● Patients with high risk for LTBI includes
☆ who were born to or lived in endemic countries
☆ Household contacts of a case of active TB infection
☆ who work or live in high-risk settings
● Limitations of these assays include
☆ Higher cost
☆ Occurrence of conversions and reversions of test results when serial
screening is performed
● In low-risk patients, IGRAs is the sole approach
● In high-risk patients, both tests could be performed
Diagnosis of active TB infection
● Relies on the detection of MTB bacilli by direct observation, by culture and nucleic acid testing.
● TST and IGRAs are recommended for diagnosing active infection
● In SOT recipients TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin.
● Xpert MTB/RIF assay is a useful rule-in diagnostic test for extrapulmonary TB and detection of rifampicin resistance
● One limitation is the false-positive results in patients whohad treated for TB
PREVENTION
● If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA.
● If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. A second TST should be performed 7 to10 days after the first TST
● Candidates who have low risk for LTBI should preferably be tested solely with IGRA.
● In high-risk candidates both tests could be performed and any positive reaction considered an evidence of LTBI.
● IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses
● Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
● This evaluation includes :
☆ checking the presence of symptoms and signs suggestive of TB
☆ performing a chest radiograph
☆ in cases with extrapulmonary manifestations, imaging of other body sites.
● If any evidence of active infection is found in this workup, appropriate clinical specimens should be collected for microbiological confirmation of the diagnosis.
● Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
● Active infection may not be considered an absolute contraindication to transplantation for candidates who urgently need it
Risk Assessment of Deceased and Living Donors
● Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
● The evaluation of the deceased donor for TB relies on:
☆ Medical history.
☆ Endemic exposures.
☆ Radiographic findings
▪︎apical fibronodular lesions
▪︎calcified solitary nodules
▪︎calcified lymph nodes
▪︎pleural thickening.
● Obtaining samples bronchoalveolar or sputum lavage, to test for MTB
● Organs from donors with known active TB infection should be discarded.
● Therapy for active infection should be immediately started in the recipient If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation
● Organs from donors with a history of TB
successfully treated for at least 6 months can be transplanted.
● Lungs with residual tuberculous lesions should not be used for transplantation.
● A history of untreated LTBI without evidence of active infection is not a contraindication to donation
but administration of preventive therapy to all recipients should be considered
TREATMENT
● LTBI therapy is recommended for
☆ Candidates with positive TST or IGRA who have not been previously treated
☆ High-risk pretransplant TB exposure if the TST or IGRA is not positive
☆ A history of active TB infection that was inadequately treated.
☆ Chest imaging suggestive of previous untreated TB especially in endemic areas
☆ Recipients whose donor has untreated or incompletely treated LTBI or TB
☆ Recipient is exposed to TB after
transplantation
Therapeutic Regimens
● For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
● Monitore ALT every 2 weeks for 6 weeks, then monthly
● Tegimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy pretransplant, but should be avoided posttransplant
● Treatment for LTBI should be started before transplant, and If urgent transplant
is indicated, the treatment can be held perioperatively and resumed when medically possible avoiding rifamycins
Recommendations for Transplanted Patients Who Travel to Endemic Areas
● INH preventive therapy should be considered during the first posttransplant year
● BCG vaccine is contraindicated in transplant recipients.
Treatment of Active TB Infection
● A 4-drug regimen is recommended.
● In SOT, many factors should be carefully considered, such as INH and rifambicin
● Concomitant use of INH, rifampicin, and pyrazinamide is associated with an increased risk of hepatotoxicity, especially in liver recipients
● 3-fold increase in ALT accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation.
Drug Interactions
● Rifamycins lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus,sirolimus cyclosporine, everolimus, and steroids).
● Close monitoring and continuous dose adjustment are highly recommended.
● Rifampin has the most potent enzyme induction effect. But it isn’t contraindicated in SOT recipients.
● Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin.
☆ Level : 5
Summary:
Introduction
Tuberculosis is a public health problem and the burden of TB in the Latin has reduced in the Latin American continent in the last decades, although according to WHO classification, Bazil still remains one of the countries with the highest burden of the disease with 110,000 prevalence disease and 7700 TB death. The national incidence varies from as low as 11 cases per 100000 in the capital city to as high as 300 per 100000 in underprivileged communities. A more challenging situation is the emergence of MDR which is known to be quite common among those previously treated with TB. Reactivation latent TB is the main cause of post-transplant TB, primary infection and infection from donor-recipient transmission is less common.
Diagnosis of Latent TB:
Two options
TST is still recommended for diagnosing latent TB whether IGRA is new and there are some advantages; avoid interpreting bias, reduce false positive results and more sensitive in CKD and cirrhotic liver.
TST alone used in 48% whether IGRA alone in 30% .
TST and IGRA simultaneously in 16%.
TST followed by IGRA in 6% cases.
Diagnosis of active TB
Options are
Risk assessment of transplant patient-recipients:
Risk assessment of transplant patient-donors and diseased donor:
Treatment for LTBI in transplant and recipient patient
Treatment of active infection:
According to the general local guidelines has been advised that the treatment should be at least 9 months. The treatment comprises the intensive phase (INH+RIF+ PYRAZINAMIDE + EHTAMBUTO), for 2 months then followed by 6-9 months of the maintenance phase of INH + RIF.
Monitoring of adverse events related to therapy:
· Monitoring for hepatotoxicity ,if liver enzymes increase by 3 to 5 fold ,stop the therapy.
· Rifampicin drug interaction with CNIs, mTORs, and corticosteroids by reducing their trough level and this could result in allograft rejection or loss.
Level of evidence: level V
TB RECOMMENDATIONS FOR SOT RECIPIENTS AND DONORS.
EPIDEMIOLOGY IN LA
-Prevalence of TB decreased from 600000-342000 btn 1990-2014.
TB AFTER SOT.
-TB in la estimated to affect 0.9% to 5.9% of recipients with LTBI being the most common source of post transplant TB.
INTERNATIONAL TRAVEL AND POST TRANSPLANT TB.
-KTR from endemic areas considered at more risk of LTBI and active TB post transplant.
DIAGNOSIS.
-TST best studied and recommended for screening SOT candidates. IGRA better with less false +VE ,no interpretation bias and more sensitive in CKD and cirrhosis. IGRA is not sensitive to R/O infection in those at high risk of LTBI.
-IGRA used as sole test in low risk and both in high risk to R/O infection and reduce false +VE.
-Dependent on detection of MTB bacilli by direct observation, culture or nucleic acid testing. TST and IGRA are not useful. Gene xpert/RIF assay is highly specific and sensitive with a sensitivity of 98% and 67% in smear +VE and -VE resp samples respectively.
-RIF sensitivity is highly predictive of MDR.
PREVENTION.
-Evaluate for LTBI with TST and IGRA with an induration of >5mm IN 48-72hrs being +VE, Rpt a second TST in 7-10/7 to evaluate for a boosted related skin conversion. Exclude active infection before LTBI treatment and postpone transplant in cases of active TB tx.
2.Risk assessment of deceased and living donor.
-TST cutoff in living donor is 10mm or greater. Deceased donor evaluation for TB based on; Medical hx of partially tx TB, Previous TST or IGRA, Endemic exposure and Radiographic finding of a fibronodular lesion, lung nodule, calcified LN or pleural thickening.
-Samples should be obtained to R/O an active infection in those at high risk of active infection.
-TX should be started ASAP if donor diagnosed with TB post transplant.
-Donor who completed 6/12 of treatment can be successfully transplanted. Lungs with residual TB lesions should not be used for transplantation.
-Those with untreated LTBI without active infection should be given preventive therapy.
TREATMENT.
>LTBI
-Criteria for initiating treatment;
-Therapeutic regimen ;
>INH -9/12 +Pyridoxine.
>Other regimens ;RIF OD for 4/12,INH and Rifapentine weekly for 12/52,Fluoroquinolones +/- ethambutol.
-Timing of treatment.
-Transplanted pts who travel to endemic areas.
>ACTIVE TB.
-Adopt local guidelines.
-4 rug regimen recommended in intensive phase.
-Duration; atleast 9/12 to decrease recurrence and mortality.
-Monitor ADE from TB and closely monitor in 1st 2/12 and monitor for hepatotoxicity. Discontinue tx if transaminases increase by x3 with symptoms or x5 without symptoms.
DI.
-Rifampicin induces cytochrome p450 and decreases CNI,MTOR inhibitor and steroids and thus increase CNI by x2-3,double steroids dose and monitor trough levels to avoid graft dysfunction. Rifampicin should be substituted with rifabutin where available as it has less drug interaction.
LEVEL OF EVIDENCE – V
III. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
Summarise the article
Epidemiology
– burden of TB has reduced considerably in Latin America countries, nonetheless, TB remains a relevant public health problem in this region
– emergence of MDR TB has become a global challenge
TB after solid organ transplantation
– incidence of TB increases markedly after SOT with the incidence being highest among lung transplant recipients
– LTBI reactivation is main cause of post-transplant TB
– in endemic areas, primary TB infection can be acquired in the community and less frequently in the nosocomial environment
– a few cases of donor-recipient transmission do occur, this has been reported in patients who received a graft from a deceased donor with active TB infection
– the effect of donor LTBI on the risk of post-transplant TB is yet to be determined
Diagnosis
o Diagnosis of LTBI
– currently, there is no standard diagnostic reference for LTBI
– TST and IGRA are commonly used to screen for LTBI
– IGRA is more sensitive than TST in patients with CKD
– IGRA cannot optimally rule out infection in patients with a high risk of LTBI due to its low negative predictive value
– both TST and IGRA should be performed in high-risk patients while in low-risk patients consider IGRA to reduce the rate of false positive results and as such reduce the number of patients being exposed to LTBI treatment unnecessarily
o Diagnosis of active TB
– diagnosis of active TB infection is based on detection of M.Tb bacilli by direct observation, culture and nucleic acid testing
– TST and IGRA are not recommended in the diagnosis of active TB
– SOT recipients have an unusual presentation due to extrapulmonary involvement
– invasive diagnostic procedures are required in some cases and this can lead to a delay in diagnosis and initiation of treatment resulting in higher mortality rates
– rapid molecular tests like the xpert MTB/ RIF assay has helped overcome this challenge
– Xpert MTB/ RIF assay is highly specific and has a sensitivity of 98% in smear positive respiratory samples and 67% in smear negative samples
– in extrapulmonary TB, Xpert MTB/ RIF assay is a useful rule-in diagnostic test since it is highly specific
– Xpert MTB/ RIF assay assesses for rifampicin resistance allowing for a timely initiation of MDR-TB treatment as the culture results and the DST (drug susceptibility test) is pending
– false positive Xpert MTB/ RIF assay can occur among patients who have been treated for TB successfully
– Xpert MTB/ RIF assay cannot replace DSTs
Prevention
o Risk assessment of transplant candidates
– assess for history of clinical or radiological TB, any treatment received
– TST and IGRA should be done to screen for LTBI in patients without a history of past TB or LTBI treatment
– TST cut off is an induraion of ≥5mm at 48-72 hours
– active TB should be ruled out in patients with a positive TST or IGRA test before initiating LTBI treatment
– in patients who have active TB, transplant should be postponed until the TB is well controlled with negative smears
– in patients who urgently need a kidney transplant, active TB is not an absolute contraindication to transplantation
o Risk assessment of deceased and living donors
– living donors should undergo LTBI screening using TST and IGRA like transplant candidates but the TST cut off is 10mm or greater
– evaluation of a deceased donor for TB relies on: –
– in deceased donors, time does not allow for TST, and IGRAs have not been validated
– always rule out active TB in high-risk donors using sputum or BAL
– data on the microbiological tests should be shared with the transplant teams for appropriate action
– discard organs from deceased donors with known active TB infection
– if the diagnosis of TB becomes available after organ transplantation, then initiate TB treatment immediately as per the local guidelines
– drug sensitivity test should be done to guide treatment
– accept organs from donors who have been successfully treated for at least 6 months
– history of untreated LBTI without evidence of active TB is not a contraindication to donation but consider using preventive therapy in the recipient
– risk of transmission is low if LTBI treatment had been completed before organ donation so such recipients can be clinically monitored without giving them LTBI therapy
Treatment
o Treatment of LTBI in transplant candidates and recipients
– always rule out active TB before initiating LTBI therapy
– LTBI treatment is recommended in the following instances: –
– treatment options include: –
– avoid rifamycins post-transplant due to the drug-drug interactions with the immunosuppressive agents
– LTBI treatment should begin pretransplant
– offer IPT (INH preventive therapy) in the 1st year post-transplant in patients who are at increased risk of exposure
o Treatment of active TB infection
– treat as per the local guidelines; 2RHZE + 4RH
– rifampicin and isoniazid are the most potent 1st line drugs against TB
– rifampicin has a strong sterilizing activity
– optimal duration of treatment of TB in KTRs is not defined but most specialists recommend at least 9 months of treatment based on the results of a few studies that showed an association between shorter regimens and greater recurrence and mortality
– consider the drug adverse effects hence close monitoring is advised
– rifamycins are potent inducers of cytochrome P450 3A4 and P-glycoprotein which lead to reduced blood levels of most immunosuppressive agents (CNIs, mTORi, corticosteroids)
– the doses of these immunosuppressive agents (CNIs, mTORi) should be increased by 2-5-fold so as to maintain the therapeutic trough levels
– enzyme induction by rifampicin starts within hours after the 1st dose but the maximum effect is reached in 1-2 weeks and it slowly declines over 2 weeks after stopping rifampicin so close monitoring of trough levels should be frequent in the first 2weeks of treatment initiation and in the first 2 weeks after stopping rifampicin
– low blood levels of the immunosuppressive agents predispose the patient to graft rejection thereby close monitoring and continuous dose adjustment is advised
– rifampicin is not contraindicated in SOT recipients and the rejection and mortality rates are not affected by treatment with rifampicin-based regimens
– rifabutin is an alternative to rifampicin, it is a weaker enzyme inducer, is as effective as rifampicin in treatment of TB among nontransplant patients
– its weaker effect on CYP3A4 males it easier to maintain therapeutic levels of CNIs and mTORi
Level of evidence provided by this article
– Level V
Summary
Epidemiology in Latin America
As Per World Health Organization report of 2014,2 Brazil remains in the group of 22 countries with the highest TB burden in the world, with 110 000 prevalent cases and 7700 TB deaths. Haiti, Bolivia, and Peru are still moderately to highly endemic, with incidence remaining over 100 cases per 100 000.Higher prevalence (between 3.0% and 6.0%) of MDR infection among new TB cases has been found in Ecuador, Guatemala, and Peru. Ongoing community transmission of MDR infection have significant impact on mortality.
TB AFTER SOLID-ORGAN TRANSPLANTATION
In studies carried out in LA, SOT centers in the last decade, TB was diagnosed in 0.9% to 5.9% of the recipients.
Most of these cases were documented in patients who received a graft from a deceased donor with active TB infection. Although it is probable that donors with untreated LTBI may also be a source of TB transmission, the influence of donor LTBI on the risk of posttransplant TB is undetermined yet.Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB after SOT. Transplant candidates originating from endemic areas have a higher prevalence of LTBI.
DIAGNOSIS
Diagnosis of LTBI
The tuberculin skin test (TST)
IFN-γ release assays (IGRAs) they offer some advantages as compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis.
The negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI.
Diagnosis of Active TB Infection
M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing
Xpert MTB/RIF assay-This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively. It also allows the simultaneous detection of rifampicin resistance but the limitation is false-positive results have been observed among patients who had been successfully treated for TB
PREVENTION
Risk Assessment of the Transplant Candidate
A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA
In high-risk candidates (ie, patients originated from endemic countries, household contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), both tests could be performed and any positive reaction considered evidence of LTBI
Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
Risk Assessment of Deceased and Living Donors
The history of untreated or insufficiently treated TB should be investigated, as well as previous reactive IGRA or TST
Endemic exposures. Travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the last 2 years, homeless or refugee status, incarceration and alcoholism may be associated with LTBI. Radiographic findings, such as apical fibronodular lesions or calcified solitary is also the risk factor.
Time does not allow for a TST and IGRAs so, have not been validated in deceased donors.
Active TB infection should be ruled out in donors at increased risk by obtaining samples, for sputum or bronchoalveolar lavage. As microbiological investigation often be available after procurement, all data should be forwarded to transplant teams as soon as possible.
Organs from donors with active TB infection should be rejected.
If the microbiologic diagnosis of TB in the donor becomes available after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines.
Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
Lungs with residual tuberculous lesions should not be used for transplantation.
A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered.
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
Chest imaging suggestive of previous untreated TB should prompt consideration for therapy, especially in areas where endemic mycoses are uncommon.
Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
Therapeutic Regimens
For treatment of LTBI, oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
Or RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks
Or INH and rifapentine weekly for 12 weeks.
Recommendations for Transplanted Patients Who Travel to Endemic Areas
If recently transplanted patients are planning to move to a highly endemic area (ie, those with prevalence ≥100/ 100000), INH preventive therapy should be considered during the first posttransplant year.
BCG is contraindicated in transplant recipients.
Treatment of Active TB Infection
The number of drugs used in the intensive phase regimen should be defined per the prevalence of drug resistance in each population.
4-drug regimen is recommended.
Treatment duration should be at least 9 months.
Monitoring of Adverse Events Related to Therapy
Concomitant use of INH, rifampicin, and pyrazinamide is associated with an increased risk of hepatotoxicity.
3-fold increase in liver enzymes accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation.
Drug Interactions
Two to 5-fold increments in the daily dose of cyclosporine, tacrolimus, and mammalian target of rapamycin inhibitors are necessary to maintain trough levels of the drug in the therapeutic range.
Although enzyme induction starts within hours after the first dose of rifampin, maximum effect is reached in about 1 to 2 weeks and slowly declines over 2 weeks after stopping its use.
The same recommendation for close therapeutic drug monitorings of drugs apply when rifabutin is used even it is weaker effect on CYP3A4
Level of evidence for narrative review- 5
Epidemiology of TB in Latin America:
prevalence and death reduced in laten America in the last two decades, still higher prevalence in Brazil ,moderate high in over 100 cases per 100 000 in Haiti, Bolivia, and Peru.
(MDR) TB, which is defined by the isolation of a causative strain of Mycobacterium tuberculosis resistant to rifampicin and isoniazid (INH), is a global challenge.
Although the estimated proportion of MDR infection among new TB cases remains below 3% in most countries of the region, higher prevalence (between 3.0% and 6.0%) has been found in Ecuador, Guatemala, and Peru.
TB after organ transplantation:
The incidence rate of TB after SOT,
the risk being highest among lung recipients.
In studies carried out in LA SOT centers in the last decade, TB was diagnosed in 0.9% to 5.9% of the recipients.
Reactivation of foci of latent TB infection (LTBI).main
. Primary infection acquired in the community, and less frequently in the nosocomial , especially among patients living in endemic areas.
A miner proportion of primary infections result from donor-recipient transmission.
LTBI.
International Travel and Posttransplant TB:
Immigration, international travel too reside at endemic countries, and transplant tourism may influence the risk of TB after SOT.
Children of immigrants parent also increased incidence of TB
Immigration may also impact the risk of donor transmission.
DIAGNOSIS Diagnosis of LTBI
low-risk patients, IGRAs could be considered as the sole approach, because the use of a more specific test might reduce the rate of false-positive results .
in high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
Diagnosis of Active TB Infection:
detection of M. tuberculosis bacilli by direct observation, by culture d nucleic acid testing.
Xpert MTB/RIF assay, is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively.
PREVENTION Risk Assessment of the Transplant Candidate A
history of clinical or radiological TB and the treatment received should be assessed in all recipients.
If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA.
If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction.
In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
If any evidence of active infection is found in this workup, appropriate clinical specimens should be collected for microbiological confirmation of the diagnosis.
Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
Risk Assessment of Deceased and Living Donors:
the cutoff for TST should be 10 mm or greater.
The evaluation of the deceased donor for TB relies on:
• Medical history. The history of untreated or insufficiently treated TB should be investigated, as well as previous reactive IGRA or TST.
• Endemic exposures. Travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the last 2 years, homeless or refugee status, incarceration and alcoholism may be associated with LTBI.
• Radiographic finding.
Organs from donors with known active TB infection should be discarded.
