WHO- as ‘a state of persistent immune response to stimulation by mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB disease’ (WHO, 2018b). Up to 10% of individuals with LTBI will develop active TB.
LTBI screening and diagnosis
In both high and low TB-endemic nations, kidney transplantation is routinely performed.
Prior to transplant, all recipients and donors of renal transplants should be screened for LTBI and active TB disease.
Kowada suggests an active TB screening with IGRA for all renal allograft recipients, as well as an individual risk assessment for each patient during LTBI treatment.
It is recommended that these patients begin anti-TB treatment while on the transplant waiting list, with the goal of completing their treatment regimen prior to transplantation.
If transplantation is necessary, it is beneficial to temporarily suspend drug consumption and resume the treatment schedule to completion once patients are clinically stable.
LTBI treatment for both donors and recipients
Due to the fact that tuberculosis could directly affect allograft function, it is of the uttermost importance to prevent transmission of TB infection in this select subgroup of patients.
In both countries with a high and low incidence of tuberculosis, a 6-month course of isoniazid monotherapy is suggested for the treatment of LTBI in both adults and children.
In countries with a high incidence of tuberculosis, Rifapentine and Isoniazid may be administered weekly for 3 months as an alternative to 6 months of Isoniazid monotherapy as a preventive treatment for both adults and children.
Alternatives to six months of isoniazid monotherapy for the treatment of LTBI in countries with a low incidence of tuberculosis include nine months of isoniazid or a three-month course.
There is a need for well-designed prospective controlled cohort trials evaluating the efficacy, tolerability, hepatotoxicity, and adherence of short course LTBI treatment regimens in transplant recipients.
The therapy for active TB
The treatment of drug-sensitive and drug-resistant active tuberculosis in kidney transplant recipients should adhere to WHO treatment guidelines (WHO, 2017, 2018c).
The treatment of patients diagnosed with active tuberculosis after renal allograft transplantation remains a difficult endeavour.
Rifampicin reduces the efficacy of numerous medications by interfering with their metabolism.
Patients taking oral contraceptives or HIV-infected individuals taking protease inhibitors or non-nucleoside reversetranscriptase inhibitors may not be optimal candidates.
Rifampicin and isoniazid can be used in conjunction to treat latent tuberculosis infection (Matteelli et al., 1999).
All renal allograft recipients should undergo proactive TB screening with IGRA, with individualised risk assessment for each patient, and monitoring of drug toxicity during LTBI treatment.
Findings
Up to 10% of individuals with LTBI will develop active TB.
Conclusion
In renal transplant recipients, tuberculosis is a serious complication that causes a great deal of morbidity and mortality.
Transplant recipients are at a greater risk of reactivating latent tuberculosis infection (LTBI) from within themselves or from the donor kidney.
Several available guidelines recommend that, whenever practicable, all donors and recipients be screened routinely for LTBI and active TB disease prior to transplantation.
All renal transplant patients must have a high level of awareness of the prospect of tuberculosis so that it can be diagnosed and treated early, thereby reducing the risk of allograft loss.
Tuberculosis is the commonest infectious cause of death worldwide. About 1.3 million people died of TB in 2017. About 1.7 billion people have latent TB worldwide.
Latent TB is a state of immune persistent response to mycobacterium TB antigens without evidence of clinically manifest active TB. About 10% of latent TB progress to active TB.
Reactivation of latent TB occurs in cases of immunosuppression as diabetes, malnutrition, HIV and prescription of biological and Immunosuppressive agents including anti-rejection therapy in transplant recipients.
Active TB is much higher among kidney recipients and can cause loss of allograft in one third of cases.
TB in renal transplant recipients occurs due to reactivation of latent TB in the recipient or from the donor or increased susceptibility to acquire new TB infection
Screening and diagnosis of latent TB
History: contact with patient with active pulmonary TB, previous TB treatment.
Symptoms: chronic cough, night sweats, weight loss and anorexia.