If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines
. Drug susceptibility tests should be performed on any M. tuberculosis specimen isolated from the donor. Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted. Lungs with residual tuberculous lesions should not be used for transplantation.
A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, especially for lung recipients.
The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, therefore, transplant recipients from such donors can be clinically monitored without receiving LTBI therapy.
TREATMENT:
Treatment of LTBI in Transplant Candidates and Recipients :
Criteria to Start Treatment :
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
Those with high-risk peri transplant TB exposure should be treated even if TST and IGRA is negative.
Chest imaging suggestive of previous untreated TB .
transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB.
the recipient is exposed to TB after transplantation.
Therapeutic Regimens :
For treatment of LTBI the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
Alternative :
RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
Start of treatment:
Should be before transplants.
If urgent ,stop during transplant and resume. After ,consider RF free regime.
Treatment of Active TB Infection :
Treatment should follow local guidelines for the general population
. The Monitor for drugs AE And interaction.
Rifamycin have an induction effect on different drug metabolizing enzyme systems, most notably the cytochrome P450 (CYP) 3A4, which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus, cyclosporine, sirolimus, Everolimus, and even corticosteroids).
Therefore, close monitoring and continuous dose adjustment are highly recommended.
Level of evidence V.
Epidemiology in Latin America:
Latin America (LA) countries have lowered their TB burden during the past two decades.
In 2014, 110,000 Brazilians developed TB and 7700 died. Haiti, Bolivia, and Peru are highly endemic.
Based on notification numbers, Brazil’s estimated 2015 national incidence was 31 cases per 100,000.
Rifampicin- and isoniazid-resistant Mycobacterium tuberculosis causes MDR TB worldwide. Ecuador, Guatemala, and Peru have 3.0%–6.0% MDR new TB cases. These nations have high-mortality community-transmitted MDR.
TB AFTER SOLID-ORGAN TRANSPLANTATION:
Lung transplant recipients have the highest TB risk.
Local disease incidence affects transplant facilities’ active TB infection rates.
infection post-transplant may be donor derived, reactivation of LTB or de-novo infection.
Most of these occurred in patients who received grafts from deceased donors with active TB, which has a 30% transfer risk. Untreated LTBI donors may transmit TB.
Diagnosis of LTBI:
– The tuberculin skin test (TST) is suggested for LTBI screening in solid organ candidates/recipients and living donors.
– IGRAs has better connection with clinical risk factors for LTBI, they reduce bias, reduce false-positive results from nontuberculous mycobacteria or BCG vaccination, and may be more sensitive in those with chronic renal failure and severe cirrhosis.
– however, IGRAs’ negative predictive value is not optimal to rule out infection in patients at high risk for LTBI, including those born to or living in endemic countries, household contacts of active TB cases, and those who work or live in high-risk settings like correctional facilities and homeless shelters.
– greater cost and numerous test result conversions and reversions during serial screening may make interpretation difficult.
– in low-risk individuals, IGRAs may be used, but to maximize screening sensitivity, high-risk patients can have both tests, and any positive result should be considered LTBI.
Diagnosis of active TB:
– M. tuberculosis bacilli are detected by direct observation, culture, and nucleic acid testing to diagnose active TB. TST and IGRA are not indicated for active infection diagnosis.
– SOT recipients may have more extrapulmonary involvement. Patients with unexplained fever should be evaluated for TB.
– The Xpert MTB/RIF assay, a fast molecular diagnostic, may improve patient management. This test has a 98% sensitivity in smear positive respiratory samples and 67% in smear negative samples. Xpert MTB/ RIF assay is a good rule-in diagnostic test for extrapulmonary TB since it performs similarly on Non respiratory samples such tissue biopsies and cerebrospinal fluid. It detects MDR-TB-predictive rifampicin resistance simultaneously. Hence, it may help start MDR-TB treatment quickly while conventional culture and drug susceptibility findings are awaited.
– This assay can produce false-positive results in TB-treated patients.
– It also cannot replace drug susceptibility tests.
Risk Assessment of the Transplant Candidate:
– A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
– If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA.
– If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
Risk Assessment of Deceased and Living Donors:
– living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be
10 mm or greater.
– risk factors:
• Medical history.
• Endemic exposures, homeless status, incarceration and alcoholism.
• Radiographic findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes,
or pleural thickening
Treatment of LTBI in Transplant Candidates and Recipients:
– LTBI therapy is advised for untreated transplant candidates with a positive TST or IGRA who have not been treated previously.
– Even if the TST or IGRA is negative, those with high-risk pretransplant TB exposure should be evaluated for medication, as should those with a history of active TB infection that was inadequately managed.
– Chest imaging findings suggestive of prior untreated tuberculosis may prompt therapeutic consideration, particularly in regions where endemic mycoses are infrequent.
– If the donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation, therapy is advised.
– Prior to start treatment for LTBI, it is crucial to exclude active TB infection.
Therapeutic regimens:
– Oral INH 300 mg/d for 9 months and oral pyridoxine 25–50 mg daily are recommended for LTBI treatment.
– 9 months of therapy is safer than six.
– Hepatotoxicity should be monitored with serum ALT every 2 weeks for 6 weeks, then monthly for transplant candidates and recipients on INH.
– RIF 600 mg daily for 4 months or INH and rifapentine monthly for 12 weeks.
– Fluoroquinolones (ethambutol) may be used for LTBI.
Recommendations for Transplanted Patients Who Travel
to Endemic Areas:
– If recently transplanted patients intend to consider moving to a highly endemic area,INH preventive therapy should be considered during the first posttransplant year.
– Prior to travel, there is no justification for BCG immunization.
– To prevent nosocomial transmission of tuberculosis, transplant recipients who travel to TB-endemic regions in order to provide medical or humanitarian aid should take basic precautions. Upon their return, anyone who may have been exposed to tuberculosis should be evaluated, and anyone exhibiting symptoms of infection should seek prompt medical assistance.
Treatment of Active TB Infection:
– Local guidelines should be followed.
– The intensive phase regimen should use medications based on drug resistance in each group. A 4-drug regimen is usually advised.
– INH and rifampicin are the strongest first-line TB medicines. Rifampicin medication interactions and Anti tuberculous therapy hepatotoxicity should be evaluated in SOT.
– TB treatment in transplant recipients has no recommended duration.
– duration recommend at least 9 months of treatment.
level 5 , a narrative review
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
1. Summarise this article.
2. What is the level of evidence provided by this article?
Summary of this Article :
EPIDEMIOLOGY:
TB after Solid-organ transplantation:
In Latin America, TB continues to be a significant public health issue.
The incidence of TB increases after SOT, the highest risk among lung recipients.
TB was diagnosed in 0.9% to 5.9% of the recipients.
Reactivation of latent TB infection (LTBI) is probably the main cause of posttransplant TB.
Primary infection acquired in the community, and less frequently in the nosocomial environment, may also account for a considerable proportion of the cases, especially among patients living in endemic areas.
A minor proportion of primary infections result from donor-recipient transmission.
The risk of TB may be impacted by immigration, travel to endemic regions, and transplant tourism.
Working with high-risk populations (convicts and the homeless can pose a potential risk.
Diagnosis of LTBI:
There is no diagnostic reference standard for LTBI.
The tuberculin skin test (TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.
IFN-γ release assays (IGRAs) offer some advantages as compared with TST:
avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination,more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients
Diagnosis of Active TB Infection:
Fever of unknown origin
Rapid molecular test, such as the Xpert MTB/RIF assay
This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively.
Tissue biopsies and cerebrospinal fluid, indicating that Xpert MTB/ RIF assay is a useful rule-in diagnostic test for extrapulmonary TB.
Risk Assessment of the Transplant Candidate:
A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA.
If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction.
In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
In high-risk candidates (ie, patients originated from endemic countries, household contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), both tests could be performed and any positive reaction considered an evidence of LTBI
If any evidence of active infection is found in this workup, appropriate clinical specimens should be collected for microbiological confirmation of the diagnosis.
Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
Risk Assessment of Deceased and Living Donors:
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
The evaluation of the deceased donor for TB relies on:
Medical history.: The history of untreated or insufficiently treated TB should be investigated, as well as previous reactive IGRA or TST.
Endemic exposures: within last 2 years
Radiographic findings: such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening.
Active TB infection should be ruled out in donors at increased risk by obtaining samples, for example, sputum or bronchoalveolar lavage, to test for the presence of M. tuberculosis.
Organs from donors with known active TB infection should be discarded.
If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines.
Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, therefore, transplant recipients from such donors can be clinically monitored without receiving LTBI therapy.
Treatment of LTBI in Transplant Candidates and Recipients:
Criteria to Start Treatment
Therapy for LTBI is an effective strategy for the prevention of active TB infection in transplant recipients.
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated.
Chest imaging suggestive of previous untreated TB should prompt consideration for therapy, especially in areas where endemic mycoses are uncommon.
Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
Therapeutic Regimens
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
Nine months of therapy is preferred over 6 months because of better protection.
Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine aminotransferase checked every 2 weeks for 6 weeks, then monthly thereafter.
Timing of treatment of LTBI:
Preferably started before transplant and can often be completed while the patient is on the waitlist.
It can be started. Perioperatively or when medically possible until completion of the course.
Recommendations for Transplanted Patients Who Travel to Endemic Areas:
If recently transplanted patients are planning to move to a highly endemic area (ie, those with prevalence ≥100/ 100000), INH preventive therapy should be considered during the first posttransplant year, especially for those planning to take part in medical or humanitarian care, given the higher risk of primary TB acquisition.
There is no indication for BCG vaccine before travel, and it is contraindicated in transplant recipient.
Treatment of Active TB Infection:
Four-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB for at least 9 months.
Side effects: hepatotoxicity
Drug interactions:
Rifampin has the most potent enzyme induction effect.
Two-to 5-fold increments in the daily dose of cyclosporine, tacrolimus, and mammalian target of rapamycin inhibitors are generally necessary to maintain trough levels of the drug in the therapeutic range.
Thus, therapeutic drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption.
What is the level of evidence provided by this article?
Review = Level of evidence (V)
Summary ofTuberculosis Recommendations for Solid Organ Transplant Recipients and DonorsEpidemiology
The cases in the region declined from about 600,000 to 342,000 between 1990-2014.
The prevalence of MDR infection in Ecuador, Guatemala, and Peru has been estimated to range from 20 -26% T.B. after SOT the highest risk of T.B. among lung recipients, the most common of T.B post-transplant is the reactivation of foci of laten T.B infection. Patients living in the endemic area have a reasonable number of they got the disease by the nosocomial environment.
International Travel and posttransplant T.B
Immigration, international travel to endemic countries, and transplant tourism may influence the risk of T.B after SOT.
Diagnosis of LTBI
No standard diagnostic test for LTBI but current guidelines recommend TST test be used for screening LTBI in SOT candidates/recipients.
IFN-Y realize assays (IGRAs) also is used in the diagnosis of LTBI, it has some advantages as compared with TST avoiding interpretation bias reducing the false-positive result to previous exposure to non-tuberculous mycobacteria or BCG vaccination, and more sensitive in CKD and advanced liver cirrhosis. but the negative predictive value of IGTAs is not accurate to rule out infection in high-risk patients for LTBI.
Limitation of IGRAs :
1- It has a higher cost.
2- Occurrence of conversion and reversion of test result when serial screening is performed.
Diagnosis of active TB infection
1- Culture to detect mycobacterium T.B.
2- Nucleic acid testing, rapid molecular test such as Xpert MTBIRIF assays is highly sensitively 98% and specifically 67% .
The limitation of this test is a false positive result.
Prevention
Risk assessment of the transplant candidate,a history of clinical or radiological T.B and should be assessed in all recipients.
If no history of past T.B or treatment for LTBI so candidate should have TST or IGRA,TST if induration is 5 mm or more at 48 to 72 hours so considered positive second TST should be repeated 7 days to 10 days after the first TST to evaluate boosted -related skin conversion.in high-risk groups patients both TST&IGRA should be performed.
Risk assessment of deceased living donors
Living donors should evaluate as recipients with the exception cut off TST should be 10 mm or greater.
Evaluation of the deceased donors:
Medical history of untreated or insufficiency-treated TB previous reactive IGRAs or TST.
Endemic exposure travel or residence in an endemic area or exposure to active T.B. infection in the household or workplace in last 2 years , homeless, refugee, increation and alcoholism associated with LTBI.
Radiological findings include:
The apical fibronodular lesion, calcified solitary nodules, calcified lymph node, and pleural thickening. untreated LTBI without active infection is not contraindicated but should start preventive therapy for all recipients.
Treatment of LTBI in transplant candidates and recipients:
Criteria to start treatment of LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
High-risk exposure pretransplant T.B considered for therapy even if the TST or IGRA is not positive and also those with a history of active T.B infection were inadequately treated.
Therapeutic regimen
INH regimen 300 mg /day for 9 months plus pyridoxine 25 -50 mg po od
Transplant candidates and recipients on INH should be monitored for alanine aminotransferase every 2 weeks for 6 weeks then monthly.
Rifampicin 600 mg daily for 4 months (pretransplant).
INH plus rifapentine weekly for 12 months.
Timing of treatment
Should treat LTBI before transplant, if urgent transplant treatment can be perioperative and resume when medically possible.
Recommendation for transplant patients who travel to the endemic area:
If recent transplant patients are planning to move to a highly endemic area (prevalence > or more 100 /100.000 )INH preventive therapy is given in the posttransplant year.
BCG is contraindicated in a transplant recipient
Treatment of active T.B infection
Four drug regimens include INH, and rifampicin optimal treatment therapy is not defined but specialized advice should be a 9-month duration.
Monitoring adverse event-related therapy
First 2 months monthly biweekly.INH, Rifampicin, and pyrazinamide are associated with a risk of hepatotoxicity
3 -5 fold increase of liver enzyme requires discontinuation.
Drug interaction
Rifampicin enzyme inducer and decrease level of CNI and mTOR.
2 to 5 fold increase of the dose of CNI or mTOR to maintain the target trough level.
Rifabutin weaker enzyme induction and alternative therapy for rifampicin
level of evidence 5
EPIDEMIOLOGY
Epidemiology in Latin America:
The burden of tuberculosis (TB) has been reduced in Latin America (LA) countries, but is still a relevant public health problem. A group of 22 countries including Brazil with the highest TB burden, with 110 000 prevalent cases and 7700 TB deaths. The national average incidence estimates may mask wide variations within a country. Emergence of multidrug-resistant (MDR) TB is a global challenge, with higher prevalence in Ecuador, Guatemala, and Peru.
TB after solid organ transplantation :
The incidence rate of TB after solid-organ transplantation (SOT) is highest among lung recipients , with active TB infection affecting 0.9% to 5.9% of SOT recipient . Reactivation of latent TB infection (LTBI) is the main cause of post-transplant TB, but donor LTBI may also be a source of transmission.
International Travel and Posttransplant TB:
The risk of TB after SOT Immigration is influenced by international travel to endemic countries, and transplant tourism . Transplant candidates originating from endemic areas are at an increased risk of developing active TB infection and a higher prevalence of LTBI . Transplant tourism is also associated with donor transmission of TB .In low-incidence countries travel-related acquisition may account for a substantial proportion of new infections among peoples there .There is increased risk of TB infection associated with a cumulative history longer than 3 months of travel to high-incidence areas . Humanitarian work with high-risk populations, long-distance flights, ground transportation, and visiting friends and relatives are all risk factors for active TB infection.
DIAGNOSIS : the tuberculin teast is the best studied test for LTBI sceening but IGRA offer advantages such as avoiding bias,reducing false-positive result and being more sensitive to chronic renal failure and advanced cirrhosis.
Diagnosis of Active TB Infection : The diagnosis of active TB infection based on the detection of M. tuberculosis bacilli by direct observation, culture, and nucleic acid testing. The Xpert MTB/RIF assay is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively. It also allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB. However, false-positive results have been observed among patients who had been successfully treated for TB
Risk Assessment of the Transplant Candidate:
All recipients should be assessed regarding history of clinical or radiological TB and the treatment received .
If history is negative, candidates should undergo evaluation for LTBI with either TST or IGRA.
Candidates who have low risk for LTBI should preferably be tested solely with IGRA, in high risk patients a dual test may be used .
Transplantation should be postponed if candidates proved to have active TB , until the disease is well controlled with adequate treatment and smears are negative.
Risk Assessment of Deceased and Living Donors:
The evaluation of the deceased donor for TB relies on: medical history.
The history of untreated or insufficiently treated TB should be investigated, as well as previous reactive IGRA or TST. •
Active TB infection should be ruled out in donors at increased risk by obtaining samples, for example, sputum or bronchoalveolar lavage, to test for the presence of M. tuberculosis.
A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, especially for lung recipients.
TREATMENT:
Treatment of LTBI in Transplant Candidatesand Recipients:
Therapy for LTBI is proved to be effective strategy for the prevention of active TB infection in transplant recipients, and is recommended for transplant candidates with positive TST or IGRA and those with high-risk pretransplant TB exposure.
Therapeutic Regimens:
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to50 mg daily. Nine months of therapy is preferred over 6 months because of better protection, monitoring for hepatotoxicity is mandatory . A recent randomized study of pretransplant levofloxacin versus posttransplant INH in liver transplant recipients was stopped early because of excessive adverse events in the levofloxacin arm.
Timing of treatment :
The timing of LTBI treatment requires balancing risks and benefits for each patient, especially liver transplant recipients .When possible, treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist.It is particularly challenging to treat liver transplant candidates before transplant.
Recommendations for Transplanted Patients Who Travel to Endemic Areas:
INH preventive therapy should be considered for transplant recipients who travel to endemic areas to provide medical or humanitarian care, and those with possible TB exposure should be evaluated on return and seek medical evaluation immediately.
Treatment of Active TB Infection:
Treatment of Active TB Infection with a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB, but there is risk of hepatotoxicity and drug interactions. The optimal length of treatment of TB in transplant recipients is not defined depend on severity and site of infection .
Monitoring of adverse events is recommended, especially during the first 2 months of treatment, due to increased risk of hepatotoxicity.
Drug Interactions:
Rifampicin is a potent enzyme inducer which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids).
Rifabutin,is as effective as rifampin for the treatment of TB in trials conducted in non-transplant patients with weaker and more limited spectrum of enzyme induction.
What is the level of evidence provided by this article?
Level V
I like your summary, level of evidence, analysis and take home messages.
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
1. TB after solid-organ transplantation
· TB was diagnosed in 0.9% to 5.9% of the recipients.
· Reactivation of foci of latent TB infection (LTBI) is probably the main cause of post-transplant TB.
· A minor proportion of primary infections result from donor-recipient transmission.
· Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB after SOT.
2. Diagnosis
Diagnosis of LTBI
· There is no diagnostic reference standard for LTBI.
· The tuberculin skin test (TST) remains the best studied test.
· IFN-γ release assays (IGRAs) reduce false-positive results related to previous exposure to BCG vaccination, and are more sensitive in candidates with chronic renal failure.
· IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI. Here both tests could be performed.
Diagnosis of Active TB Infection
· Neither TST nor IGRAs are recommended for diagnosing active infection.
· SOT recipients may present unusual manifestations, TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin.
· The availability of a rapid molecular test, such as the Xpert MTB/RIF assay, may have a major impact in the management of these patients.
· Due to its high sensitivity and specifity, Xpert MTB/ RIF assay is useful in diagnosis of pulmonary and extrapulmonary TB.
· Xpert MTB/ RIF assay also allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB.
1. Prevention
Risk Assessment of the Transplant Candidate
· A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
· Candidates should un dergo evaluation for LTBI with either TST or IGRA if no history of past TB.
· In TST, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction.
· A second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
· Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
· Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
Risk Assessment of Deceased and Living Donors
Living donors should undergo the same evaluation as candidates, but the cutoff for TST should be 10 mm or greater.
The evaluation of the deceased donor for TB
· Medical history: The history of untreated TB, and reactive IGRA or TST should be elicited.
· Assessment of risk factors for TB infection
· Assessment for radiological evidence of previous TBI.
· Active TB infection should be ruled out in donors at increased risk by obtaining samples, for example, sputum or bronchoalveolar lavage.
· Because the results of micro- biological investigation will be available after procurement, it must be ensured that all data will be forwarded to transplant teams.
· Organs from donors with known active TB infection should be discarded.
· If diagnosis of TB in the donor becomes available only after organ transplantation, therapy for TBI should be immediately started in the recipient.
· Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
· Lungs with residual tuberculous lesions should not be used for transplantation.
· A history of untreated LTBI is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered.
2. Treatment
Treatment of LTBI in Transplant Candidates and Recipients
· LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
· Those with high-risk pre-transplant TB exposure and those with history of active TB infection that was inadequately treated should be considered for therapy even if the TST or IGRA is negative.
· Chest imaging suggestive of previous untreated TB should prompt consideration for therapy.
· Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB.
· Therapy is also recommended, if the recipient is exposed to TB after transplantation.
Therapeutic Regimens· For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months with oral pyridoxine 25 to 50 mg daily with monitoring for hepatotoxicity· Alternative regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks. These regimens can be considered pre-transplant, but should be avoided post-transplant.· When possible, treatment for LTBI should be started before transplant.· If recently transplanted patients are planning to move to a highly endemic area, INH preventive therapy should be considered du ing the first post-transplant year. Treatment of Active TB Infection
· Treatment should follow local guidelines for the general population.· In the context of SOT, many factors should be considered, such as the risk of hepatotoxicity related to the antituberculous treatment and drug interactions of rifampicin.· Many specialists recommend that treatment duration should be at least 9 months. Monitoring of Adverse Events Related to Therapy· Close monitoring of adverse events is highly recommended, mainly during the first 2 months of treatment.· A 3-fold increase aminotransferases accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation.
Drug Interactions · Rifamycins leads to a reduction in the blood levels ta crolimus, cyclosporine, sirolimus, everolimus, and corticosteroids. · A lower blood level of these drugs is associated with higher risk of graft rejection.· Rifabutin, which has a weaker enzyme induction is an alternative for rifampin. It has been demonstrated to be as effective as rifampin for the treatment of TB in non-transplant patients.· When rifabutin is used , drug monitoring of immunosuppressive is indicated.
I admire your clarity of thought process and I quote from your write-up in italics:
Those with high-risk pre-transplant TB exposure and those with history of active TB infection that was inadequately treated should be considered for therapy even if the TST or IGRA is negative.
Summarise this article
Epidemiology in Latin America:
In Latin America, most countries in the region are still moderately to highly endemic, with incidence remaining over 100 cases per 100 000 in Haiti, Bolivia, and Peru.
Multidrug-resistant (MDR) TB, which is defined by the isolation of a causative strain of Mycobacterium tuberculosis resistant to rifampicin and isoniazid (INH), is a global challenge, and accounts < 3% of the newly diagnosed cases, the risk increases in those previously treated for TB infection.
The prevalence of MDR-TB in Ecuador, Guatemala, and Peru, is in the range of 20-26%.
TB after solid organ transplantation:
The incidence rate of TB markedly increases after solid organ transplantation (SOT), the risk being highest among lung recipients, and correspond to the local TB prevalence.
Reactivation of the latent infection is the most common cause of post transplant TB infection, then community acquired primary infection, and rarely donor derived active disease transmission are the sources to disease.
International Travel and Posttransplant TB:
Immigration, travel to high endemic area and transplant tourism increases the risk of LTBI, Humanitarian work with high-risk populations, such as prisoners and homeless people, may also be a significant risk factor, long time flights, underground and puplic transportation are risk factors for active TB infection.
DIAGNOSIS:
1- Latent tuberculosis:
TST is the most recommended screening for latent TB for both donor and recipient worldwide. and IGRAs – interferon gamma release assay is widely used in the last decade with major PROS in: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis.
IGRAs CONS– (1) poor negative predictive value in high risk population cannot rule out the disease, (2) higher cost and (3) the frequent occurrence of conversions and reversions of test results when serial screening is performed, which may complicate the interpretation of their results among SOT candidates.
2- Primary tuberculosis:
The diagnosis of primary TB relies on the detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing. Which may take long time and increase the morbidity and mortality from a disease.
Xpert MTB/RIF assay, highly specific, rapid test to start treatment, with a sensitivity of 67% in smear negative and 98% in smear positive body secretions, and allows the simultaneous detection of rifampicin resistance.
PREVENTION:
– Risk Assessment of the Transplant Candidate:
A history and radiological assessment and treatment for TB should be taken before transplant, until the disease is well controlled and smears are negative.
Evaluation for LTBI to all transplant candidate is a must, TST for high risk candidates, TST of 5 mm or more considered positive and mandate treatment., and IGRAs for low risk candidates should be considered.
Active infection is not an absolute contraindication to transplantation when urgently needed.
– Risk Assessment of Deceased and Living Donors:
The TST 10 mm or more considered positive and required treatment.
The evaluation of the deceased donor for TB relies on:
a. Medical history. The history of untreated or insufficiently treated TB should be investigated, as well as previous reactive IGRA or TST.
b. Endemic exposures. Travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the last 2 years, homeless or refugee status, incarceration and alcoholism may be associated with LTBI.
c. Radiographic findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening.
So, microbiological evalutation of sputum or bronchoalveolar lavage with drug susceptibility should done in deceased donors and transmitted to transplant team as soon as the result comes.
Untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered.
TREATMENT:
1- Treatment of LTBI in Transplant Candidates and Recipients:
Treatment for the followings after ruling out active disease:
· All transplant candidate with positive TST and IGRAs.
· Those with high risk TB exposure should receive even if both TST and IGRAs are negative.
· Those with exposure to TB patients post transplant.
· Those with history of active TB infection that was inadequately treated, or chest X-ray findings suggestive of not well treated TB.
Therapeutic Regimens:
Isoniazid 300 mg + pryridoxin 25-50 mg daily for 9 months, with frequent monitoring of ALT every two weeks for 6 weeks then monthly- the preferred regimen.
Rifampin 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks – can be considered before transplant but should be avoided after transplant due to drug-drug interactions.
Fluoroquinolones (± ethambutol), a recent randomized study of pretransplant levofloxacin versus posttransplant INH in liver transplant recipients was stopped early because of excessive adverse events in the levofloxacin arm.
Timing of Treatment:
LTBI treatment should start before organ transplantation, if urgent transplant is indicated then the treatment should be held perioperatively and resumed after medically feasible, avoiding rifamycin based therapy.
For Transplanted Patients Who Travel to Endemic Areas INH prophylaxis in the first year of transplantation is indicated, No indication for BCG vaccine before travel, and it is contraindicated in transplant recipients.
2- Treatment of Active TB Infection:
Treatment should follow local guidelines for the general population, 4 drug regimen INH+RIF based for 9 months.
Monitoring the adverse effects of drugs biweekly for 2 months then monthly, with 3-5 times dose increment of CNI and m-TORi, doubling steroid and frequent drug level monitoring.
Drug Interactions:
Rifamycin is a strong enzyme inducer, decreasing the levels of immunosuppressive drugs, making them prone to rejection, enzyme induction starts within hours after the first dose of rifampin, maximum effect is reached in about 1 to 2 weeks and slowly declines over 2 weeks after stopping its use.
Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin.
Liver function test monitoring if ALT increases 3 times with symptoms, or 5 times normal with no symptoms, consider discontinuation of INH+RIF.
What is the level of evidence provided by this article?
Level of evidence is I – recommendations and guidelines by the transplantation society.
Is it really a level 1 evidence?
I appreciate your debate regarding the use of TST Vs IGRA in risk assessment of those with suspected latent TB.
Introduction:
In Latin America, the burden of TB has reduced in the last 2 decades, but it remains a high TB endemic zone. The prevalence varies in each country. The emergence of multidrug resistant TB (MDR TB) is a challenge. It is defined by the isolation of a causative strain of Mycobacterium tuberculosis resistant to rifampicin and isoniazid (INH). The transmission of MDR TB has a significant impact on mortality.
TB after solid organ transplantation:
The incidence rate of TB increases after solid organ transplantation (SOT), the risk is highest after lung transplantation. The main cause of TB after transplantation is reactivation of foci of latent TB infection (LTBI). Primary infection after exposure to a patient with active TB is also a major cause of TB after SOT. Another cause is transmission to the recipient via the donor graft.
International travel and post-transplant TB:
Transplant candidates from endemic area have a higher prevalence of LTBI and are, hence, at an increased risk of developing active TB infection after SOT. Immigration may also affect the risk of donor transmission. The time spent in the endemic areas also influences the risk of TB infection. Humanitarian work with high-risk populations, such as prisoners and homeless people, may also be a significant risk factor.
Diagnosis of LTBI:
The tuberculin skin test (TST) is recommended for the screening of LTBI in solid organ donor candidates/recipients and living donors. Interferon gamma release assays (IGRAs) off more advantages over TST. They avoid interpreting bias, reduce false-positive results related to exposure to BCG vaccinations, and are more sensitive in candidates with chronic renal failure and advanced cirrhosis. Unfortunately, they are more expensive.
Diagnosis of active TB infection:
The diagnosis of active TB requires detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing. Neither TST or IGRAs are recommended for diagnosing active infection. SOT recipients may present with unusual clinical manifestations. Invasive diagnostic procedures are required in this population. This results in a delay in diagnosis and higher mortality. The Xpert MTB/RIF assay is highly specific and sensitive to TB infection diagnosis. It also allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB. Unfortunately, it has been associated with false-positive results in patients previously treated for TB.
Prevention:
Risk assessment of the transplant candidate For the recipients, a history of clinical or radiological TB and any treatment received should be assessed. If there is no history of past TB or treatment for LTBI, then the potential recipients should undergo evaluation for LTBI with either TST or IGRA, both for patients living in high risk settings. If the tests are positive, active TB infection must be excluded before LTBI treatment is started. If active TB infection is present, the transplant should be postponed until the disease is well controlled, but it is not an absolute contraindication for the procedure.
Risk assessment of deceased and living donors Living donors should undergo the same evaluation as the potential recipients. Deceased donor evaluation relies on their medical history, endemic exposure and radiographic findings. Active TB should be ruled out in donors at increased risk. The organs with active TB infection from deceased donors should be discarded. If the diagnosis is made after the transplantation, then therapy for active TB should be initiated in the recipient.
Treatment
Treatment of LTBI in transplant candidates and recipients Treatment for LBTI is reported to be effective in preventing active disease, in transplant recipients. LTBI therapy is recommended for potential transplant recipients with:
The preferred treatment for LTBI is INH 300mg/day for 9 months, with pyridoxine 25-50mg/day. The treatment should ideally be started before the transplant if the transplant is not an emergency procedure. INH preventative therapy should be considered during the first year post-transplant for patients in high-risk areas, or traveling to high-risk areas.
Treatment of active TB infection Treatment should follow local guidelines. The optimal length of treatment is not defined, most specialists recommend at least 9 months of treatment.
Adverse effects and drug levels should be monitored closely. A three-fold increase of aminotransferases with any symptoms, or a five-fold increase regardless of a symptom requires discontinuation of the anti-TB medications.
Monitoring of Adverse Events Related To Therapy:
There is an increased risk of adverse events and drug to drug interactions that will need very close monitoring. Both, INH and rifampin interact with CNIs, mTOR inhibitors and glucocorticoids. Therefore, it is important, especially at the beginning of therapy for the first two to four weeks and after completing therapy, to monitor the drug levels.
This is a narrative review: LOE V
I admire your debate regarding the use of TST Vs IGRA in risk assessment of those with suspected latent TB. I like the way you mitigate against bias when interpreting tests.
I like your summary, level of evidence, analysis and take home.
Thank you Professor Sharma
Tb recommendations for Solid Organ Transplant Patients and Donors
Reactivation of latent TB infection (LTBI) is likely the main cause of post-transplant TB, and DDI for TB primarily results from deceased donation. The incidence rate of TB infection is considerably raised following solid organ transplantation (SOT), with the risk being highest among lung recipients.
There are numerous risk factors for SOT recipients that include working with high-risk populations, including prisoners and the homeless, being exposed on long-distance flights, and visiting endemic regions.
Latent Tb infection diagnosis
Although there are no universally accepted diagnostic standards for LTBI, all recommendations call for tuberculin skin testing (TST) in solid organ candidates, recipients, and living donors. IFN-release assays (IGRAs), a recent development in diagnostic tools, serve as the second test. The benefits of IGRA over the tuberculin test include the avoidance of interpretation bias, the reduction of false-positive results resulting from prior exposure to nontuberculous mycobacteria or BCG vaccination, and the likelihood that they are more sensitive in candidates with advanced cirrhosis and chronic renal failure.
The use of a more specific test may lower the rate of false-positive results, so in low-risk patients, IGRAs were thought to be the only approach. On the other hand, in high-risk patients, both tests could be used, and any positive result should be taken as evidence of LTBI to maximize screening’s sensitivity.
Active TB infection diagnosis
The Xpert MTB/RIF assay is highly specific and has an estimated sensitivity of 98% and 67% in smear-positive and -negative respiratory samples, respectively. It also plays a role in the detection of rifampicin resistance. TST and IGRAs have no role in the diagnosis of active TB, but Mycobacterium tuberculosis bacilli can be confirmed by culture, and nucleic acid testing is the cornerstone of the diagnosis.
Prevention
Transplant Candidate Risk Assessment
Assess all recipients for clinical or radiological TB and therapy. TST or IGRA for LTBI evaluation if no history of TB or therapy. High-risk patients can undergo both tests, with a positive result indicating LTBI. Active TB infection should be treated before donation according to local/international protocols.
Donor Risk Assessment
Organs from donors with known active TB infection should be discarded, as TSTs are difficult and time-consuming and IGRAs have not been validated in deceased donors. If active TB infection is confirmed in the donor, treatment should be started in the recipient immediately per local guidelines. History of untreated LTBI without evidence of active infection is not a contraindication to donation, but all recipients should receive preventive therapy.
Transplant Candidates and Recipients LTBI Therapy
Treatment Requirements
1- Untreated transplant candidates with positive TST or IGRA should receive LTBI.
2- Active TB infection untreated.
3- Transplant recipients whose donors have LTBI or TB should receive therapy.
Treatment options for Latent Tb infection
Oral INH 300 mg/d for 9 months, with pyridoxine 25 to 50 mg daily.
Alternatively, rifampicin given as 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
Recommendation for transplanted Patients Traveling to Endemic Areas
INH preventative therapy should be considered in the first year post-transplant. Before visiting endemic areas, BCG vaccination is not recommended and contraindicated. Infected kidney recipients should seek medical help.
Therapy for Active Tuberculosis
Typically, a 4-drug regimen is advised. The most effective first-line treatments for TB are indomethacin (INH) and rifampicin, which are typically given for nine months. The first two months of treatment are very important for close monitoring, which should be done every two weeks. If the LFT is 5 times higher than normal, medication should be stopped.
Adverse drug reactions-drug interactions
Rifampicin is a powerful drug inducer that increases drug metabolism and, as a result, lowers blood levels of drugs like (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids), which can cause graft rejection. Rifabutin has the advantage over Rifampicin in that it is less of a drug inducer, but drugs should still be strictly monitored.
Level of evidence
Level V- review article
I appreciate your debate regarding the use of TST Vs IGRA in risk assessment of those with suspected latent TB.
I like your summary, level of evidence, analysis and take home.
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors.
The incidence rate of TB infection is markedly increased after solid organ transplantation (SOT) and the risk being highest among lung recipients, reactivation of latent TB infection (LTBI) is probably the main cause of post-transplant TB and DDI for TB is mainly occurring from deceased donation.
Many risk factors for developing TB in SOT recipients such as work with high-risk populations, such as prisoners and homeless people, exposure in long-distance flights, and travelling to endemic areas.
Diagnosis of LTBI.
There is no standard diagnostic criteria for LITB but all guidelines recommend The tuberculin skin test (TST) in solid organ candidates/recipients and living donors and the second test is IFN-γ release assays (IGRAs) which is a new diagnostic tools in the last decade, the advantages of it compared with TST are avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis.
So, in low-risk patients, IGRAs was considered as the sole approach, because the use of a more specific test might reduce the rate of false-positive results and on the other hand, in high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
Diagnosis of Active TB Infection.
TST and IGRAs have no role inactive TB diagnosis but detection of M. tuberculosis bacilli by culture, and nucleic acid testing is the quintessential of the diagnosis, the Xpert MTB/RIF assay is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98%and 67%, respectively and also has a role in detection of rifampicin resistance .
Prevention:
Risk Assessment of the Transplant Candidate.
1- A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
2- No history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA.
3- For high-risk candidates, both tests could be performed and any positive reaction considered an evidence of LTBI.
4- Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
Risk Assessment of Deceased and Living Donors.
Organs from donors with known active TB infection should be discarded, it is not easy and time does not allow for a TST and IGRAs have not been validated in deceased donors, and if active TB infection confirmed in the donor, immediately treatment should be started in the recipient per local guidelines, history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered and lung with residual TB should be discarded.
Treatment of LTBI in Transplant Candidates and Recipients
Criteria to Start Treatment.
1- LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
2- Those with history of active TB infection that was inadequately treated.
3- Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB.
Therapeutic Regimens.
1- The preferred regimen for LTBI is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
2- Alternative regimens containing rifampicin can be considered pre-transplant, these regimens include RIF 600mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
Timing of Treatment.
Better to complete the treatment course before transplantation but if urgent transplant is indicated, the treatment can be held preoperatively and resumed when medically possible until completion of the originally planned course.
Recommendations for Transplanted Patients Who Travel to Endemic Areas.
– INH preventive therapy should be considered during the first post-transplant year.
-BCG vaccine is contraindicated and not indicated before traveling to endemic area.
– Anyone kidney recipient with symptoms of infection should seek medical evaluation immediately.
Treatment of Active TB Infection.
In most cases, a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB and usually for 9 months not least. Close monitoring is highly recommended, mainly during the first 2 months of treatment when it should be performed biweekly and if LFT is 5 folds than normal, medications should be discontinued.
Drug Interactions.
Rifampicin is considered potent drug inducer which leads to increasing drugs metabolism and hence, decreasing their level in blood such as (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids) that may lead do graft rejection, and so frequent monitoring of these drugs is such important, Rifabutin has an advantage over Rifampicin that it is less drug inducer but still drugs should be strictly monitored.
Level of evidence: V Narrative study .
I appreciate your debate regarding the use of TST Vs IGRA in risk assessment. I like your comment, “TST and IGRAs have not been validated in deceased donors”,
I like your summary, level of evidence, analysis and take home messages
SUMMARY
Introduction
The burden of TB in the Latin has reduced in the Latin American continent in the last decades, although according to WHO classification, Bazil still remains one of the countries with the highest burden of the disease with 110,000 prevalence disease and 7700 TB death. Moreso, the national incidence varies from as low as 11 cases per 100000 in the capital city to as high as 300 per 100000 in underprivileged communities. A more challenging situation is the emergence of MDR which is known to be quite common among those previously treated with TB
TB after solid organ transplantation
Diagnosis of Latent TB
Advantages of IGRA over TST
Limitation of IGRA
The advice given by some specialists is to use IGRA in low-risk patients and in those with high risk for TB
Diagnosis of active TB
It relies on the detection of M. Tuberculosis in samples via tests like
Risk assessment of transplant patient-recipients
Risk assessment of transplant patient-donors and diseased donor
Lungs with residual TB lesions should not be used for donation
Treatment for LTBI in transplant and recipient patient
Treatment of active infection
The general local guideline of the country or region be followed based on the endemicity of TB in the area and it has been advised that the treatment should be at least 9 months. The treatment comprises the intensive phase (INH+RIF+ PYRAZINAMIDE + EHTAMBUTO), for 2 months then followed by 6-9 months of the maintenance phase of INH + RIF.
Drug interaction
The major challenge is a rifampicin drug interaction with CNIs, mTORs, and corticosteroids by reducing their trough level and this could result in allograft rejection or loss.
Other toxicities of concern are neurotoxicity, hepatotoxicity, and nephrotoxicity
The level of evidence 5
I like your summary, level of evidence, analysis and take home.
I appreciate your debate regarding the use of TST Vs IGRA in risk assessment.