Full clinical examination: examine for active pulmonary TB and exclude extrapulmonary TB.
Investigation: CBC,CRP,LFT,KFT,microscopy for acid fast bacilli and culture for M.tb in sputum and early morning samples
Histology of biopsy or aspirate ( acid fast bacilli and granuloma)
Test for latent TB
,,, Tuberculin skin test but may be unreliable in patients with advanced CKD and those on Immunosuppressive agents.
,,,, Interferon gamma release assays(IGRA) test either TSPOT.TB or QuantiFERON). They are more sensitive than TST in patients with renal transplantation
Pathogenetic mechanism of latent TB
TB free transplant or denovo infection : if the pre transplant recipient and donor are free of TB infection
Donor derived TB: if the donor has previous TB infection and the recipient free of TB infection
Endogenous reactivation: if the donor free of TB infection and the recipient has previous TB infection
Guidelines recommend that all kidney transplant candidates should be routinely screened for latent TB
Treatment of latent TB
Isoniazide monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Rifampcin plus Isoniazide daily for 3months for children and adults less than 15 years as a preventive treatment in countries with a high TB incidence
Rifapentine and Isoniazide weekly for three months as preventive treatment for adults and children in countries with a high incidence TB
The following options can be used in countries with a low incidence of TB: 9 months of Isoniazide or 3 months of weekly rifapentine plus Isoniazide, 3 to 4 months of Isoniazide plus Rifampcin or 3 to 4 months Rifampcin alone
Conclusion
Due to immunosuppression, transplant recipients are at higher risk of reactivation of LTBI from within themselves or from the donor kidney
Routine Screening for LTBI should be done in donors and recipients prior to transplant
All kidney recipients are liable to TB , early diagnosis and early treatment can save the allograft
Tb is an important cause of morbidity and death in renal transplant recipients which may end with loss of kidney allograft. This is a review of the prevention, diagnosis and treatment of tuberculosis in renal transplant recipients which was done through research of PubMed database.
screening for LTBI and active TB disease should be applied to all renal transplant recipients and their donors prior to transplant. There is no gold standard test for diagnosing LTBI accurately but the WHO recommends three tests for screening for LTBI: Tuberculin skin test and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T.
prevention is important to prevent Tb affection of the graft. it is extremely important to make the utmost effort to prevent transmission of TB infection in such a select subgroup of patients.
Treatment of LTBI should follow WHO 2018 guidelines.
– Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
– Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15
– Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
– The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-mont regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone
level of evidence is 5
Screening and diagnosis of latent tuberculosis infection (LTBI):
Renal transplant recipients and their donors should undergo screening for LTBI and active TB disease before transplantation.
The World Health Organization (WHO) recommends three tests for LTBI screening: Tuberculin skin test (TST), QuantiFERON-TB Gold In-Tube (QFT), and T-SPOT.TB.
Clinical workup for donors and transplant recipients to screen for LTBI and active TB:
History: Check for contact with a person having TB and previous TB treatment history.
Symptoms: Evaluate for cough, fever, weight loss, night sweats, and anorexia.
Examination: Look for signs of active TB and exclude extrapulmonary TB.
Investigations: Conduct blood tests, sputum and urine samples for microscopy and culture, biopsy and aspirate for acid-fast bacilli and granuloma, and GeneXpert/RIF assay.
Tests for LTBI:
Tuberculin skin testing and/or interferon gamma release assays (IGRAs) such as T-SPOT.TB or QuantiFERON can be used.
Imaging, such as chest X-ray, renal scan, CT or MRI, and PET/CT scan, may be performed if required.
Treatment of LTBI in donors and recipients:
WHO guidelines recommend isoniazid monotherapy for 6 months as the primary treatment for LTBI in both adults and children in high- and low-incidence TB countries.
Rifampicin plus isoniazid for 3 months is an alternative to isoniazid monotherapy for children and adolescents in high-incidence TB countries.
Rifapentine and isoniazid weekly for 3 months may be offered as an alternative to isoniazid monotherapy for both adults and children in high-incidence TB countries.