This is a review with an evidence level of 5
There is a around 50% decrease both in the number and mortality of TBC in Latin America. TB-associated death reduced from 43000 to 22000; this data belongs to the years 1990 and 2014. According to WHO, Brazil is still one of the countries with a high endemic rate. The incidence is variable among countries. Recently, we have been in the challenge of multidrug-resistant TBv (MDR-TBC), defined as resistance to rifampicin and INH.
After solid organ transplantation, the reactivation of latent TBC seems to be the most common cause. Nosocomial or primary active infection is less. Donor-related transmission can also be seen with a transmission risk of %30.
LTBI is high in patients from high-endemic areas. Guidelines still suggest normal Tuberculin skin test, as it is in most studied. Recently IGRA is offered but still not optimal to rule out infection in patients with a high risk of latent TBC infection. Still, it has the advantage of reducing interpretation bias, and low false positive results due ton on tuberculous tbc or previous infection as well. IGRA is still not widely used by transplantation centres. Some use it in combination with TST.
For diagnosis of active tbc neither TST nor IGRA is recommended. The real challenge is suspicion which is not easy because of non-specific or symptoms that can be attributed to other reasons.
Prevention is key. All patients should be evaluated for latent infection by history and x-ray. Candidates without previous history of TBC should be screened by either TST or IGRA. An induration of more than 5 mm should be considered positive. For those with very high risk or those with suspected contact or those from endemic areas, both tests need to be performed.
Treatment of active LTBI
Those who are at a high risk of exposure and those with positive skin or IGRA tests should be treated to prevent an active infection. Usually, the preferred treatment is INH 300 mg/day (9 months) combined with vitamin B6.
Management of active TBC: should comply with the guidelines but usually is based on 4 drugs regimen. INH and rifampicin constitute the backbone of treatment. Close monitoring is essential. Interaction with rifampicin should be considered. We need to consider that the net effect is seen oardas the second week and subsides likewise after discontinuation.
I appreciate your debate regarding the use of TST Vs IGRA in active TB.
I like your summary, level of evidence, analysis and take home messages.Please use headings and sub-headings to make easier to read your write-up. Please use bold or underline to highlight headings and sub-headings.
Epidemiology
Tuberculosis is a public health problem ,but in period from 1990 to 2014 prevalent cases declining ( from 600,000 to 342000) and mortality rate( 43000 to 22000 ) this data from latin America counteries .
Brazil remains in the group of 22 counteries with the highest tuberculos burden in the world.
MDR (multi drug resistant ) is below 3% in new TB cases.
TB after solid –organ transplantation.
The incidence of TB increases after solid organ transplantation which is higher in lung transplantation.
Reactivation latent TB is main cause of posttransplant TB, primary infection is less common and less common also in infection from donor-recipient transmission .
International travel and post transplant TB
Immigration and travel to endemic area may influence in posttransplant TB.
Prisoner and homeless are risk factor.
DIAGNOSIS of latent TB:
TST is still recommended for diagnosing latent TB.
IGRA is new ,and there is some advantage like : avoid interpreting bias,reduce false positive results ,
And more sensitive in CKD and cirrhotic liver.
The use of TST and IGRA differ from centre to another ,as in Europian survey :
TST alone used in 48% .
IGRA alone in 30% .
TST and IGRA simultaneously in 16%.
TST followed by IGRA in 6%.
Diagnosis of active TB:
the diagnosis of active TB relies on detection of mybacterium TB bacilli by direct observation ,by culture and nucleic acid testing.
Gene expert test MTB/RIF assay is highly specific and sensitivity depend on if smear positive sensitivity 98% ,if smear negative respiratory sample 67%.
Expert assay use to rule- in extra pulmonary TB.
Expert assay use in detection of rifampicin resistance .
Limited use of expert assay is that false positive results in already treated for TB.
Risk assessment of the transplant candidates :
The history of any TB treatment and radiological manifestation for all recipient must be assessed.
If no history latent TB should be assessed by TST.
IGRA alone or combination with TST .
Active TB must be exclude in any TST or IGRA positive test.
Risk assessment of deceased and living donor
History of any TB ,treatment ,endemic area and any radiological findings.
In high risk donor ,sputum test must be taken.
Exclusion of the donor if had active TB.
If donor treated for 6 month later can donate .
Treatment of latent TB in transplant candidates and recipient
Any positive TST or IGRA therapy is recommended .
In high risk pre transplant inspite of negative TST or IGRA therapy is recommended .
INH 300 mg/d for 9 month ,with oral 25 to 50 mg pyridoxine daily .
Monitoring of adverse events related to therapy
Monitoring for hepatotoxicity ,if liver enzymes increase by 3 to 5 fold ,stop the therapy.
Drug interaction
Rifamycins have an inuction effect through cytochrome P450.
Close monitoring and dose adjustment regularly is highly recommended.
Level of evidence V
I appreciate your debate regarding the use of TST Vs IGRA.
I like your summary, level of evidence, and analysis.
Summarise this article
* TB incidence increases after SOT, with the highest risk in lung recipients.
* TB was diagnosed in 0.9% to 5.9% of the recipients.
* Reactivation of foci of latent TB infection (LTBI) is probably the main cause of post transplant TB.
* Primary infection acquired in the community, and less frequently in the nosocomial environment
* Transplant candidates originating from endemic areas have a higher prevalence of LTBI and increased risk of developing active TB infection
* Transplant recipients from low-incidence countries may be exposed to primary infection while traveling to an endemic area.
* the actual impact of such exposure in this specific population has not been assessed.
* risks to increase incidence of TB infection are : immunocompetent travelers returning from endemic countries, travellers who were involved in Healthcare or academic medical exchange programs. Humanitarian work with high-risk populations.
* Time spent in the endemic area ( more than 3 months) ·
Diagnosis of LTBI ( TST the standard ) , next is (IGRAs)
* There is a marked variation across transplant centers regarding the approach for screening LTBI in candidates, with TST alone being used in 48% of the participating centers, IGRA alone in 30%, TST and IGRA simultaneously in 16% and TST followed by IGRA in 6%.
Diagnosis of Active TB Infection
* by detection of M. tuberculosis bacilli by direct observation, culture, and nucleic acid testing.
* Neither TST nor IGRAs are recommended for diagnosing active infection.
*SOT recipients may present unusual manifestations,or aysmptomatic and most of time with extra pulmonary symptoms .
SOT candidates evaluation :
*A history of clinical or radiological TB and treatment for LTBI should be assessed in all recipients.
* If TST induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction.
* A second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
* Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
* If active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
DONORS evaluation :
* Living donors should undergo the same evaluation as candidates for TB with Medical history, endemic exposures, and radiographic findings, but induration of TST 10 mm or greater.
* for deceased donors, TST and IGRAs should be considered
* Organs from donors with active TB infection should be discarded and therapy for active infection should be immediately started.
* Lungs with residual tuberculous lesions should not be used for transplantation.
TREATMENT
* LTBI therapy is recommended for transplant candidates with positive TST or IGRA, those with high-risk pretransplant TB exposure, and those with a history of active TB infection.
* It is also recommended for transplant recipients whose donor has a history of untreated LTBI or TB, or if the recipient is exposed to TB after transplantation.
* oral INH 300 mg/d for 9 months, with pyridoxine 25 to 50 mg daily.
* Alternative regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
* Treatment for LTBI should be started before transplant, and if an urgent transplant is indicated, held perioperatively and resumed when medically possible until completion of the course.
* Monitoring of INH, rifampicin, and pyrazinamide is recommended due to the increased risk of hepatotoxicity.
* Rifampycins have an induction effect on different drug-metabolizing enzyme systems, leading to a reduction in the blood levels of immunosuppressive drugs used after SOT.
* maintain therapeutic blood levels of calcineurin and mammalian target of rapamycin inhibitors during TB treatment.
level of evidence provided by this article
Level V
I appreciate your debate regarding the use of TST.
I like your summary, level of evidence, analysis and take home messages.
III. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
===================================================================
Summarise this article
EPIDEMIOLOGY
Epidemiology in Latin America
====================================================================
TB AFTER SOLID-ORGAN TRANSPLANTATION
International Travel and Posttransplant TB
====================================================================
DIAGNOSIS
Diagnosis of LTBI
Diagnosis of Active TB Infection
====================================================================
PREVENTION
Risk Assessment of the Transplant Candidate
Risk Assessment of Deceased and Living Donors
====================================================================
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients
Criteria to Start Treatment
Therapeutic Regimens
Timing of Treatment
Recommendations for Transplanted Patients Who Travel to Endemic Areas
Treatment of Active TB Infection
Monitoring of Adverse Events Related to Therapy
Drug Interactions
==================================================================
What is the level of evidence provided by this article?
The level of evidence is 5
==============================================
Typing whole sentence in bold or typing in capitals amounts to shouting.
I like your detailed summary. I appreciate your debate regarding the uncertainty on optimal duration of therapy
Summary:
Epidemiology of TB in SOT:
International travel and post transplant T.B:
Diagnosis of latent T.B
Diagnosis of active T.B
Prevention:
a- Recipient:
b- Donor
Treatment of latent T.B:
a- Recipient with positive tests who have not previously treated.
b- Those with history of active TB infection that was inadequately treated.
c- donor with history of untreated or incompletely treated LTBI or TB,
d- if the recipient is exposed to TB after transplantation.
Recipient travelling to endemic area:
Treatment of active T.B:
Monitor of adverse events:
Drug interaction:
level of evidence: V
I like your approach in interpreting TST and IGRA.
Summary of the article
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
1. Diagnosis:
A. Diagnosis of latent TB: There is no diagnostic reference standard for LTBI.
a) The tuberculin skin test (TST) remains the best studied test.
b) IFN-γ release assays (IGRAs)
I. offer some advantages as compared with TST:
· avoid interpreting bias.
· reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination.
· probably more sensitive in candidates with chronic renal failure and advanced cirrhosis.
II. Limitations of IGRAs:
· the negative predictive value of IGRAs is not optimal to rule out infection in patients at high risk for LTBI.
· higher cost.
· the frequent occurrence of conversions and reversions of test results.
B. Diagnosis of active TB infection:
a) The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation(culture and nucleic acid testing).
b) Neither TST nor IGRAs are recommended for diagnosing active infection.
c) Rapid molecular test(the Xpert MTB/RIF assay) is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively.
· The Xpert MTB/ RIF assay is a useful rule-in diagnostic test for extrapulmonary TB(when testing nonrespiratory samples, such as tissue biopsies and cerebrospinal fluid).
· The Xpert MTB/ RIF assay is highly predictive of MDR-TB.
· The Xpert MTB/ RIF assay has a limitation of false-positive results( have been observed among patients who had been successfully treated for TB).
2. Prevention of TB
a) Risk Assessment of the Transplant Candidate:
· A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
· Candidates should undergo evaluation for LTBI with either TST or IGRA.
· When using TST, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction.
· A second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
· Candidates who have low risk for LTBI should preferably be tested solely with IGRA.
· In high-risk candidates, both tests could be performed and any positive reaction considered an evidence of LTBI.
· Whenever dual-test approach is used, IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses.
b) Although, active infection may not be considered an absolute contraindication to transplantation,once active TB infection is diagnosed, transplantation should be postponed.
c) Risk Assessment of Deceased and Living Donors
· Living donors should undergo the same evaluation, with the exception that the cutoff for TST should be 10 mm or greater.
· The evaluation of the deceased donor for TB relies on: medical history, endemic exposuresand radiographic findings.
· Organs from donors with known active TB infection should be discarded.
· Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
· Lungs with residual tuberculous lesions should not be used for transplantation.
· A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered.
3. Treatment
a) Treatment of LTBI in Transplant Candidates and Recipients:
I. Criteria to Start Treatment
· LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
· Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive.
· Chest imaging suggestive of previous untreated TB should prompt consideration for therapy.
· Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
II. Therapeutic Regimens
· For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
· Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
· Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
III. Timing of Treatment
· treatment for LTBI should be started before transplant.
· if urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible until completion of the originally planned course, with the caveat that rifamycins are usually avoided after transplant.
IV. Recommendations for Transplanted Patients Who Travel to Endemic Areas
· INH preventive therapy should be considered during the first post-transplant year.
· There is no indication for BCG vaccine before travel, and it is contraindicated in transplant recipients.
b) Treatment of Active TB Infection
· The optimal length of treatment of TB in transplant recipients is not defined. Many specialists recommend that treatment duration should be at least 9 months.
c) Monitoring of Adverse Events Related to Therapy
· close monitoring is highly recommended, mainly during the first 2 months of treatment when it should be performed biweekly.
· Low-grade elevation of aminotransferases can be observed during the first 2 months of treatment, but a 3-fold increase accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation.
d) Drug interaction:
1) Rifamycins
· Rifamycins have an induction effect on different drug- metabolizing enzyme systems, most notably the cytochrome P450 (CYP) 3A4, which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus, cyclosporine, sirolimus, everolimus, and even corti- costeroids).
· Two- to 5-fold increments in the daily dose of cyclosporine, tacro- limus, and mammalian target of rapamycin inhibitors are generally necessary to maintain trough levels of the drug in the therapeutic range.
2) Rifabutin
· a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin.
· It has been demonstrated to be as effective as rifampin for the treatment of TB in trials conducted in nontransplant patients.
· Its weaker effect on CYP3A4 makes it easier to maintain therapeutic blood levels of calcineurin and mammalian target of rapamycin inhibitors during TB treatment.
· the same recommendation for close therapeutic drug monitorings of immunosuppressive drugs apply when rifabutin is used.
The level of evidence provided by this article:
This is a narrative reviews and expert opinions with level of evidence grade 5.
I like your summary, level of evidence, analysis and take home messages. I like your discussion regarindg choice between rifamycin and rifabutin.
Summarise this article
EPIDEMIOLOGY
Epidemiology in Latin America
· The burden of tuberculosis (TB) has decreased significantly in Latin America (LA) countries, with the estimated absolute number of prevalent cases declining from 600,000 to 342,000 between 1990 and 2014.
· However, Brazil remains in the group of 22 countries with the highest TB burden, with 110 000 prevalent cases and 7700 TB deaths.
· It is important to be aware that national average incidence estimates may mask wide variations within a country. In Rio de Janeiro, for instance, the incidence in some underprivileged neighborhoods remains around 300 cases per 100 000.
· MDR is a global challenge, with higher prevalence in Ecuador, Guatemala, and Peru, with a significant impact on mortality.
TB AFTER SOLID-ORGAN TRANSPLANTATION
· TB incidence increases after SOT, with the highest risk in lung recipients.
· LTBI is the main cause of posttransplant TB, but primary infection acquired in the community and nosocomial environment may also be a factor.
International Travel and Posttransplant TB
· Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB after SOT.
· Transplant recipients from low-incidence countries may be exposed to primary infection while traveling to an endemic area, but the actual impact of such exposure in this specific population has not been assessed.
· Among immunocompetent travelers returning from endemic countries, the estimated risk of acquisition of TB infection has generally ranged from 0.4% to 2.0%.
· Higher rates (1.8% to 4.2%) were reported among travelers who were involved in Healthcare or academic medical exchange programs.
· Time spent in the endemic area influences the risk of TB infection, with a cumulative history longer than 3 months of travel to high-incidence areas associated with a significantly higher risk. Humanitarian work with high-risk populations may also be a significant risk factor.
· Visiting friends and relatives is a known risk factor for acute diseases, but the impact of such activity on the risk of acquiring TB has not been established.
DIAGNOSIS
Diagnosis of LTBI
· The tuberculin skin test (TST) is the best-studied test for LTBI, and most current guidelines recommend its use for the screening of solid organ candidates/recipients and living donors.
· IFN-γ release assays (IGRAs) have emerged as new diagnostic tools, but their negative predictive value is not optimal to rule out infection in patients considered to be at high risk for LTBI.
· There is a marked variation across transplant centers regarding the approach for screening LTBI in candidates, with TST alone being used in 48% of the participating centers, IGRA alone in 30%, TST and IGRA simultaneously in 16% and TST followed by IGRA in 6%.
· Some specialists suggest adapting the diagnostic approach per the estimated risk of being infected.
Diagnosis of Active TB Infection
· The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, culture, and nucleic acid testing. SOT recipients may present unusual manifestations, with a greater proportion of extrapulmonary involvement.
· The Xpert MTB/RIF assay is a useful rule-in diagnostic test for extrapulmonary TB, with an estimated sensitivity in smear-positive and smear-negative respiratory samples of 98% and 67%, respectively.
· However, false-positive results have been observed among patients who had been successfully treated for TB, and it cannot fully replace the execution of conventional drug susceptibility tests.
PREVENTION
Risk Assessment of the Transplant Candidate
· A history of clinical or radiological TB and treatment for LTBI should be assessed in all recipients.
· If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction.
· A second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
· IGRA should be formed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses. Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
· If active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
Risk Assessment of Deceased and Living Donors
· Living donors should undergo the same evaluation as candidates for TB, with a cutoff of 10 mm or greater. Medical history, endemic exposures, and radiographic findings should be taken into account.
· TST and IGRAs should be validated in deceased donors, and samples should be obtained to test for M. tuberculosis.
· Organs from donors with active TB infection should be discarded and therapy for active infection should be immediately started.
· Drug susceptibility tests should be performed on any M. tuberculosis specimen.
· Lungs with residual tuberculous lesions should not be used for transplantation.
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients
Criteria to Start Treatment· LTBI therapy is recommended for transplant candidates with positive TST or IGRA, those with high-risk pretransplant TB exposure, and those with a history of active TB infection.
· It is also recommended for transplant recipients whose donor has a history of untreated LTBI or TB, or if the recipient is exposed to TB after transplantation.
· LTBI therapy is recommended for transplant candidates with positive TST or IGRA, those with high-risk pretransplant TB exposure, and those with a history of active TB infection.
· It is also recommended for transplant recipients whose donor has a history of untreated LTBI or TB, or if the recipient is exposed to TB after transplantation.
Therapeutic Regimens· The preferred regimen for LTBI is oral INH 300 mg/d for 9 months, with pyridoxine 25 to 50 mg daily.
· Alternative regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
Timing of Treatment· Treatment for LTBI should be started before transplant, and if an urgent transplant is indicated, held perioperatively and resumed when medically possible until completion of the originally planned course.
Recommendations for Transplanted Patients Who Travel to Endemic Areas
· INH preventive therapy should be considered for transplanted patients in highly endemic areas, and BCG vaccine is contraindicated in transplant recipients.
Treatment of Active TB Infection
· The optimal length of treatment of TB in transplant recipients should be at least 9 months, based on studies suggesting an association between shorter regimens and greater recurrence and mortality.
Monitoring of Adverse Events Related to Therapy· Monitoring of INH, rifampicin, and pyrazinamide is recommended due to the increased risk of hepatotoxicity. Drug Interactions· Rifamycins have an induction effect on different drug-metabolizing enzyme systems, leading to a reduction in the blood levels of immunosuppressive drugs used after SOT.
· Close monitoring and continuous dose adjustment are recommended.
· Rifabutin is an alternative to rifampin, but its weaker effect on CYP3A4 makes it easier to maintain therapeutic blood levels of calcineurin and mammalian target of rapamycin inhibitors during TB treatment.
==========================================================
What is the level of evidence provided by this article?
Level V
I like your approach in interpreting TST and IGRA.
III. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
1. Summarise this article
Epidemiology
Diagnosis of LTBI
Diagnosis of active TB Infection in SOT recipients
Advantages of Xpert MTB/RIF assay:
Limitations of the assay:
Prevention
Risk assessment of the transplant candidate
Risk assessment of deceased & living donors
Treatment of LTBI in transplant candidates & recipients
Therapy is recommended for:
Therapy is considered in:
Therapeutic regimens
Timing of treatment of LTBI
Treatment of active TB infection
Drug interactions
=========================
2. What is the level of evidence provided by this article?
I like your approach in interpreting TST and IGRA. I appreciate your debate ‘Risk assessment of deceased & living donors’.
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
Guilherme S and colleagues in this review article examines the recommendations for the management of tuberculosis for organ transplant recipients and donors.
EPIDEMIOLOGY
Epidemiology in Latin America
In the last 2 decades, the burden of tuberculosis (TB) has been considerably reduced in Latin America (LA) countries. Although the estimated proportion of MDR infection among new TB cases remains below 3% in most countries of the region, higher prevalence (between 3.0% and 6.0%) has been found in Ecuador, Guatemala, and Peru. Emergence of multidrug-resistant (MDR) TB, which is defined by the isolation of a causative strain of Mycobacterium tuberculosis resistant to rifampicin and isoniazid (INH), is a global challenge. Recent reports from the latter country provide evidence of ongoing community transmission of MDR infection with significant impact on mortality. Moreover, the prevalence of MDR infection is expectedly higher among patients who were previously treated for TB. In those 3 countries, this prevalence has been estimated to range from 20% to 26%.
TB AFTER SOLID-ORGAN TRANSPLANTATION
The incidence rate of TB markedly increases after solid organ transplantation (SOT), the risk being highest among lung recipients. The proportion of patients affected by active TB infection also varies widely among transplant centers in correspondence with the local prevalence of the disease. In studies carried out in LA SOT centers in the last decade, TB was diagnosed in 0.9% to 5.9% of the recipients.
International Travel and Posttransplant TB
Transplant recipients from low-incidence countries may be exposed to primary infection while traveling to an endemic area. Among immunocompetent travelers returning from endemic countries, the estimated risk of acquisition of TB infection has generally ranged from 0.4% to 2.0%.20-22 Higher rates (1.8% to 4.2%) were reported among travelers who were involved in healthcare or academic medical exchange programs.
Transplant candidates originating from endemic areas have a higher prevalence of LTBI and are, hence are at an increased risk of developing active TB infection after SOT.
DIAGNOSIS
Diagnosis of LTBI
There is no diagnostic reference standard for LTBI. Most current guidelines still recommend tuberculin skin testing for the screening of LTBI in solid organ candidates/recipients and living donor.
IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade. It has numerous advantages over tuberculin skin testing because it: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination. They are also probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients. Despite these advantages, the negative predictive value is not sufficient to rule out LTBI in high-risk patients such as those who were born to or lived in endemic countries, household contacts of a case of active TB infection, and those who work or live in high-risk settings, such as correctional facilities and homeless shelters. Other limitations of these assays include their higher cost and the frequent occurrence of conversions and reversions of test results when serial screening is performed, which may complicate the interpretation of their results among SOT candidates.
Diagnosis of Active TB Infection
The diagnosis of active TB infection relies on high index clinical suspicion and the detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing. SOT recipients may present unusual manifestations, with a greater proportion of extrapulmonary involvement. TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin. Invasive diagnostic procedures are more frequently required in this population, resulting in a delay of the proper diagnosis and higher mortality.
PREVENTION
Risk Assessment of the Transplant Candidate
First step is adequate and thorough history including radiological investigations in the past. If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA. If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
Candidates who have low risk for LTBI should preferably be tested solely with IGRA. In high-risk candidates (i.e., patients originated from endemic countries, household contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), both tests could be performed, and any positive reaction considered evidence of LTBI. Whenever this dual-test approach is used, IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses.
Treatment of LTBI should be commenced only when active TB has been excluded. Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative. Despite this, active infection may not be an absolute contraindication when transplantation is urgently needed.
Risk Assessment of Deceased and Living Donors
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater. The evaluation of the deceased donor for TB relies on: thorough history, physical examination and radiological testing. Organs from donors with known active TB infection should be discarded. If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines. Drug susceptibility tests should be performed on any M. tuberculosis specimen isolated from the donor, since the detection of drug resistance may be of critical importance for guiding therapy in the recipients. Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted. Lungs with residual tuberculous lesions should not be used for transplantation. A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, especially for lung recipients.
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients
Criteria to Start Treatment
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated. Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated. Chest imaging suggestive of previous untreated TB should prompt consideration for therapy, especially in areas where endemic mycoses are uncommon. Treatment is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
Therapeutic Regimens
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily. Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine aminotransferase checked every 2 weeks for 6 weeks, then monthly thereafter. Alternative regimens containing rifamycins can be considered pretransplant but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks. Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
Timing of Treatment
Balancing the risk of infection and benefit of transplantation is important. It’s preferred to treat before transplantation but urgent need for transplantation might warrant treatment commencing in the perioperative period.
Recommendations for Transplanted Patients Who Travel to Endemic Areas
Those traveling to endemic regions after transplantation should use INH prophylaxis in the first post-transplant year. BCG vaccination is contraindicated. Those with possible TB exposure should be evaluated on return, and anyone with symptoms of infection should seek medical evaluation immediately.
Treatment of Active TB Infection
Treatment should follow local guideline just like in general population. However, there is need for monitoring for drug interaction and toxicity.
Level of evidence – level V
I like your very sensible clinical approach as to when to treat for latent TB in a transplant recipient. I appreciate your debate regarding the uncertainty on optimal duration of therapy
Summary
TB after solid organ transplantation
Incidence TB increases after SOT more so in lung recipients.
Main cause of post-transplant TB is reactivation of latent TB.
Rarely primary infection may occur in people living in endemic areas.
However in minority of cases can have donor-recipient transmission.
Diagnosis of LTBI
There is no gold standard.
TST is most studied test hence most guidelines recommend it.
IGRA has advantages over TST:
However is disadvantages include:
Low risk patients IGRA is recommended, while in high risk patients both TST and IGRA should be done.
Diagnosis of active TB
TST and IGRA not recommended.
Relies on detection of MTB bacilli by direct observation, culture and nucleic acid amplification test.
High index of suspicion is crucial because recipients do not present with the classical clinical presentation and there is a high proportion of extra pulmonary TB.
Xpert MTB/RIF: is highly sensitive and specific in pulmonary TB.
Risk assessment of the recipient
A through history including history of prior treatment of TB should be obtained.
In absence of prior treatment, they should be assessed for LTBI with either TST or IGRA.
TST induration of ≥ 5mm after 48 to 72 hrs is considered positive.
High risk patients should ideally have the IGRA done before the TST to avoid TST mediated boasting of the IGRA response.
Before initiation of LTBI treatment, active TB should be ruled out with a CXR, through history and physical examination and imaging of other body sites in cases of extra-pulmonary TB.
Presence of active TB is not an absolute contraindication of transplant, however treatment should be started and transplant postponed until smears are negative.
Risk assessment in donor
Similar to recipient but the TST induration should be ≥ 10mm.
Deceased donor evaluation relies on medical history, endemic exposure and radiological findings.
Deceased donors with active TB the organs should be discarded. If the information because available after transplantation then recipient should be treated for active TB promptly.
Organs from donors successfully treated for 6 months can be accepted.
History of untreated LTBI is not a contraindication of donation.
If donor had been treated for LTBI infection prior to donation then the risk of transmission is considered to be low, thus recipients can be monitored without receiving treatment.
Treatment of LTBI in recipients and donors
Should be considered in recipient or donor who have a positive TST or IGRA and have not been treated prior.
In high risk patients, treatment should be considered with or without TST or IGRA being positive and also in those with history of incomplete treatment of active TB.
Recipients receiving from a donor with history of incomplete treatment of LTBI/active TB should also receive treatment.
Preferred treatment is oral INH 300mg/ day for 9 months.
Nine months preferred over six months due to better protection.
Monitoring for serum alanine transaminase should be done every 2 weeks for the first 6 weeks then monthly after due to the risk of hepatotoxicity.
Rifamycins can be considered pre transplant and avoided post-transplant due to drug interactions.
Alternative regimens include: RIF 600mg/day for 4 months or INH and rifapentine weekly for 12 weeks.
Ideally treatment should begin before transplant and completed while on the waiting list.
However if transplant is to be done before completion of treatment then the treatment can be withheld peri-operatively and resumed when medically possible.
If recently transplanted patients plan to travel to highly endemic areas in the first year post transplant then INH preventive therapy should be given.
Vaccinations is contraindicated in recipients.
Treatment of active TB
Should follow the local guidelines.
Four drug treatment regimen is recommended.
Optimal duration is not defined, some specialist recommend 9 months duration due to studies that have suggested an association between shorter duration with high recurrence and mortality.
Monitoring of adverse events
First 2 months monitoring should be bi-weekly.
Discontinuation of treatment should be considered when there is a 3 fold increase of aminotransferase with symptoms or 5 fold increase with or without symptoms.
Drug interactions
Rifamycins are inducer of the cytochrome P 450 which leads to reduced drug levels of immunosuppressive drugs- cyclosporine, tacrolimus, sirolimus and corticosteroid.
Their sub therapeutic levels is associated with allograft rejection.
Hence close monitoring and dose adjustments is recommended.
Enzyme induction begins after few hours of the first doses, reaches maximally effect in 1-2 weeks and slowly declines 2 weeks after stopping the drug.
Rifabutin a rifamycin with weaker enzyme induction is an alternative to rifampicin.
Level of evidence V
I like your detailed summary. I appreciate your debate regarding the uncertainty on optimal duration of therapy
Tuberculosis after solid organ transplantation:
The incidence of tuberculosis increased significantly after solid organ transplantation (SOT).
In studies conducted at LA SOT centers over the past decade, TB was diagnosed in 0.9% to 5.9% of beneficiaries.
Primary infection, especially in patients living in endemic areas.
Most of these cases have been documented in patients who received transplants from deceased donors with active TB infection, a condition associated with an approximately 30% risk of transmission.
Migration, international travel to endemic countries, and transplant tourism may affect the risk of TB at SOT.
Transplant recipients from low prevalence countries may be exposed to primary infection when traveling to endemic areas, but the true impact of this exposure in this specific population has not been assessed
Diagnosis
Diagnosis of LTBI:
Tuberculin) is still the best documented test. Most current guidelines still recommend its use for screening solid organ candidates/recipients and living donors for LTBI.
IFN-γ release assays (IGRA) as new diagnostic tools.
Pros:
1- Avoid interpretation bias.
2- Reduction of false positives linked to previous exposure
3- Non-tuberculous mycobacteria or BCG vaccination.
4- More sensitive to candidates with chronic renal failure and advanced cirrhosis.
Limitations:
1- Higher cost
2- Conversion and inversion of test results often occurs when performing continuous screening, which can make it difficult for SOT candidates to interpret their results .
Diagnosis of active tuberculosis infection:
Detection of Mycobacterium tuberculosis by direct observation, culture and nucleic acid testing
Rapid molecular tests such as the Xpert MTB/RIF test
A limitation of this test is false positive results
Prevention
Transplant Candidates Human Risk Assessment:
All recipients should be evaluated for clinical or radiological history of tuberculosis and treatment received.
Applicants should be assessed for LTBI using the TST or IGRA if there is no history of treatment for TB or LTBI. If the TST is chosen as a screening test, a duration of 5 mm or more within 48 to 72 hours should be considered a positive response.
In addition, a second TST should be performed 7-10 days after the first TST to assess boost-related transitions.
Low-risk candidates for ITL would be better off taking only the IGRA test.
Among high-risk candidates (i.e., patients from endemic countries, household contacts of tuberculosis infection active and those who work or live in correctional facilities or homeless shelters), two tests may be administered, and any positive response is considered an LTBI
Applicants with a positive result on either of these tests must be ruled out for active TB infection before starting treatment for ITL.
Risk assessment for deceased and living donors:
Medical history
Endemic exposures
Radiological findings
Increased risk should be excluded by obtaining specimens (e.g. Tuberculosis
Organs from donors known to have active TB infection should be eliminated.
Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all
recipients should be considered, especially for lung recipients
Treatment of LTBI in Transplant Candidates and Recipients:
Criteria to Start Treatment:
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated
Those with high-risk pre transplant TB exposure should be
considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated
Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation
Therapeutic Regimens:
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily Nine months of therapy is preferred over 6months because of better protection
Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine amino transferase checked every
2 weeks for 6 weeks, then monthly thereafter.
Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600mg daily for 4 months or INH and rifapentine weekly for 12 weeks.51,52 Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy
The timing of LTBI treatment requires balancing risks and benefits for each patient
Transplant recipients who are traveling to TB endemic areas to provide medical or humanitarian care should follow standard precautions to prevent nosocomial
acquisition of infection.
BCG vaccination is not indicated before travel and is contraindicated in transplant recipients.
Treatment should follow local guidelines for the general population.
Monitoring for treatment-related adverse events Due to the increased risk of adverse events and potential drug interactions, close monitoring is strongly recommended, primarily during the first 2 months of treatment, which should be performed every two weeks
Level 5
I like your summary, level of evidence, analysis and take home messages. I appreciate that you have explained postive points of IGRA and limitations as well.
Summary
Introduction
This article is about TB infection in SOTR and donors. This is especially important because risk of TB increases after SOT, particular lung transplant recipients.
TB incidence in SOTR is usually from reactivation of latent TB. Nosocomial infection and primary infection from the environment are also possible because of the immunocompromised status of the recipient. A small percentage of cases can develop from donor transmission.
Discussion
Travel from different places such as TB endemic countries can increase the risk of TB in the recipient. Immigration impacts the risk of donor transmission.
Current guidelines recommend screening for LTBI in recipients and live donors of SOT. This is done through tuberculin skin test or TST. Another recent diagnostic tool is IFN -gamma release assay. The latter tool has advantages over TST such as avoiding interpreting bias, reduced false positive results related to prior exposure to TB or BCG vaccine. However, higher cost for performing these assays can be a deterrent in some centres, thus preventing standardization.
Recommendations include performing IGRA alone for low risk patients and both TST and IGRA for high risk patients. This is done in order to maximize the sensitivity and accuracy of screening protocols.
Diagnosis of TB infection involves detecting Mycobacterium tuberculosis bacilli directly, via culture and nucleic acid test. IGRA and TST are not recommended for the diagnosis of active TB infection in the patient.
Another aspect to consider is the extrapulmonary manifestation of TB in SOT recipients. This is often more difficult to diagnose compared to the classic presentation of TB. One recommendation is to consider TB in patients with fever of unknown origin. Availability of MTB/RIF assay can help in managing these patients because of its high specificity and sensitivity.
Limitations for this method of diagnosis include false positive results in the case of patients who have been successfully treated for TB.
Prevention and treatment strategies
Prevention of TB in the recipient involves rigorous assessment of donor, including IGRA and TST. Appropriate risk assessment profiles are also to be done to prevent donor transmission as well as primary incidence in recipient from other sources.
Treatment involves oral INH 300 mg/day for 9 months, with oral pyridoxine 25-50 mg daily. Extended period of 9 months is preferred to 6 months because it gives better protection for the patient.
Monitoring for hepatotoxicity is crucial in these patients with serum ALT being checked every 2 weeks for a period of 6 weeks, and then every month.
Alternative regimen pre-transplant include rifamycin, which should be avoided post transplant to prevent interaction with immunosuppressive drug interactions. Fluoroquinolones are recommended for LTBI therapy.
Level of evidence
Level of evidence is 5.
I like your short summary, level of evidence, analysis and preventive strategies.
TB after Solid-organ transplantation:
Diagnosis of LTBI
Diagnosis of Active TB Infection
Risk Assessment of the Transplant Candidate
Risk Assessment of Deceased and Living Donors
Treatment of LTBI in Transplant Candidates and Recipients
Recommendations for Transplanted Patients Who Travel to Endemic Areas
Treatment of Active TB Infection
Level of evidence: Level V (Review)
I like your detailed well structured summary, level of evidence, analysis and take home messages.
Typing whole sentence in bold amounts to shouting.
Summarise this article
Burden of tuberculosis (TB) has been considerably reduced in Latin America (LA) in the last two decades.
Brazil remains in the group of 22 countries with the highest TB burden
Marked geographical variation in incidence
Marked emergence of Mycobactarium- MDR (the isolation of a causative strain of Mycobacterium)
TB after solid-organ transplantation
Incidence increases after transplant with highest incidence in lung transplant recipients
Main cause is reactivation of foci of latent TB infection (LTBI)
Other cause can be Primary infection acquired in the community or nosocomial infection
Donor derived -documented in patients who received a graft from a deceased donor with active TB infection
Immigration, international travel to endemic countries may affect incidence
Diagnosis of Active TB Infection
Detection of M. tuberculosis bacilli by direct observation, by culture and nucleic acid testing
Xpert MTB/RIF assay, may have a major impact in the management
RIF assay is a useful rule-in diagnostic test for extrapulmonary TB
Latent TB-
TST and IGRA
Advantages of IGRA-
Avoid interpreting bias
Reduce false-positive results
More sensitive in candidates with chronic renal failure and advanced cirrhosis
Higher yield
Better correlation with clinical risk factors for LTBI
However the negative predictive value of IGRAs is not optimal
Low-risk patients- IGRAs
High risk-Both
PREVENTION
Risk Assessment of the Transplant Candidate
No history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA
TST- induration of 5 mm or greater at 48 to 72 hours should be considered a positive
Perform second TST should be performed 7 to 10 days after the first TST
Low risk for LTBI should preferably be tested solely with IGRA
High Risk – Both test
Active TB infection must be excluded in all candidates- Detailed history, Chest radiographs, Other imaging in case suspected extrapulmonary TB.
Active infection- transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative
Risk Assessment of Deceased and Living Donors
Cutoff for TST should be 10 mm or greater.
Medical history of of untreated or insufficiently treated TB/ previous reactive IGRA or TST
Endemic exposures
Radiographic findings- apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening.
Active TB infection should be ruled out in donors at increased risk
Organs from donors with known active TB infection should be discarded
If diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started
Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted
Treatment of LTBI in Transplant Candidates and Recipients
Start treatment if positive TST or IGRA who have not been previously treated
High-risk pretransplant TB exposure
Chest imaging suggestive of previous untreated TB
History of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation
Treatment of Active TB Infection
4-drug regimen is recommended- 2 month intensive phase
Treatment duration should be at least 9 months
Close monitoring is highly recommended, mainly during the first 2 months of treatment- Bi weekly
Rifampicin induces cytochrome P450 and reduces the levels of tacrolimus, cyclosporine, sirolimus, everolimus, and corticosteroids
This can potentially lead to higher risk of rejection
Therapeutic drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption
Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction- efficacy similar to Rifampicin
I like your detailed summary.
Thank you Prof
TB after SOT:
Diagnosis of LTBI:
Diagnosis of active TB:
Risk assessment in transplant candidates:
Risk assessment of deceased & live donors:
Treatment of TB in candidates & recipients:
Treatment of active TB:
Level of evidence is 5
I like your level of evidence, and analysis.
This narrative review addresses the epidemiology of mycobacterial tuberculosis( TB ) from the Latin American region with the challenges of the rise of MDR -resistant TB strains with increased clustering of new cases in certain countries with prevalence reported between3.0% and 6.0%) have been found in Ecuador, Guatemala, and Peru with the continuous spread of MDR TB in the community level even more than 20% according to the recent data with increased mortality rate and its higher among those with previous TB treatment MDR TB infection defined as failure to respond to an anti-TB regimen including ( INH, REFAMPCIN )after two months of starting therapy with an overall prevalence of < 3 % but can go even higher in endemic areas.
TB AFTER SOLID-ORGAN TRANSPLANTATION
· TB after SOT is more prevalent compared to the general population and also the incidence varies according to the local epidemiology with higher reports from endemic areas, higher rate after lung transplantation
· Reactivation of latent TB infection (LTBI) is the most common source of infection after SOT
· A small percentage of primary infections result from donor-recipient transmission, especially DD sources with active TB and to less extent LTBI in the donor.
·International Travel and Posttransplant TB
·Immigration, as per US data children born to parents from the endemic area are at high risk of active TB, also donor source of TB In Spain, the prevalence of active TB infection was obviously increased in deceased donors who originated from a high-incidence country in eastern Europe.
· Travel to endemic states, and the duration spent usually > 3 months also impacts the risk of getting a TB infection
· Commercial transplantation may impact the risk of TB after SOT.
· Transplant recipients from endemic areas have more risk of LTBI with an increased risk of active TB post-transplantation
· Type of work like Humanitarian work with high-risk populations, such as prisoners and homeless people, may also be an important risk factor
· Use of public transportation or long travel time in the endemic area is also considered a risk factor for TB exposure
Diagnosis of TB and its challenges
Diagnosis of LTBI
There is variation among SOT centers in screening for LTBI, with more prevalence use of TST alone at 48%, and IGRA alone at 30% while the combination of IGRA, and TST is around 16%.