Different treatment options are recommended for low-incidence TB countries, including extended courses of isoniazid, rifampicin plus isoniazid, or rifampicin alone.
Treatment of active TB:
Follow WHO guidelines while considering drug interactions and risk of toxicity. Emphasize adherence and completion of treatment.
Conclusions:
Immunocompromised patients, including transplant recipients, are at high risk of TB.
Early diagnosis and treatment are crucial, requiring a high index of suspicion.
Level 5 evidence
TB is the most common infectious diseasecausing death worldwide. Screening and diagnosis of LTBI as recommended by the WHO:
-Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs).
CBC & differential ,CRP ,IGRAS test , Microscopy & culture for AFB ,Gene Xpert MTB test.
-Treatment of active TB :Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines
Proactive TB screening with IGRA and monitoring the drug toxicity during LTBI treatment is recommended for all renal allograft recipients.
-LTBI and active TB infection post transplantation leads to high morbidity and mortality.
Introduction
Who said, Tuberculosis (TB) is the commonest infectious disease cause of
death worldwide .
Recent epidemiology studies report that there are 1.7 billion people worldwide with latent
Mycobacterium tuberculosis infection (LTBI)
About 10% of LTBI will progress to active TB during lifetime.
risk factors for re-activation LTBI
1- Diabetes.
2- Malnutrition.
3- HIV.
4- prescription of biologics and immunosuppressive agents.
The incidence of active TB disease among renal transplant recipients is much higher than in the general population and causes much morbidity and death in these patients . TB is also responsible for loss of the renal allograft in approximately one third of cases.
The clinical presentation of TB occurring in transplant recipients is said to differ from that in the general population and an increased frequency of extra pulmonary TB is seen.
Screening and diagnosis of LTBI:
All renal transplant recipients and their donors should undergo screening for LTBI and active TB
disease prior to transplant.
There is no gold standard test for diagnosing LTBI accurately.
WHO recommends three tests for screening for LTBI:
A- Tuberculin skin test (TST) .
B- two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT T.
diagnostic approach:
A. history.
Ø Contact with TB patient.
Ø Old TB treatment.
B. symptoms.
Chronic cough, fever, night sweat, weight loss, anorexia.
C. Full clinical examination.
Ø For active pulmonary TB.
Ø For extra pulmonary TB.
D. Investigation.
Ø CBC
Ø CRP
Ø Renal and liver function.
Ø AFB and culture for mycobacterium TB.
Ø Tissue biopsy .
Ø geneXpert MTB assay.
E. Investigation for LTBI
Ø Tuberculin skin test.
Ø IGRA test.
F. Imaging.
Ø CXR.
Ø Renal ultrasound.
Ø MRI or CT scan.
ØPET/CT scan.
Treatment of LTBI in donor and recipient:
tuberculosis could directly affect the allograft function.
Every effort
must be made to diagnose and treat LTBI and active tuberculosis in
both live donor and recipient before transplantation.
Treatment of LTBI should follow WHO 2018 guidelines
Ø Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Ø Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment .
Ø Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment.
Ø The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-monthregimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB
Treatment follow WHO treatment guidelines . Treatment of patients with active
tuberculosis post transplantation is a challenging task.
Hepatotoxicity and Peripheral neuropathy should be kept in mind.
Drug interaction with oral contraceptives and anti-retro viral medication.
Proactive TB screening with IGRA with individualized risk assessment of each of the patients and monitoring the drug toxicity during LTBI treatment is to be recommended for all renal allograft recipients.
2- What is the level of evidence provided by this article
Level of evidence is 5.
Latent tuberculosis infection is defined by the World Health Organisation (WHO) as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’ (WHO, 2018b). Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime. The highest risk for developing TB disease occurs when a range of risk factors for re-activation LTBI .occur when conditions of immunosuppression are present such as diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients. Most of the TB cases in renal transplant recipients are due to re-activation of LTBI in the recipient .