1. Tuberculin skin test (TST) is still considered for screening of LTBI for SOT recipients and donors as per most guidelines
2. IFN-γ release assays (IGRAs) have been used more recently for LTBI screening with more sensitivity compared to TST and suitable for CKD and liver cirrhosis candidates screen with less interpretation bias and less false positive results from previous exposure or BCG vaccination however despite its better yield and better correlation with clinical risk still the negative predictive value(NPV) of IGRAs is not ideal to rule out infection in high-risk candidates for LTBI, The limitation of the IGRA test is more cost and there is variation in interpretation among SOT candidates mandate serial testing
3. Among those with low risk it’s preferred to go for the IGRA test and in candidates from high-risk areas it’s preferred to do both TST, and IGRA together to increase the sensitivity
of screening.
Diagnosis of active TB
1. Both TST and IGRA are not used for the diagnosis of active TB
2. The diagnosis of active TB depends on the isolation of M. tuberculosis bacilli by direct examination. Either by culture or rapid molecular tests like Xpert MTB/RIF assay which is more specific, especially in extrapulmonary TB and MDR – TB diagnosis with high predictive value, the only concern with this test is that false-positive results have been observed in patients who had been effectively treated for TB
3. more invasive testing like tissue biopsy and histology, one of the diagnostics challenges after SOT is due to atypical presentation and nonspecific symptoms, especially with extrapulmonary TB or disseminated infection which leads to a delay in diagnosis and initiation of treatment in the appropriate time and carries high morbidity and mortality rate.
Prevention
Risk assessment for transplant recipients
Full history of previous exposure or sick contact previous history of TB and treatment course, previous history of LBTI epidemiological risk, and social background
Candidates from low-risk areas can be screened for LTBI by either TST or IGRA test only while those from the high endemic areas can do both TST and IGRA testing
TST with an induration of 5 mm or more at 48 to 72 hours should be considered a positive reaction. In addition, a second TST should be performed 7 to
10 days after the first TST to evaluate a boosted-related skin conversion
Any suspected case of Active TB should go for comprehensive history and examination, CXR in case of PTB, or other organs images in case of extra-renal manifestation including invasive tissue biopsy
DD risk assessment
. Living donors should follow the same protocol of recipient risk assessment but for LTBI the TST cutoff value for a positive test is> 10mm.
.The evaluation of DD for TB
1. Will be very important to focus on a history of active TB or treatment from previous exposure, previous positive IGRA or TST, sick contact
2. Endemic contact risk, travel history to an endemic area, duration and exposure to active TB in the workplace or households within the last 2 years
3. social history including homeless, alcohol addiction, refugee status (LTBI risk).
4. X-RAY findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening
5. Both TST and IGRA tests not validated for DD screen and in high clinical suspicion for active TB in DD samples like sputum and BAL fluid for microbiology testing for MTB should be sent and usually need time for confirmation so the OPT should effectively communicate and track the results for the transplantation team
6. Organs from donors with known active TB infection should be discarded (absolute contraindication for SOT).
7. The organs from DD with previous active TB and completed 6 months of anti-TB still can be used as DD but lungs with remaining focus of infection should be discarded, donors with LTBI still can be used but with starting the recipients on prophylaxis course according to local protocol.
TREATMENT
Criteria for Treatment of LTBI in Transplant Candidate and Recipient
1. All donors and recipients with positive TST or IGRA test should be treated for LTBI, including those from high-risk endemic areas should be treated for, possible LTBI regardless of the TST or IGRA test in order to reduce the risk of active TB after transplantation
2. Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
Therapeutic regimens
LTBI preferred to use INH 300 mg/day for 9 months per oral in combination with B6 25-50mg OD, 9 months duration gives better prevention from active TB, and needs close monitoring for hepatotoxicity with LFT monitoring every two weeks for the first 6 weeks then monthly.
rifampicin regimen RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks preferred use pre-transplant not after TX to avoid drug interaction with CNI
1.Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy stopped based on evidence from RCT due to toxic side effects with levofloxacin arm
preferred to get the treatment course before transplantation but in case of an urgent need for transplantation then still can consider starting the treatment but avoid rifampicin due to drug interaction.
BCG is contraindicated for organ transplantation candidates
Treatment of active TB
Should follow up the same local protocol for the treatment of active TB in the general population taking into consideration the risk of hepatotoxicity, drug safety, and interactions with immunosuppression like rifampicin with CNI,m TOR inhibitors, steroids inhibitory effect as its enzyme inducer (P450 (CYP) 3A4), and need higher doses 3-5 time increase in tacrolimus or cyclosporine dose with frequent monitoring ( sometimes given TID dose ) also important to early identification of MDR – TB cases but Rifabutin, a rifamycin have weaker induction effect of CYP3A4 with similar sterilization efficacy as rifampicin and can be tolerated as an alternative with close monitoring of CNI, EVEROLIMUS or sirolimus level
Hepatotoxicity with INH, Pyrazinamide needs frequent monitoring with LFT level every week in the first two months, 5 fold increase in ALT is an indication to stop the treatment.
A 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB. At least for 9 months in most recommendations as shorter courses are associated with higher relapse rates and mortality.
Level of evidence
level 5, narrative review
I like your well structured and well-organizzed detailed summary. I like your level of evidence, and analysis.
this is for the next journal (Latent tuberculosis infection and renal transplantation – Diagnosis and management) because I have a problem in submitting the answer
Summarise this article
Some facts
The prevalence of active TB is significantly higher in SOT than general populationIt is estimated that around 1.7 billion people are suffering from latent TB worldwide10 % of patients with latent TB can develop active TB during their lifetime, if they are immunosuppressed Active TB in renal transplant recipients is associated with increased morbidity and mortality and one third of cases can lose the graftMode of transmission
Activation of latent TB (the most common)Acquiring the disease from the graft (donor derived)Acquiring new infection through air born transmission (not common, rapidly progressing to military TB)Diagnosis of latent TB
Recipients with latent TB are at high risk of conversion to active TB after transplantation, on the other hand, if the donor has latent TB and did not receive treatment it carry a risk of transmission to the recipientSo all recipients and donors should both be undergo careful evaluation of the risk, history, examination and CXR, together with test for latent TBIn general, all transplant recipients and donors with latent TB should be received2 test are used to detect latent TB, tuberculin skin test (TST) and IGRA (Quantiferon, T-SPOT), both are usually negative in immunosuppressed patients due to their dependence on the host immune response which is impaired in these sets of patientsIn SOT candidates with ESRD (renal transplant candidate), it is preferred to use IGRA over TST due to its higher sensitivity in these sets of patientsAll transplant recipients and donors should have thorough history taking and CXRRenal transplant recipients should have no symptoms, CXR should be normal and no evidence of exra-pulmonary TB in order to settle the diagnosis of latent TBIf radiology is suspicious for TB (apical fibronodular lesions, calcified solitary nodule, calcified lymph nodes, or pleural thickening) thorough evaluation including microbiological assessment is indicated to exclude TB as a causeIf TB diagnosed in the recipient transplantation should be delayed till complete treatment of TBProtocol for treatment of latent TB
INH for 6-9 months (the preferred regimen)Rifampin for 3-4 months INH+ rifapentine for 3 monthsINH + rifampin for 3 monthsPatient should be monitored for liver enzymes and bilirubin when using INH
oral pyridoxine 50 mg given daily with INH decrease the incidence of peripheral neuropathy
What is the level of evidence provided by this article?
This is a narrative review, level of evidence V
I like your summary.
Summarise this article
Mode of transmission
Diagnosis of latent TB
Which test to use?
Interpretation of the result
Indications of treatment of latent TB in transplant recipient and donor
Protocol for treatment of latent TB
Ideally, regimen should be started before transplantation, but if it started after transplantation, Rifampicin containing regimen should be avoided
Patient should be monitored for liver enzymes and bilirubin at baseline, every 2 weeks for 6 weeks then monthly, if there is 3 fold rise of liver enzymes with symptoms or 5 fold rise without symptoms , INH should be stopped
Recommendations for Transplanted Patients Who Travel to Endemic Areas
The diagnosis is challenging (needs high index of suspicion) due to the following
The treatment of TB in SOT is challenging due to the following
Protocols used in treatment of TB
What is the level of evidence provided by this article?
I like your well structured and well-organizzed detailed summary.
This is a narrative review (level V of evidence) for tuberculosis-related care in solid organ transplant patients (donor and recipient).
Epidemiology
South America has several cases of tuberculosis per year, with Brazil being the largest with 110,000 cases of prevalence with areas reaching 300 cases per 100,000 inhabitants. The emergence of multidrug-resistant strains is also a concern.
Tuberculosis after solid organ transplantation
It is more worrisome in patients who have received lung transplants, with the reactivation of latent disease being the main cause of infection.
Immigration, travel to endemic countries, medical tourism, and humanitarian work can be risk factors.
Diagnosis
1. LTBI
TST and IGRA are the most used methods, the latter being more specific and without the interference of the vaccine context and pre-exposure.
IGRA seems to be better for screening low-risk patients, while for those who are exposed to risk factors, the most appropriate is the joint use of TST and IGRA.
2. Active tuberculosis
Detection of mycobacteria either by culture or by molecular methods. Transplanted patients are at higher risk for extrapulmonary disease.
Molecular methods may give false positives after previous treatment for tuberculosis.
Prevention
Clinical history and radiological investigation added to a screening test should be performed on all candidates. Active disease is an exclusion factor for organ donation.
In deceased donors, it makes adequate screening tests are impossible, and samples are collected by bronchoalveolar lavage in addition to radiological findings. After six months of successful treatment, you should move on to the transplant queue. Lungs with sequelae should not be considered.
Treatment
1. LTBI
Isoniazid 300mg for nine months
Rifampicin 600mg for four months
or weekly combinations of Rifapentine and Isoniazid for 12 weeks.
2. Active tuberculosis
Classic scheme RHZE for 6 to 9 months. It is important to monitor for side effects, particularly liver damage. Drug interactions, especially with regard to rifampicin, should be considered and immunosuppressants measured frequently.
I like your detailed summary. I appreciate your mention in the last heading regarding the uncertainty on optimal duration of therapy
Summarise this article
Epidemiology
o Most countries in Latin America are moderately to highly endemic TB infectiono Brazil is in the group of 22 countries with the highest TB burden in the world (110 000 prevalent cases and 7700 TB deaths)
o Higher prevalence of multidrug-resistant (MDR) (between 3.0% and 6.0%) found in Ecuador, Guatemala, and Peru
Epidemiology in Latin America:
TB after solid organ transplantation
o The incidence rate of TB infection markedly increases after SOT, with the highest among lung recipients
o Diagnosed in 0.9%-5.9% of the recipients according to a study
o Reactivation of LTBI is the main cause of posttransplant TB (other causes are primary infection and donor-recipient transmission)
o Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB after SOT
o Transplant candidates from endemic areas have a higher prevalence of LTBI and increase risk of active TB infection after SOT
o Time spent in the endemic area influences the risk of TB infection (longer than 3 months of travel to high-incidence areas is associated with a significantly higher risk)
o Transplant recipients from low-incidence countries may be exposed to primary infection while traveling to an endemic area
Diagnosis
Diagnosis of LTBI:
1. Tuberculin skin test (TST)
2. IFN-γ release assays (IGRAs)
Advantages of IGRAs:
1. Avoid interpreting bias
2. Reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination
3. More sensitive in candidates with CRF and advanced cirrhosis
Limitations of IGRAs:
1. The NPV of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI
2. Higher cost
3. Frequent occurrence of conversions and reversions of test results when serial screening is performed (may complicate the interpretation of their results among SOT candidates)
o In low-risk patients: do only IGRAs, because the use of a more specific test might reduce the rate of false-positive results and, consequently, the number of patients who will unnecessarily be exposed to LTBI therapy
o In high-risk patients: do both tests (IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses), and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening
Diagnosis of active TB:
o Detection of M. tuberculosis bacilli by direct observation, culture, and NAT
o Active infection IN SOT recipients may present with unusual manifestations, with a greater proportion of extrapulmonary involvement
o Diagnosis should be considered in any patient presenting with fever of unknown origin
o Xpert MTB/RIF assay: a rapid molecular test. It is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively. Useful rule-in diagnostic test for extrapulmonary TB (tissue biopsies and cerebrospinal fluid). It allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB. Limitations are false-positive and cannot fully replace the execution of conventional drug susceptibility tests
Prevention
Risk assessment of the transplant candidate:
o Clinical or radiological history of TB and prior treatment in all recipients
o Do LTBI with TST or IGRA if no history of past TB or treatment for LTBI
o TST: induration of 5 mm or greater at 48-72 hours is a positive test. A second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion
o Active TB infection must be excluded in all candidates with a positive LTBI before treatment
o If active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative
Risk assessment of deceased and living donors:
Evaluation is the same for living donors but the cutoff for TST in donors should be 10 mm or more
The evaluation of the deceased donor for TB:
1. Clinical history of untreated or insufficiently treated TB should be investigated and any previous reactive IGRA or TST
2. Endemic exposures: travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the last 2 years, homeless or refugee status, incarceration and alcoholism
3. Radiology: apical fibronodular lesions calcified solitary nodules, calcified lymph nodes, or pleural thickening
4. Active TB infection should be ruled out in donors at increased risk by obtaining samples (sputum or bronchoalveolar lavage) for M. tuberculosis.
Treatment
Treatment of LTBI in transplant candidates and recipient:
Criteria to Start Treatmento First rule out active TB infection
o Therapy is recommended for transplant candidates with positive TST or IGRA and not treated previously
o High-risk pretransplant TB exposure should be treated even if the TST or IGRA is not positive, and also those with history of active TB infection that was inadequately treated
Therapy for transplant recipients:
1. Donor has a history of untreated or incompletely treated LTBI or TB
2. If the recipient is exposed to TB after transplantation
Therapeutic Regimenso Oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily is the preferred regimen
o Monitor for hepatotoxicity with at least serum ALT checked every 2 weeks for 6 weeks, then monthly thereafter
o Alternative regimens containing rifamycins (RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks) can be considered pretransplant (should be avoided posttransplant because of immunosuppressive drug interactions)
Timing of Treatmento Balancing risks and benefits
o Treatment for should be started before transplant if possible, and can often be completed while the patient is on the waitlist
o If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible
Recommendations for Transplanted Patients Who Travel to Endemic Areaso For recently transplanted patients planning to move to a highly endemic area (prevalence ≥100/100 000), INH preventive therapy should be considered during the first posttransplant year
o Follow standard precautions to prevent nosocomial acquisition of infection
o Possible TB exposure should be evaluated immediately on return
Treatment of active TB infection:
o Follow local guidelines (4-drug regimen)
o INH and rifampicin are the most powerful first-line drugs
o Consider the risk of hepatotoxicity related to the antituberculous treatment and drug interactions of rifampicin IN SOT
o The duration of treatment of TB in transplant recipients is not defined (may be at least 9 months)
Monitoring of Adverse Events Related to Therapyo Close monitoring during the first 2 months of treatment (biweekly)
o Low-grade elevation of aminotransferases can be observed during the first 2 months of treatment, but a 3-fold increase with symptoms or a 5-fold increase regardless of symptoms requires discontinuation
Drug Interactionso Rifamycins have intract with cytochrome P450 (CYP) 3A4, which lead to a reduction in the blood levels of most immunosuppressive drugs (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids)
o Rifampin has the most potent enzyme induction effect
o Enzyme induction start within hours after the first dose of rifampin but the maximum effect is reached in about 1-2 weeks and slowly declines over 2 weeks after stopping its use
o Drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption
o Rifampicin is not contraindicated in SOT recipients
o Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin (as effective as rifampin for the treatment of TB in trials conducted in nontransplant patients.)
What is the level of evidence provided by this article?
Level V (narrative review)
I like your really very well structured summary, level of evidence, analysis and take home messages.
Name of the study: Tuberculosis Recommendations for Solid Organ
Transplant Recipients and Donors
Year of the study: February 2018
journal: transplant journal
the level of evidence: narrative review with evidence V.
TB AFTER SOLID-ORGAN TRANSPLANTATION
Causes
1. Reactivation of foci of latent TB infection (LTBI)
2. Primary infection acquired in the community
3. donor-recipient transmission.
DIAGNOSIS
Diagnosis of LTBI: There is no diagnostic reference standard for LTBI.
Definition of latent TB is persistent immunological response to TB antigen with no evidence of active disease
Immunological response can be diagnosed either by
· The tuberculin skin test (TST) remains the best studied test and still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.
· IFN-γ release assays (IGRAs):
1. Advantages: compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and more sensitive in candidates with chronic renal failure and advanced cirrhosis.
2. disadvantages: negative predictive value of IGRAs is not optimal to rule out
infection in patients considered to be at high risk for LTBI.
Diagnosis of Active TB Infection
persistent immunological response with evidence of active infection based on clinical,radiological and laboratory investigations like detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing. Molecular test, such as the Xpert MTB/RIF assay, may have a major impact in the management of these patients. This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%.
Clinical presentation in SOT recipients may present as unusual manifestations, with a greater proportion of extrapulmonary involvement that’s why TB should be considered in patients presenting with fever of unknown origin.
Risk Assessment of the Transplant Candidate(recipient)
· screening is needed with either TST or IGRA. the screening strategy may be adapted per the patient’s characteristics. both tests could be performed and any positive reaction considered an evidence of LTBI.
· Active TB infection transplantation should be postponed until the disease is well controlled
with adequate treatment and smears are negative. Nevertheless, active infection may not be considered an absolute contraindication to transplantation for candidates who urgently need it.
Risk Assessment of Deceased and Living Donors
· Living donors: screening and diagnosis same like recipient.
· deceased donor for TB relies on: Medical history, Endemic exposures and Radiographic findings. Time does not allow for a TST and IGRAs have not been validated in deceased donors.
We can classify donors into 3 main categories:
1. Organs from donors with known active TB infection should be discarded but If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines. Drug susceptibility tests should be performed on any M. tuberculosis specimen isolated from the donor, since the detection of drug resistance may be of critical importance for guiding therapy in the recipients.
2. Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
3. A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, the risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, therefore,
transplant recipients from such donors can be clinically monitored without receiving LTBI therapy.
TREATMENT
· Treatment of LTBI in Transplant Candidates and Recipients
Criteria to Start Treatment
all recipient with LTBI who have not been previously treated should be treated.
· Active infection should be excluded
Therapeutic Regimens
· oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.Nine months of therapy is preferred over 6 months because of better protection.
· Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions.
· Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy. However, a recent randomized study of pretransplant levofloxacin versus posttransplant INH in liver transplant recipients was stopped early because of excessive adverse events in the levofloxacin arm.
Timing of Treatment
treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist. If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible until completion of the originally planned course, with the caveat that rifamycins are usually avoided after transplant.
Recommendations for Transplanted Patients Who Travel
to Endemic Areas
· INH preventive therapy should be considered during the first posttransplant year
· BCG vaccine is contraindicated in transplant recipients.
· Transplant recipients should follow standard precautions to prevent nosocomial acquisition of infection. On return symptoms of infection should seek medical evaluation immediately.
Treatment of Active TB Infection
Treatment should follow local guidelines for the general population. The optimal length of treatment of TB in transplant recipients is not defined. Many specialists recommend that treatment
duration should be at least 9 months with close monitoring of Adverse Events Related to Therapy and drug Interactions.
I like your summary, level of evidence, analysis and take home messages. What is your suggestion regarding communication gap between availability of newer diagnostic tests and promptness of action?
Thanks Prof Ajay
GeneXpert will make revolution regarding rapid detection of TB in just couple of hours solving the problem regarding routine culture which may take 2 months average to get the results.
– Summary
Epidemiology
In the last 2 decades, the absolute numbers of tuberculosis (TB) infection and mortality has decreased in Latin America (LA) countries but TB still represents a public health burden in this area.
In Brazil, the estimated average national incidence in 2015,varied between cities and even in the same city .
Multidrug-resistant (MDR) TB, resistant to rifampicin and isoniazid (INH) is a global problem particularly for cases treated previously with anti TB drugs.
TB after SOT
TB risk is higher after SOT specially after lung transplantation.
SOT centers in LA during the last decade, TB infection was in 0.9% to 5.9% of the recipients caused mainly by reactivation by latent TB foci ,primary infection and nosocomial infection is less common.
Recipients mostly acquire infection from deceased donor with active TB ,infection rate from donor with latent TB foci is not assessed yet .
International Travel and Posttransplant TB
International travel to endemic areas ,immigration and transplant tourism can increase the risk of TB after SOT.
Recipients from endemic areas are highly liable to reactivation of latent TB infection LTBI after transplant.
The estimated risk of acquiring TB infection among immunocompetent travellers returning from endemic countries, ranged from 0.4% to 2.0% but higher rates (1.8% to 4.2%) was noticed among travellers who were working in health care .
The duration spent in endemic area and duration exposure is a risk factor as those involved in humanitarian works .
Diagnosis of LTBI
Guidelines recommend using Tuberculin skin test (TST) for screening of LTBI in solid organ candidates/recipients and living donors.
IFN-γ release assays (IGRAs)compared to TST has less bias, less false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and is more sensitive in candidates with chronic renal failure and advanced cirrhosis.
IGRAs is not the best test to exclude cases at high risk of LTBI.
The limitations of IGRAs are it’s high cost , having reversions and conversions when used serially.
Therefore screening approach is variable between centers .
It was suggested in low risk cases IGRA can be used and for high risk both IGRA and TST can be used.
Diagnosis of active TB
Is done by culture and nucleic acid testing ,it’s diagnosis is based on clinical suspicion and in SOT it can have extrapulmonary manifestations. Invasive methods are needing for diagnosis which can delay it.
Rapid molecular test, as the Xpert MTB/RIF assay is highly specific with variable sensitivity for respiratory and non respiratory specimens , it can aid in the management of these patients and it is highly predictive of rifampicin resistant -TB on the other hand it can give false-positive results among patients successfully treated for TB.
Prevention
If candidates has no past TB history or LTBI treatment then either TST or IGRA need to be used for LTBI assessment.
TST test can be done twice to assess boosted related skin conversion.
Screening method has to be individualised for each case.
Active TB infection have to be excluded in cases with a positive TST or IGRA result before LTBI treatment is started.
Transplantation need to be postponed for candidates with active TB till treated and well cured
Less active TB might not necessitate delay of transplantation if urgently indicated.
Risk assessment of deceased and living donors
Living donors have the same evaluation as recipients except for TST ,it has to be 10 mm or more
For deceased donors evaluation depends on medical history , travelling to endemic areas and radiological imaging.
Active TB has to be excluded by sputum testing or BAL testing for Mycobacterium tuberculosis .
Organs from donors with active TB are contraindicated to be used , if active TB is discovered after transplant ,urgent therapy has to be started also drug susceptibility need to be tested.
Donors with a history of TB treated well for at least 6 months can be included in donation.
Untreated LTBI history without active infection can be a donor candidate but preventive therapy to all recipients should be applied.
Treatment of LTBI in Transplant candidates and recipients
LTBI has to be treated to avoid TB infection.
Transplant candidates with positive TST or IGRA without previous therapy have to be treated
High-risk cases of pretransplant TB exposure , those with history of active TB infection that
was inadequately treated and those with radiological suggestive findings have to be treated too.
Recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation also needs treatment.
For treatment of LTBI
The preferred regimen is oral INH 300 mg/d with oral pyridoxine 25 to 50 mg daily for 9 months with liver function tests follow up for hepatotoxicity every 2 weeks for 6 weeks then monthly.
Another regimen is rifampicin 600 mg daily for 4 months or INH and rifapentine weekly for 12 week but rifampicin interacts with immunosuppressives.
for LTBI therapy, Fluoroquinolones (± ethambutol) have been proposed.
LTBI treatment need to be started before transplant, and completed while the patient is on the waitlist. If urgent transplant treatment can be held perioperatively and continued when applicable
till the course is finished.
INH preventive therapy during the first posttransplant year must be considered for recipients travelling to endemic areas particularly participating in medical care.
Active TB treatment is the same as general population 4 drug regimen for 9 months minimum with close monitoring for hepatoxicity and drug interaction.
Rifamycin as an enzyme inducer lowers immunosuppressives ‘ level increasing rejection risk.
Rifabutin, has a weaker enzyme induction activity so can be used as an alternative to rifampicin meanwhile needs close monitoring.
-level of evidence is V
I like your detailed summary, level of evidence, analysis and take home messages. What kind of network would you suggest?
As you discussed GeneXpert, do you think this test in comparison to IGRA has a better specificity and therefore higher LR ratio?
I think both tests can be done if financially feasible to increase the diagnostic yield also GeneXpert guides mainly the treatment
summary:
TB AFTER SOLID-ORGAN TRANSPLANTATION:
During solid organ transplantation (SOT), lung patients had the greatest risk of TB. Transplant facilities’ active TB infection rates vary according to local disease incidence. In the recent decade, LA SOT clinics identified 0.9% to 5.9% of patients with TB.
Posttransplant TB likely results from LTBI reactivation. In endemic locations, community-acquired primary infections may account for a significant number of infections. Donor-recipient transmission causes fewer initial infections.
LTBI diagnosis:
LTBI diagnosis has no standard. Most current recommendations propose screening solid organ candidates, recipients, and live donors for LTBI using the tuberculin skin test (TST), the best-studied test. IFN-release assays (IGRAs) are emerging diagnostic techniques.
They have benefits over TST: they avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and may be more sensitive in candidates with chronic renal failure and advanced cirrhosis due to their higher yield and better correlation with clinical risk factors for LTBI. Despite their better yield, IGRAs’ negative predictive value is not optimal to rule out infection in patients at high risk for LTBI, including those born to or living in endemic countries, household contacts of active TB cases, and those who work or live in high-risk settings like correctional facilities and homeless shelters.
These assays’ greater cost and numerous test result conversions and reversions during repeated screening may make SOT candidate interpretation difficult. Because of TST and IGRA restrictions, transplant hospitals examine candidates for LTBI differently.
Diagnosing Active TB
Direct observation, culture, and nucleic acid testing for M. tuberculosis bacilli determine active TB infection. TST and IGRA are not indicated for active infection diagnosis.
Clinical suspicion of a current infection is the hardest. SOT recipients may have more extrapulmonary involvement. Patients with unexplained fever should be evaluated for TB.
This group requires more invasive diagnostic procedures, delaying diagnosis and increasing death.
The Xpert MTB/RIF assay, a fast molecular diagnostic, may improve patient treatment. This test has a 98% sensitivity in smear-positive respiratory samples and 67% sensitivity in smear-negative samples.
Donor Risk Assessment:
Live donors should be evaluated like candidates, but their TST should be 10 mm or above.
• Medical history Untreated TB and reactive IGRA or TST should be explored.
Endemic exposures. Travel to or residency in endemic regions, active TB infection in the family or workplace within 2 years, homeless or refugee status, imprisonment, and drinking may be linked to LTBI. With LA’s dropping TB incidence, current TB prevalence estimates may not adequately represent prior exposure risk in these nations.
• Radiographic features including apical fibronodular lesions, calcified isolated nodules, lymph nodes, or pleural thickening.
LTBI treatment :
prevents active TB infection in transplant patients. Untreated transplant candidates with positive TST or IGRA should get LTBI treatment.
High-risk pretransplant TB exposure and poorly treated active TB infection need medication even if the TST or IGRA is negative. In places without endemic mycoses, chest imaging suggests that untreated TB warrants treatment. Transplant patients exposed to TB after transplantation or whose donors have untreated or incompletely treated LTBI or TB should get therapy. First, rule out active TB.
Active TB Treatment:
Local population guidelines should guide treatment. Each population’s medication resistance should determine the intensive phase regimen’s drug count. A 4-drug regimen is usually advised. INH and rifampicin are the best first-line TB medicines. Rifampicin medication interactions and antitubercular therapy hepatotoxicity should be evaluated in SOT.
TB therapy in transplant patients has no recommended duration. Based on a few studies linking shorter regimens to higher recurrence and death, many physicians advocate at least 9 months of therapy.
Treatment Adverse Events Monitoring:
Close monitoring, especially biweekly in the first two months, is advised because of the increased risk of adverse events and medication interactions. INH, rifampicin, and pyrazinamide induce hepatotoxicity, particularly in liver recipients. 60 During the first two months of therapy, aminotransferases may rise slowly, but a 3-fold increase with any symptom or a 5-fold increase without symptoms warrants termination.
narrative review , level V
I like your summary, level of evidence, analysis and take home messages. What kind of network would you suggest?
I think a national network with the following characteristics: easy access, a complete history of the patient, and vaccination will be a good choice.
Summary of the Article
TB after SOT
TB has a higher incidence after transplantation, which varies among centers and according to the local prevalence of the disease.
The incidence rate in Latin America varies from 0.6 to 5.6% of the recipients.
Source of the infection
Diagnosis of LTBI
Diagnosis of active TB
Prevention
Risk assessment of recipients
Risk assessment of deceased and living donors
Treatment
Treatment of LTBI in recipients and donors
Criteria to start treatment
Therapeutic regiment
Timing;
Transplant recipients who travel to an endemic area
Treatment of Active TB infection
Level of evidence
Level ((V))
Review Article
I like your summary, level of evidence, analysis and take home messages. What kind of network would you suggest?
What is your suggestion regarding communication gap between availability of newer diagnostic tests and promptness of action on these reports?
Summary of the Article
TB after SOT
TB has a higher incidence after transplantation, which varies among centers and according to the local prevalence of the disease.
The incidence rate in Latin America varies from 0.6 to 5.6% of the recipients.
Source of the infection
Diagnosis of LTBI
Diagnosis of active TB
Prevention
Risk assessment of recipients
Risk assessment of deceased and living donors
Treatment
Treatment of LTBI in recipients and donors
Criteria to start treatment
Therapeutic regiment
Timing;
Transplant recipients who travel to an endemic area
Treatment of Active TB infection
Level of evidence
Level ((IV))
Review Article
Why level 4 evidence for a review article?
Tuberculosis Recommendations for SOT Recipients and Donors
Summary
· Diagnosis of latent TB in recipients and potential donors:
o Tuberculin skin test (TST) remains the most studied test.
o TST (induration ≥ 5 mm at 48 to 72 hours is considered positive). In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
o IGRA has better sensitivity and many advantages over TST.
o IGRA advantages: it avoids interpreting bias of TST, reduce false +ve results related to previous exposure to nontuberculous mycobacteria or BCG vaccine, and are probably more sensitive in candidates with CKD and advanced cirrhosis.
o IGRA disadvantages: suboptimal -ve predictive value (not exclude latent infection in high risk individuals as endemic areas).
o Mostly, in high risk (endemic areas, household contacts of active TB infection, homeless shelters) we use both tests to increase sensitivity.
o Whenever dual-test approach is used, IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses (false +ve result).
o Any case diagnosed with latent TB, active TB disease must be excluded by clinical symptoms, CXR and other body imaging) as treatment varies between both latent and active TB (regarding dose and duration).
o Active TB in recipient must be fully treated prior to transplantation (until clinical and bacteriological cure, negative smear. While, in latent TB we can start and continue therapy even after transplantation. So, TB is not absolute CI to transplantation.
o Latent TB in potential living donor is the same by TST and IGRA, but TST cut off is ≥ 10 mm.
o TB in deceased donor is excluded by excluding hx of prior TB ttt, prior +ve TST or IGRA, exposure to TB cases, travel or residency in endemic area, radiographic findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening.
o Organs from active TB in deceased donor must be discarded, while those who were successfully treated for at least 6 months, can donate.
o Deceased donor with hx of untreated latent TB, start immediate prophylactic therapy with transplantation.
o If diagnosis is made after organ retrieval, start immediate therapy for TB.
· Diagnosis of active TB in recipients and potential donors:
o High index of suspicion due to atypical and extrapulmonary manifestations.
o Early diagnosis and treatment are essential for early ttt and prevent graft loss and mortality.
o Detection of MTB in sputum, or need invasive bronchosciopy and BAL to do special stain (ZN) or culture on L J or rapid culture on BACTEC system.
o Rapid molecular test, such as the Xpert MTB/RIF assay.
§ Additionally, performance of gene Xpert is also observed when testing non respiratory samples, such as tissue biopsies and cerebrospinal fluid, indicating that it is a useful rule-in diagnostic test for extrapulmonary TB.
§ Also, it helps to detect both rifampin and multi drug resistant TB (so earlier than conventional culture).
§ But it can give false positive results in already treated cases.
· Treatment of latent TB in recipients:
o Treatment should be completed prior to transplantation, but if urgent indication of transplantation (no line for dialysis for example), we can complete course post-transplant with better avoidance of rifampin.
o INH + vit B6 for 6-9 months.
o Oral rifampin for 4 months (but better avoided post-transplant, to minimize drug-drug interaction.
· Precautions for recipients travelling to endemic areas:
o JUST avoid exposure while BCG vaccine is CI in transplant recipients.
· Treatment of active TB in recipients:
o Start immediately after diagnosis.
o Consider epidemiological criteria of the disease and drug resistant strains.
o Duration of therapy ranges from 6-24 months, at least 6 months,
o 2 Regimens:
1. Intensive therapy for 2 months with 4 drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) followed by continuation phase of 2 drugs (isoniazid and rifampicin) for 4 months.
o Rifampin is enzyme inducer and lower trough level of CNI and mTORi so increase their dose 3-5 folds and double dose of steroids to avoid risk of rejection.
o After stoppage of rifampin, decrease dose according to the trough level is essential.
o Rifabutin is an alternative, less enzyme inducer but not well-studied in transplant cases. While fluoroquinolones are another safe and effective alternative in transplant cases.
2. Intensive phase of 2-month of 3 drugs (should contain isoniazid, ethambutol and pyrazinamide or levofloxacin), followed by a continuation phase of 12–18 months with 2 drugs (isoniazid and ethambutol or pyrazinamide). Longer period of treatment is recommended.
a. Monitoring of adverse effects as hepatotoxicity.
b. Hepatotoxicity is The most common adverse event associated with anti-TB therapy; therefore, liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter
Level of evidence: narrative review (level V)
Do you think IGRA has a better specificity and therefore higher LR ratio?
What is your comment on this statement of mine. You may or may not agree with me.
Thanks dear professor,
Yes, I think it has higher specificity than TST as it is not affected by BCG vaccine or presence in high endemic area in addition, it has better sensitivity in immunocompromised patients as CKD, ESKD and transplant recipients.
Epidemiology in latin America
In the last 2 decades, the burden of tuberculosis(TB) has been considerably reduced in Latin Anerican countries.
The estimated proportion of MDR infection among new TB cases remains below 3% in most countries of the region, higher prevalence has been found in Ecuador, Guatemala, and Peru.
3.0% and 6.0%) has been found in Ecuador, Guatemala, and Peru
Recent reports from the latter country provide evidence of ongoing community transmission of MDR infection with significant impact on mortality.
The prevalence of MDR infection is expectedly higher among patients who were previously treated for TB
In those 3 countries, this prevalence has been estimated to range from 20% to 26%.
Most of these cases were documented in patients who received a graft from a deceased donor with active TB infection, a situation that has been associated with a risk of transmission of approximately 30%.13,14 it is probable that donors with untreated LTBI may be a source of TB transmission, the influence of donor LTBI on the risk of posttransplant TB is undetermined yet.
International travel and post transplant TB
Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB after.
Transplant candidates originating from endemic areas have a higher prevalence of LTBI and are, at Received 2 July 2017.
Funded by a technical cooperation agreement between the Pan American health organization(PAHO) and the Ministry of Health of Brazil
Recommendations for management of endemic
Diseases and Travel Medicine in Solid-Organ Transplant Recipients and Donors:Latin America supplement.
In Spain, the prevalence of active TB infection was markedly increased in deceased donors who originated from a high-incidence country in eastern Europe.
Transplant recipients from low-incidence countries may be exposed to primary infection while traveling to an endemic area, but the actual impact of such exposure in this specific population has not been assessed.
Such figures are lower than those reported for other diseases, such as dengue fever and malaria, they are not negligible, and it is possible that travel-related acquisition may account for a substantial proportion of new infections among people living in low-incidence countries.
The use of public transportation in a high-incidence area in Peru was an independent risk factor for active TB infection.
Visiting friends and relatives is a known risk factor for acute diseases, such as traveler’s diarrhea, but the impact, if any, of such activity on the risk of acquiring TB has not been established.
Diagnosis of LTBI
There is no diagnostic reference standard for LTBI. The tuberculin skin test (TST) remains the best studied test and, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors. IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade.
IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade
They offer some advantages as compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients.
In high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
Diagnosis of active TB infection
The diagnosis of active TB infection relies on the detection of M-tuberculosis bacilli by direct observation, by culture, FIGURE 1.
The availability of a rapid molecular test, such as the Xpert MTB/RIF assay, may have a major impact in the management of these patients.
This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of.
It allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB
It may have a critical role for providing the timely start of MDR-TB treatment while results of conventional culture and drug susceptibility tests are pending.
It is noteworthy that it cannot fully replace the execution of conventional drug susceptibility tests
Risk assessment of the transplant candidate
A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
In high-risk candidates, both tests could be performed and any positive reaction considered an evidence of LTBI.
Whenever this dual-test approach is used, IGRA should be performed before or concurrently with TST placement to avoid.
Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
This evaluation includes checking the presence of symptoms and signs suggestive of TB, performing a chest radiograph and, in cases with extrapulmonary manifestations, imaging of other body sites.
Active infection may not be considered an absolute contraindication to transplantation for candidates who urgently need it.
Risk assessment of deceased and living donors
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
Travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the last 2 years, homeless or refugee status, incarceration and alcoholism may be associated with LTBI.
In this regard, it is important to notice that, given the declining trend of TB incidence in LA current estimates of TB prevalence may not accurately reflect the actual risk of past exposure in these countries.
If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines.
The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, transplant recipients from such donors can be clinically monitored without receiving LTBI therapy
Criteria to start treatment
Therapy for LTBI is an effective strategy for the prevention of active TB infection in transplant recipients, TBI therapy is recommended for transplant candidates with positive.
Therapy for LTBI is an effective strategy for the prevention of active TB infection in transplant recipients.
LTBI therapy is recommended for transplant candidates with positive.
Transplant journal.com considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated.
Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
In considering treatment for LTBI, it is imperative to first rule out active TB infection
Therapeutic regimens
300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily. Nine months of therapy is preferred over 6 months because of better protection.
Nine months of therapy is preferred over 6 months because of better protection.
Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine aminotransferase checked every.
Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions.
These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for.
Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
A recent randomized study of pretransplant levofloxacin versus posttransplant.
INH in liver transplant recipients was stopped early because of excessive adverse events in the levofloxacin arm.
Timing of treatment
The timing of LTBI treatment requires balancing risks and benefits for each patient.
Treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist.
If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible until completion of the originally planned course, with the caveat that rifamycins are usually avoided after transplant.
It can be challenging to treat liver transplant candidates before transplant.
In several small studies, INH has been shown to be safe in those with compensated cirrhosis awaiting transplant with careful monitoring, some experts do prefer waiting until after transplant to begin INH once liver function has been normalized
Recommendation for transplanted patients who travel endemic area
If recently transplanted patients are planning to move to a highly endemic area
If recently transplanted patients are planning to move to a highly endemic area, INH preventive therapy should be considered during the first posttransplant year, especially for those planning to take part in medical or humanitarian care, given the higher risk of primary TB acquisition.
Transplant recipients who are traveling to TB endemic areas to provide medical or humanitarian care should follow standard precautions to prevent nosocomial acquisition of infection.
There is no indication for BCG vaccine before travel, and it is contraindicated in transplant recipients.
Those with possible TB exposure should be evaluated on return, and anyone with symptoms of infection should seek medical evaluation immediately
Treatmenmt of active TB infection
Treatment should follow local guidelines for the general population.
The number of drugs used in the intensive phase regimen should be defined per the prevalence of drug resistance in each population.
INH and rifampicin are the most powerful first-line drugs against TB.
In the context of SOT, many factors should be carefully considered, such as the risk of hepatotoxicity related to the antituberculous treatment and drug interactions of rifampicin.
The optimal length of treatment of TB in transplant recipients is not defined.
Many specialists recommend that treatment duration should be at least 9 months, based on the results of a few studies that have suggested an association between shorter regimens and greater recurrence and mortality.