Screening and diagnosis of LTB
All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant. There is no gold standard test for diagnosing LTBI accurately. WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT T.
The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agents.IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients., There are likely to be more false positive, false negative and indeterminate results of IGRAs in transplant recipients.. A higher rate of LTBI was found in patients undergoing renal transplantation than those undergoing other organ transplantation, especially when IGRA tests were used compare to the TST. Thus IGRAs (both QFT and T-SPOT) have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation
Treatment of LTBI in donor and recipient
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone
Introduction
Tuberculosis (TB) is the commonest infectious disease cause of death worldwide (WHO, 2018a). An estimated 1.3 million people died of tuberculosis in 2017. Recent modelling re-calculations indicate that there are 1.7 billion people worldwide with latent Mycobacterium tuberculosis infection (LTBI) (Houben and Dodd 2016). Latent tuberculosis infection is defined by the World Health Organisation (WHO) as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’ (WHO, 2018b). Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime.
Screening and diagnosis of LTBI
Kidney transplantation is now universally performed in high and low TB endemic countries. All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant. There is no gold standard test for diagnosing LTBI accurately. WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T (WHO, 2018b). The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agents (Guirao-Arrabal and Torre- Cisneros, 2018). IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients (Pai et al., 2014; Guirao-Arrabal and Torre-Cisneros, 2018).
A diagnostic approach for detection of active and latent tuberculosis has been outlined by Demir and Sever (2017). Clinical workup of donors and transplant recipients to screen for LTBI and active TB The TBNET consensus group has summarized pathogenesis of LTBI in post-transplant patients (Bumbacea et al., 2012).
In low TB endemic countries, LTBI screening is recommended for
population subgroups with a high prevalence of TB or those with a high likelihood of progression from LTBI to active disease. These include close contacts of patients with active tuberculosis, recently arrived foreign-born persons, drug users, incarcerated persons, and homeless individuals and were advised screening for LTBI (Horsburgh, 2004). Chest X-ray, detailed background history of previous exposure to patients with TB and risk factor assessment for travel or migration from endemic areas was the most frequent recommendation for LTBI screening in immunosuppressed individuals and those undergoing Solid Organ Transplant
Treatment of LTBI in donor and recipient As tuberculosis could directly affect the allograft function, it is
extremely important to make the utmost effort to prevent transmission of TB infection in such a select subgroup of patients. Every effort must be made to diagnose and treat LTBI and active tuberculosis in bothlivedonorandrecipientbeforetransplantation.TreatmentofLTBI should follow WHO 2018 guidelines (WHO, 2018b). The Consensus Statement from the Spanish Group for the Study of
Infectious DiseasesinTransplant Recipients defines the indications for treatment of LTBI in SOT recipients (Aguado et al., 2009). The WHO 2018 guidelines outline the following treatment options for LTBI (WHO, 2018b).
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month
regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Renal transplantation is now widely available globally. TB is a serious complication in renal transplant recipients and causes much morbidity and mortality. Due to immunosuppression, transplant recipients are at a higher risk of re-activating LTBI from within themselves or from the transplanted donor kidney. Several guidelines are available and are consistent in recommending that all donors and recipients are routinely screened for LTBI and active TB disease prior to transplant whenever possible. A high degree of awareness of the possibility of TB is required in all renal transplant patients so that it can be diagnosed and treated early, reducing the risk of loss of allograft
Introduction :
Latent tuberculosis infection is defined as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (TB) which is the commonest infectious disease cause of death worldwide . Latent Mycobacterium tuberculosis infection (LTBI)affects 1.7 billion people worldwide
.
The incidence of active TB disease among renal transplant recipients is much higher compared with the general population; it causes increased morbidity and mortality in these patients .
Commonly caused by reactivation of LTBI in the recipient or to a lesser extent from donor kidney
The diagnosis and treatment of LTBI and active TB disease in donors and transplant recipients is quite challenging and needs a high degree of awareness of the possibility of TB.