Monitoring of adverse events related to therapy
Due to the increased risk of adverse events and potential drug interactions, close monitoring is highly recommended, mainly during the first 2 months of treatment when it should be performed biweekly.
Concomitant use of INH, rifampicin, and pyrazinamide is associated with an increased risk of hepatotoxicity, especially in liver recipients.
Low-grade elevation of aminotransferases can be observed during the first.
2 months of treatment, but a 3-fold increase accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation
Findings
The estimated proportion of MDR infection among new TB cases remains below 3% in most countries of the region, higher prevalence
Drug interaction
Rifamycins have an induction effect on different drugmetabolizing enzyme systems, most notably the cytochrome.
Twoto 5-fold increments in the daily dose of cyclosporine, tacrolimus, and mammaliantarget of rapamycin inhibitors are generally necessary to maintain trough levels of the drug in the therapeutic range.
Therapeutic drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption.
Despite these drug interactions, rifampicin is not contraindicated in SOT recipients.
Its weaker effect on CYP3A4 makes it easier to maintain therapeutic blood levels of calcineurin and mammalian target of rapamycin inhibitors during.
Close therapeutic drug monitorings of these immunosuppressive drugs apply when rifabutin is used
I like your detailed summary. I appreciate your debate regarding the uncertainty on optimal duration of therapy
1-Summarise this article;
TB after SOT;
-The incidence rate of TB markedly increases after solid organ transplantation (SOT),
-The risk being highest among lung recipients.
-Reactivation of foci of latent TB infection (LTBI) is probably the main cause of post-transplant TB.
-Patients who received a graft from a deceased donor with active TB infection, are associated with a risk of transmission of approximately 30%.
-The possibility of donor transmission of TB has also been associated with transplant tourism.
Diagnosis of LTBI;
-There is no diagnostic reference standard for LTBI.
-Most current guidelines still recommend using tuberculin skin test (TST) for the screening of LTBI in solid organ candidates/recipients and living donors.
-IFN-γ release assays (IGRAs) offer some advantages as compared with TST:
*Reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination,
*More sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a better correlation with clinical risk factors for LTBI in these patients.
-Other limitations of these assays include:
*Their higher cost
*The frequent occurrence of conversions and reversions of test results when serial screening is performed, which may complicate the interpretation of their results among SOT candidates.
Diagnosis of Active TB Infection;
-The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing.
-Neither TST nor IGRAs are recommended for diagnosing active infection.
-It also allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB.
-Thus, it may have a critical role for providing the timely start of MDR-TB treatment while results of conventional culture and drug susceptibility tests are pending
Prevention;
Risk Assessment of the Transplant Candidate;
-In high-risk candidates (ie, patients originated from endemic countries, household contacts of active TB infection) both tests (TST& IGRAs) could be performed and any positive reaction considered an evidence of LTBI.
-Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
-Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
Risk Assessment of Deceased and Living Donors;
-Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
-Time does not allow for a TST and IGRAs have not been validated in deceased donors.
-Organs from donors with known active TB infection should be discarded.
-If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines.
-Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
-Lungs with residual tuberculous lesions should not be used for transplantation.
-A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, especially for lung recipients.
-The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, therefore, transplant recipients from such donors can be clinically monitored without receiving LTBI therapy.
Treatment;
Treatment of LTBI in Transplant Candidates and Recipients;
-LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
-Those with high-risk pre-transplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, as should those with history of active TB infection that was inadequately treated.
-Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
Therapeutic Regimens;
-For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
-Nine months of therapy is preferred over 6 months because of better protection.
-If recently transplanted patients are planning to move to a highly endemic area (ie, those with prevalence ≥100/ 100000), INH preventive therapy should be considered during the first post-transplant year.
-There is no indication for BCG vaccine before travel, and it is contraindicated in transplant recipients.
Treatment of Active TB Infection;
-The number of drugs used in the intensive phase regimen should be defined per the prevalence of drug resistance in each population.
-In most cases, a 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB.
-The optimal length of treatment of TB in transplant recipients is not defined.
-Many specialists recommend that treatment duration should be at least 9 months, based on the results of a few studies that have suggested an association between shorter regimens and greater recurrence and mortality.
Monitoring of Adverse Events Related to Therapy;
-Due to the increased risk of adverse events and potential drug interactions, close monitoring is highly recommended, mainly during the first 2 months of treatment when it should be performed biweekly.
-Low-grade elevation of aminotransferases can be observed during the first 2 months of treatment, but a 3-fold increase accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation.
-Rifamycins have an induction effect on different drug metabolizing enzyme systems , which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids).
-A lower blood level of these drugs is associated with higher risk of graft rejection.
-Therefore, close monitoring and continuous dose adjustment are highly recommended.
2-What is the level of evidence provided by this article?
-This article is narrative review (LOE 5).
We would do drug monitoring 3 times a week, rather than 2 times a week as per your suggestion, once drugs that do interfere with cytochrome enzymes have been commenced.
MMF would need to be discontinued for 6 weeks when treating active tuberculosis in a transplant recipient. Please do not forget to recommence once the patient gets better.
noted
thanks so much
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
DOI: 10.1097/TP.0000000000002014
Incidence:
The incidence rate of TB markedly increases after transplantation and highest in lung tx. incidence in LA ranges from 1-6%.
Reactivation of foci of latent TB infection (LTBI) is probably the main cause of posttransplant TB. It is more common in recipients from endemic areas or if they live more than 3 months in endemic areas.
Diagnosis of LTBI
The tuberculin skin test (TST) or IFN-γ release assays (IGRAs), there is variation in its use.
Low risk: IGRA
High risk: use both.
Diagnosis of Active TB Infection
1- Detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing.
2- Xpert MTB/RIF assay is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively. It also allows the simultaneous detection of rifampicin resistance.
PREVENTION
A) Risk Assessment of the Transplant Candidate
B) Risk Assessment of Deceased and Living Donors
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
The evaluation of the deceased donor for TB relies on: Medical history, Endemic exposures within the last 2 years, homeless or refugee status, incarceration and alcoholism may be associated with LTBI and Radiographic findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated
Recommendations for Transplanted Patients Who Travel to Endemic Areas
If recently transplanted patients are planning to move to a highly endemic area (ie, those with prevalence ≥100/ 100000), INH preventive therapy should be considered during the first post transplant year
There is no indication for BCG vaccine before travel, and it is contraindicated in transplant recipients
Treatment of Active TB Infection should follow local guidelines for the general population with 4 drug regimens.
Drug Interactions
Rifamycins induce cytochrome P450 which lead to a reduction in the blood levels of most immunosuppressive drugs. Two to five fold increase in the dose is generally necessary to maintain trough levels of the drug. Therapeutic drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption.
***************
Level of evidence: Narrative review written 2017.
Funded by the Pan American Health organization (PAHO) and the Ministry of Health of Brazil.
It is important before it is use to look for higher level of evidence/ recent guidance.
I like your summary, level of evidence, and analysis.
What is your comment in regards to the utility of TST as a screening test?
Epidemiology in Latin America
-TB is a public health problem worldwide.
-Most countries in Latin America are moderately to highly endemic, with incidence remaining over 100 cases per 100 000
-In the last 2 decades, the prevalence and number of TB associated death decreased significantly by 50 %
-Significant variations in the incidence based on notification.
–MDR infection is a global challenge, its prevalence of MDR is expectedly higher among patients in some Latin American countries.
TB after SOT .
-The risk is increased among SOT, being highest among lung recipients.
– LA SOT centers, TB was diagnosed in 0.9% to 5.9% of the recipients, with some variations due to local prevalence
– Most of the cases resulted from reactivation of latent TB, Also, primary TB infection reported in people live in endemic areas, minority acquired from donor transmission especially donors with untreated LTBI.
International Travel and Posttransplant TB
– Immigration, international travel to endemic countries, and transplant tourism may influence the risk of TB after SOT (the risk of donor transmission, and Travel-acquired infection)
– Time spent in the endemic area influences the risk of TB infection
– Humanitarian work with high-risk populations,
– The use of public transportation in a high-incidence area and long distant flight.
Diagnosis of LTBI
– There is no diagnostic reference standard for LTBI.
– Most current guidelines still recommend using tuberculin skin test TST for screening of LTBI in SOT.
– IFN-γ release assays (IGRAs); offer some advantages as compared with TST but has some limitations.
-IGRA is more sensitive and correlate better with clinical risk factor for LTBI.
– Despite the NPP of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI
– Variation in screening protocols for LTBI.
– Some suggests; in low-risk patients to use IGRAs alone, in high-risk patients, both IGRA and TST used to maximize the sensitivity of screening.
Diagnosis of Active TB Infection
-It relies on the detection of M. tuberculosis bacilli by direct observation, by culture and nucleic acid testing.
-Neither TST nor IGRAs are recommended for diagnosing active infection.
– The diagnosis usually delayed in SOT, as they present with atypical manifestations, extrapulmonary involvement and frequent requirement to invasive diagnostic procedure.
– Rapid molecular test (Xpert MTB/RIF assay):
– It is highly specific and sensitivity
– It is a useful rule-in diagnostic test for extrapulmonary TB.
– Allows detection of rifampicin resistance, which is highly predictive of MDR-TB.
– Limitations: false-positive results in successfully treated for TB and cannot replace conventional drug susceptibility tests.
Risk Assessment of the Transplant Candidate
– A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
– Screening for LTBI; If there is no history of past TB or treatment for LTBI either TST or IGRA
– Induration of > 5 mm is considered a positive reaction.
– Low risk Candidates for LTBI tested solely with IGRA.
– High-risk candidates both tests performed.
– IGRA should be done before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses.
– Active TB infection must be excluded in all candidates ( symptoms, radiologically).
– Active infection should delay the transplantation till candidate is treated.
Risk Assessment of Deceased and Living Donors
– They undergo the same evaluation as candidates, with the exception that the cutoff for TST should be > 10 mm.
– Reviewing medical history, exposure history and radiographic findings.
– Organs from donors with known active TB infection should be discarded.
– If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation,
therapy should be immediately started .
– Drug susceptibility tests should be performed on any M. tuberculosis specimen
– Untreated LTBI without evidence of active infection is not a contraindication to donation, and preventive therapy to all
recipients should be considered.
-Donors with completed treatment for LTBI, recipients will require clinical monitoring without therapy.
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients
Indication :
– Rule out active TB infection first.
-Transplant candidates with positive TST or IGRA who have not been previously treated.
– High-risk pre-transplant TB exposure even if the TST or IGRA is not positive.
– History of active TB infection that was inadequately treated.
– Chest imaging suggestive of previous untreated TB.
– Donor has a history of untreated or incompletely treated LTBI or TB.
-Recipient exposure to TB after transplantation.
Therapeutic Regimens
-Oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
– Monitored for hepatotoxicity q 2 weeks for 6 weeks, then monthly.
– Alternative regimens can be considered pre-transplant only RIF 600mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
Timing of Treatment
-Should be started before transplant
– If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible
Travel to Endemic Areas
– INH preventive therapy should be considered during the first posttransplant year.
– There is no indication for BCG vaccine before travel, and it is contraindicated in transplant
recipients.
Treatment of Active TB Infection
– Follow local guidelines for the general population.
– 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB.
– Treatment duration should be at least 9 months
– Careful consideration to drug interaction and hepatotoxicity.
– Treatment should be discontinued if ; 5-fold increase in liver enzymes regardless of symptomatology or 3-fold increase accompanied by any symptom.
Drug Interactions
-Rifamycins is cytochrome inducer that reduce the level of most immunosuppressive drugs used.
– close monitoring dose adjustment are highly recommended to reduce the risk of rejection.
– Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin.
– Rifampicin is not contraindicated in SOT recipients.
Level of Evidence: Level 5 narrative review
I like your summary, level of evidence, and analysis.
What is your comment in regards to the utility of TST nor IGRAs as a screening test or in diagnosing active infection.”
Thank you Prof.
– Neither TST nor IGRAs are recommended for diagnosing active infection as both test may be falsely negative in active TB and immunocompromised patients, as these test assess the immune response of the body to MTB.
-For LTBI either TST or IGRA can be used depend on the availability and the result should be interrupted with cautions.
Both test can be negative in immunocompromised individuals.
TST can be falsely positive if BCG vaccination received.
IGRAs result will not be affected by prior BCG vaccination, and it is more sensitive and correlate better with clinical risk factor for LTBI.
Summary of Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors by Guilherme Santoro-Lopes
TB AFTER SOLID-ORGAN TRANSPLANTATION
TB was diagnosed in 0.9% to 5.9% of the recipients.
The incidence rate of TB markedly increases after solid organ transplantation (SOT), the risk being highest among lung recipients.
Reactivation of foci of latent TB infection (LTBI) is probably the main cause of posttransplant TB. Primary infection acquired in the community, and less frequently in the nosocomial environment.
A minor proportion of primary infections result from donor-recipient transmission. Most of these cases were documented in patients who received a graft from a deceased donor with active TB infection, a situation that has been associated with a risk of transmission of approximately 30%.
DIAGNOSIS
Diagnosis of LTBI:
There is no diagnostic reference standard for LTBI.
· The tuberculin skin test (TST) remains the best studied test. Most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.
· 2 IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade. They offer some advantages as compared with TST:
Ø Advantages:
§ Avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination,
§ Sensitive in candidates with chronic renal failure and advanced cirrhosis.
Ø Disadvantages:
§ The negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI, which includes those who were born to or lived in endemic countries, household contacts of a case of active TB infection, and those who work or live in high-risk settings, such as prisons and homeless shelters.
§ Higher cost
§ Frequent occurrence of conversions and reversions of test results when serial screening is performed.
In low-risk patients, IGRAs could be considered as the sole approach.
In the high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
Diagnosis of Active TB Infection:
· Neither TST nor IGRAs are recommended for diagnosing active infection.
· The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing.
· Invasive diagnostic procedures are more frequently required in this population, resulting in a delay of the proper diagnosis and higher mortality.
· Rapid molecular test, such as the Xpert MTB/RIF assay, may have a major impact in the management of these patients. This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively. It also allows the simultaneous detection of rifampicin resistance, which is highly predictive of MDR-TB. One limitation of this assay is that false-positive results have been observed among patients who had been successfully treated for TB.
PREVENTION
Risk Assessment of the Transplant Candidate
· A history of clinical or radiological TB and the treatment received should be assessed in all recipients.
· If there is no history of past TB or treatment for LTBI, candidates should undergo evaluation for LTBI with either TST or IGRA. If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction.
· In addition, a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
· Candidates who have low risk for LTBI should preferably be tested solely with IGRA.
· In high-risk candidates (ie, patients originated from endemic countries, household contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), both tests could be performed, and any positive reaction considered evidence of LTBI.
Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started.
If any evidence of active infection is found in workup, appropriate clinical specimens should be collected for microbiological confirmation of the diagnosis.
Once active TB infection is diagnosed, transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative. Nevertheless, active infection may not be considered an absolute contraindication to transplantation for candidates who urgently need it.
Risk Assessment of Deceased and Living Donors
Living donors should undergo the same evaluation as candidates, with the exception that the cut-off for TST should be 10 mm or greater.
The evaluation of the deceased donor for TB relies on:
• Medical history. The history of untreated TB should be investigated, as well as previous reactive IGRA or TST. Endemic exposures. Travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the last 2 years, homeless or refugee status, incarceration and alcoholism may be associated with LTBI.
• Radiographic findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening.
Active TB infection should be ruled out in donors at increased risk by obtaining samples, for example, sputum or bronchoalveolar lavage, to test for the presence of M. tuberculosis. Because the results of microbiological investigation will more often be available after procurement, it must be ensured that all data will be forwarded to transplant teams as soon as possible to enable appropriate actions. Organs from donors with known active TB infection should be discarded.
If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines. Drug susceptibility tests should be performed.
Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
Lungs with residual tuberculous lesions should not be used for transplantation.
A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered, especially for lung recipients.
The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, therefore, transplant recipients from such donors can be clinically monitored without receiving LTBI therapy.
TREATMENT
Treatment of LTBI in Transplant Candidates and Recipients
Criteria to Start Treatment Therapy for LTBI
LTBI therapy is recommended for:
· Transplant candidates with positive TST or IGRA who have not been previously treated.
· Those with high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive,
· Those with history of active TB infection that was inadequately treated.
· Chest imaging suggestive of previous untreated TB should prompt consideration for therapy, especially in areas where endemic mycoses are uncommon.
· Transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB.
· If the recipient is exposed to TB after transplantation.
Therapeutic Regimens For treatment of LTBI:
· The preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily. Nine months of therapy is preferred over 6 months because of better protection. Transplant candidates and recipients on INH should be monitored for hepatotoxicity with at least serum alanine aminotransferase checked every 2 weeks for 6 weeks, then monthly thereafter.
· Alternative regimens containing rifamycins can be considered pre-transplant but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
· Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
Timing of Treatment
· When possible, treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist.
· If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible until completion of the originally planned course, with the caveat that rifamycins are usually avoided after transplant.
Recommendations for Transplanted Patients Who Travel to Endemic Areas
· If recently transplanted patients are planning to move to a highly endemic area, INH preventive therapy should be considered during the first posttransplant year.
· Transplant recipients who are traveling to TB endemic areas to provide medical or humanitarian care should follow standard precautions to prevent nosocomial acquisition of infection.
· Those with possible TB exposure should be evaluated on return, and anyone with symptoms of infection should seek medical evaluation immediately.
Treatment of Active TB Infection
Treatment should follow local guidelines for the general population.
The number of drugs used in the intensive phase regimen should be defined per the prevalence of drug resistance in each population. Nevertheless, in most cases, a 4-drug regimen is recommended.
· INH and rifampicin are the most powerful first-line drugs against TB.
· The optimal length of treatment of TB in transplant recipients is not defined. Many specialists recommend that treatment duration should be at least 9 months.
Monitoring of Adverse Events Related to Therapy
· Close monitoring is highly recommended, mainly during the first 2 months of treatment when it should be performed biweekly.
· Low-grade elevation of aminotransferases can be observed during the first 2 months of treatment, but a 3-fold increase accompanied by any symptom or a 5-fold increase regardless of symptomatology requires discontinuation.
Drug Interactions
Rifamycins have an induction effect on different drug metabolizing enzyme systems, most notably the cytochrome P450 (CYP) 3A4, which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids). A lower blood level of these drugs is associated with higher risk of graft rejection. Therefore, close monitoring and continuous dose adjustment are highly recommended.
Therapeutic drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption.
Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin. Nonetheless, the same recommendation for close therapeutic drug monitoring of these immunosuppressive drugs apply when rifabutin is used.
It is level 5 evidence, narrative review.
I like your very detailed summary, level of evidence, and analysis.
Why do you state that, “Neither TST nor IGRAs are recommended for diagnosing active infection.”
Do you think you would like to use a test or battery of tests with good likelihood ratio of >10, rather than those with high predictive value, of diagnosing TB in an immuno-suppressed patients?
Q1.
Epidemiology in Latin America
TB after solid-organ transplantation
Risk factors
Diagnosis
1.Latent TB
2.Active tuberculosis
Prevention
1.Risk assessment of the transplant candidate
2.Risk assessment of the deceased and living donors
The living donor is evaluated the same way as the recipient except that the cut off for TST is 10 mm
The evaluation of the deceased donor depend on;
Rules of deceased donation;
*Donor organ with active TB should be discarded
*If the diagnosis of donor TB is established after transplantation, the recipient should be treat immediately according to the local guidelines
*MDR TB testing should be carried on all donor microbiological specimens
*Organs from donor treated for TB for at least 6 months can be accepted for transplantation
*Untreated LTBI without evidence of active infection is not contraindication to donation, but preventive therapy should be given to all recipients
*In a case of treated LTBI, the risk of transmission is low and therefore, all recipients for such donors should only be monitored without any treatments
Treatment
1.Latent infection(LTBI)
2.Active TB
Q2.
I like your summary, level of evidence, analysis and take home messages. How would you envisage doing the following and I quote your suggestion, “MDR TB testing should be carried on all donor microbiological specimens.”
If we wait for this report, we would miss those cadaveric donors.
What kind of screening program would you suggest that all those clinicians (stakeholders) can be informed well in time?
Thnxs prof