There is an increased frequency of extrapulmonary TB in transplant recipients than in the general population Screening and diagnosis of LTBI:
Screening for LTBI is recommended for all renal transplant candidates and their donors , especially those with history of TB, previous rejection, or other risk factors. LTBI screening is recommended for population subgroups with high prevalence of TB or high likelihood of progression to active disease, including close contacts, foreign-born persons, drug users, incarcerated persons, and homeless individuals
WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T .
There limited data on the sensitivities and specificities of TST and IGRAs in screening for LBI in renal transplant recipients,but IGRAs have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients candidates for renal transplantation.
Undiagnosed LTBI in a recipient during pretransplant evaluation, either persists as LTBI or may undergo endogenous reactivation in the period of immunosuppression . Treatment of LTBI in donor and recipient :
The treatment of LTBI should be as recommended by WHO 2018 guideline :
Isoniazid monotherapy for 6 months
Rifampicin plus Isoniazid daily for 3 months
Rifapentine and Isoniazid weekly for 3 months
TB has a direct effect on the allograft function, so transmission of TB infection should be prevented Treatment of active TB:
Treatment of both drug-sensitive and drug resistant active TB in renal transplant recipients should follow WHO treatment guidelines. adverse events caused by Isoniazid ( hepatotoxicity and peripheral neuropathy)can be prevented by pyridoxine co-administration
Rifampicin is a potent enzyme inducer which decrease the level of immunosuppressant and other drugs and may not be an ideal choice for patients taking oral contraceptives or HIV-infected individuals on protease inhibitors or non-nucleoside reverse- transcriptase inhibitors.
Proactive TB screening with IGRA is to be recommended for all renal allograft recipients. Conclusion :
TB is a serious infection in renal transplant recipients because of immunosuppression. All donors and recipients are screened for LTBI and active TB disease prior to transplant to reduce the risk of loss of allograft as recommended by several guidelines .
What is the level of evidence provided by this article?
The incidence of active TB in renal transplant recipients is much higher than in the general population
The authors highlighted the very important issue of diagnosis and management of latent TB in transplant population.
Latent TB infection ; by the World Health Organization (WHO) definition is ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (MTB) antigens without evidence of clinically manifest active TB disease’ (WHO, 2018b). Up to 10% of people with LTBI will develop active TB disease during their lifetime.
-Screening and diagnosis of latent TB:
The first step is to take history, proper physical examination and relevant lab investigations including radiology.
No gold standard test for diagnosing LTBI accurately. WHO recommends 3 tests for screening for LTBI: TST and two interferon gamma release assays (IGRAs) :QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T (WHO, 2018b). The TST may be inaccurate in patients with advanced CKD and in those on immunosuppressive medications.
IGRAs are more specific to M.TB antigens and has high specificity in detection of LTBI in immunosuppressed patients.
-Treatment of LTBI in donor and recipient
INH monotherapy for 6 months is recommended for ttt of LTBI in adults and children in areas with high and low TB incidence.
Rifampicin plus INH daily for 3 months must be offered as an alternative to 6 months of INH monotherapy as preventive measure for children and adolescents aged less than15 years in areas with a high TB prevalence.
Rifapentine &INH every week for 3 months may be given as alternative to 6 months of INH monotherapy as preventive measure for adults and children in areas with high TB prevalence.
The following regimens are recommended for treatment of LTBI in areas with low TB incidence as alternatives to 6 months of INH monotherapy: 9 months of INH, or a 3-month regimen of weekly rifapentine plus INH, or 3–4 months of INH plus rifampicin, or 3 to 4 months of rifampicin only.
Treatment of active TB:
Treatment of both drug-sensitive and drug resistant active TB in renal transplant recipients must follow WHO treatment guidelines (WHO, 2017, 2018c). The most important issue is to avoid serious drug interactions of Rifampicin . It is essential that all centers must revise there policies in this aspect based on local guidelines.
Introduction: Tuberculosis (TB) is the commonest infectious cause of death worldwide – WHO estimated 1.3 million people died of tuberculosis in 2017, and 1.7 billion people worldwide harbour latent Mycobacterium tuberculosis infection (LTBI). LTBI is defined by WHO as ‘a state of persistent immune response to stimulation by M.tb antigens with no clinical manifestation of active TB disease’. 10% of them progress to active TB disease during lifetime, high risk reactivation occur in presence of diabetes, malnutrition, HIV, immunosuppressive medications, post-transplant. Active TB incidence in kidney transplant recipients (KTRs) is higher than the general population, associated with high morbidity, graft loss and mortality. Most cases are due to reactivation of LTBI; but can also be donor-derived or a de novo infection. The diagnosis can be challenging due to atypical presentation, and more extrapulmonary features. Screening and diagnosis of LTBI:
· There is no gold standard test for diagnosing LTBI accurately. · WHO recommends screening by tuberculin skin test (TST) and interferon gamma release assays (IGRAs) using either QuantiFERON-TB Gold In-Tube or T-SPOT TB tests. IGRAs are more sensitive that TST for LTBI.
· IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in CKD and immunosuppressed patients.
· IGRAs (both QFT and T-SPOT) have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation · In low resource settings, TST continues to be used for diagnosing LTBI. Diagnostic approach for detection of active and latent tuberculosis involves · history – TB treatment / contact with TB patient · Symptoms – chronic cough, night sweats, weight loss, anorexia · clinical examination – pulmonary and extrapulmonary · investigations – CBC, CRP, LFT, RFT, M.tb microscopy and culture histology of aspirates and biopsy for AFB and granuloma · Gene X-pert MTB / RIF assay on sputum, urine, or biopsy · imaging – CXR, renal ultrasound, MRI, CT or PET-CT Treatment of LTBI in donor and recipient: (WHO 2018 guidelines) high-endemicity areas v INH monotherapy x 6 months for both children and adults v INH + Rifampicin daily x 3months should be offered for children n adolescent <15 years v INH + Rifampicin weekly x 3months may be offered for adults and older children (>15 years) low endemicity regions – recommended for treatment of LTBI in countries with a low TB incidence
Ø 6-9 months of isoniazid monotherapy
Ø 3–4 months of INH + Rifampicin
Ø 3-month regimen of weekly Rifampicin + INH Ø 3–4 months of Rifampicin alone Adverse effects, drug interactions, and longer duration of treatment are the challenges faced during LTBI treatment. Rifabutin can be used in place of rifampicin in case of high drug reactions in transplant recipients. Treatment of active TB: To follow local / WHO guidelines – intensive phase 4 drug regimen, maintenance phase 2drugs (Rifampicin based preferable), Total duration of 9-12 months. Close monitoring of liver enzymes, other adverse effects, and looking for drug interactions. Conclusions: v TB is a serious complication in renal transplant recipients and increases morbidity and mortality. Transplant recipients have increased risk of developing TB due to reactivation of LTBI, a donor-derived infection, or a de novo infection. v All donors and recipients should be screened for LTBI and active TB disease prior to transplant – screening with IGRA and individualized risk assessment is important to diagnose TB / LTBI. v Increasedawareness in patients regarding possibility of TB post-transplant may lead to early diagnosis and treatment, which may reduce graft loss.
v Monitoring of adverse reactions as well as drug interactions during treatment is essential for good patient and graft outcomes. 2. What is the level of evidence provided by this article? Level of evidence: level 5 – Narrative review.
Latent tuberculosis infection and renal transplantation – Diagnosis and management Introduction · Tuberculosis (TB) is the most common cause of death from infectious diseases. · There are about 1.7 billion people worldwide with latent TB. · WHO definition of LTB: ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB disease’ · Risk factors of activation of LTB: DM, malnutrition, HIV, and biologic and immunosuppressive drugs. · In recipients, TB increases mortality, morbidity, and graft loss. · The commonest cause of TB in recipients is the activation of LTB. · As LTB is asymptomatic, diagnosis and treatment could be challenging. · Transplant recipient’s clinical presentation is different from the general population and has more incidence of extrapulmonary TB. Screening and diagnosis of LTBI · WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon-gamma release assays (IGRAs) namely, QuantiFERON-TB (QFT) Gold In-Tube and T-SPOT T · TST could be unreliable in advanced CKD and in those immunosuppressed patients. · IGRAs are more specific to M.tb antigens and are highly specific in LTBI in immunosuppressed patients · transplant recipients have falser positive, falser negative and indeterminate results of IGRAs · IGRAs found to be more sensitive than the TST for the diagnosis of LTBI in renal transplant candidates. Treatment of LTBI in donor and recipient · Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence. · Rifampicin plus Isoniazid daily for 3 months is an alternative as preventive treatment for children and adolescents (<15 y) in countries with a high TB incidence. · Rifapentine and Isoniazid weekly for 3 months is an alternative as preventive treatment for both adults and children in countries with a high TB incidence. · Treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 1) 9 months of isoniazid, 2)or a 3-month regimen of weekly rifapentine plus isoniazid, 3)or 3–4 months of isoniazid plus rifampicin, 4)or 3–4 months of rifampicin alone. Treatment of active TB · should follow WHO treatment guidelines ( · Isoniazid and Rifampicin have hepatotoxicity limiting its use. · Peripheral neuropathy caused by Isoniazid can be prevented by co-administration of pyridoxine · Rifampicin has many drug-drug interactions, while Rifabutin has fewer interactions Conclusions · TB is a serious complication in renal transplant recipients and increases morbidity and mortality. · Immunosuppression increases the risk of activation of LTBI · All donors and recipients should be screened for LTBI and active TB disease prior to transplant. · Increasedawareness of the possibility of TB in renal transplant recipients may lead to early diagnosis and treatment, which may reduce graft loss. This is a narrative review with evidence V.
One of the commonest disease which has increased mortality rate globally is Tuberculosis. And immunocompromised patients like renal transplant have even more chances of acquiring T.B compared to general population.Latent T.B is the presence of Mycobacterium organism in the patient with no symptoms and around 10% of such patients have chances to progress to full blown active T.B during their lifetime. Screening and diagnosis of LTBI Both donor and recipient should be screened for LTBI and there is no gold standard test available. BTS recommends LTBI screening should be done for patients having risk factors like patients having past history of T.B, diabetes ,history of rejection and taking steroids .However, in areas with low incidence of TB , patients having close contacts with active tuberculosis patients, recent history of travel,drug users, incarcerated persons, and homeless individuals should be screened..According To WHO ,: three tests are available: Tuberculin skin test (TST) and interferon gamma release assays (IGRAs) i.e., QuantiFERON1-TB (QFT) Gold Test and T-SPOT .Reliable test in renal transplant patient is IGRA assays. After detailed history and examination, following investigations should be carried out to rule out active T.B and LTBI .Tests include:CBC,CRP,RFTs,LFTs, LTBI test(Quantiferon T.B gold test, TSPOT ),for ruling out active infection -sputum and urine for microscopy for AFB, Gen-expert MTB-RIF assay and culture for M.T.B, Tissue sample for histology and Genexpert-RIF, followed by X-Ray Chest and Ultrasound Abdomen .CT scan ,MRI Abdomen ,PET scan as per requirement. Treatment of LTBI in donor and recipient Various treatment options available as mentioned in the WHO 2018 guidelines 1- Isoniazid monotherapy for 6 months 2- Rifampicin plus Isoniazid daily for 3 month 3- Rifapentine and Isoniazid weekly for 3 months 4- For low TB incidence areas: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone. Treatment of active TB Drug-sensitive and drug resistant active TB disease treatment –similar as in general population and should follow WHO guidelines ,but should be cautious of the drug-drug interactions with the immunosuppression as can have drastic consequences. Conclusions In short, renal or any solid organ transplant patients should be thoroughly screened for T.B as timely detection and management can help in reducing the morbidity . mortality and also allograft loss.
Introduction; According to WHO 2018 it was estimated more than 1.3 million people, LTBI 1.7million, up-to 10% develop active TB, TB is risk is much higher than general population, most of the cases are re-activation of LTBI. The clinical presentation of TB occurring in transplant recipient is to differ from that in the general population and an increased frequency of extrapulmonary TB is seen. Screening and diagnosis of LTBI; There is no gold standard test for diagnosis LTBI, however, WHO recommends these tests, 1. TST, may be unreliable in CKD, and immunocompromissed, 2. IGRA, (QFT, T-SPOT) more specific and high specific in detection. 3. Clinical approach and workup, A good history, Constitutional symptoms, Baseline investigation, microscopy, GeneXpert MTB/Rif Assay. Imaging. In low TB endemic countries LTBI screening is recommended with high prevalence of TB, and those with close contacts, drug users, and homeless individuals. It’s recommended an active TB screening with IGRA for all renal allograft recipient. Aiming at complete treatment schedule prior to transplantation. Treatment of LTBI in donor and recipient; Isoniazid immunotherapy for six months with high and low TB incidence. Rifampicin plus Isoniazid daily for 3 months as alternate to immunotherapy with age <15 years. As a preventive RIF + INH weekly for three months in high TB incidence, Other options with LTBI in countries with low TB incidence as alternatives 6 months INH, or 9 month INH, or 3 months regimen of weekly RIF + INH, or 3 months INH + RIF, or RIF alone. Treatment of active TB; According to 2018 guidelines showed be followed for drug sensitive and drug resistant TB disease. Drug induced toxicity has been major issue in treatment of recipient. To prevent peripheral neuropathy co-administration of pyridoxine. Drug interaction with RIF, rifabutin has fewer side effects. Conclusion; Transplant recipient has high morbidity and mortality with TB disease. Due to immunosuppression there is high risk of re-activation of LTBI. It is highly recommended to screen donor and recipient prior to transplantation. level of evidence V
Latent tuberculosis infection is defined by the World Health Organisation (WHO) as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB disease’. Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime. The highest risk for developing TB disease occurs when a range of risk factors for re-activation LTBI occur when conditions of immunosuppression are present such as diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients.
The incidence of active TB disease among renal transplant recipients is much higher than in the general population and causes much morbidity and death in these patients. TB is also responsible for loss of the renal allograft (transplanted kidney) in approximately one third of cases. Most of the TB cases in renal transplant recipients are due to re-activation of LTBI in the recipient or from donor kidney.
All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant. There is no gold standard test for diagnosing LTBI accurately. WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs). The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agentes and IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
British Thoracic Society guidelines suggest screening for LTBI where tuberculosis incidence rates are high or in patients with risk factors for developing tuberculosis in low incidence áreas. Various meta-analyses and subsequent guidelines recommend that all renal transplant candidates should be routinely screened for LTBI.
Treatment of LTBI in donor and recipiente
The Consensus Statement from the Spanish Group for the Study of InfectiousDiseases inTransplantRecipientsdefines the indications for treatment of LTBI in SOT recipients and the WHO 2018 guidelines outline the following treatment options for LTBI:
– Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
– Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged < 15 years in countries with a high TB incidence.
– Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
– The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone
Treatment of active TB
Treatment of patients with active tuberculosis detected after renal allograft transplantation remains a challenging task. Hepatotoxicity is a serious dose limiting side effects of both Isoniazid and Rifampicin and this risk is further accentuated in patients with pre-existing liver disease and alcoholics. Peripheral neuropathy caused by Isoniazid can be prevented by co-administration of pyridoxine. Rifampicin interferes with the efficacy of many drugs by interfering with their metabolism. It may not be an ideal choice for patients taking oral contraceptives or HIV-infected individuals on protease inhibitors or non-nucleoside reverse- transcriptase inhibitors. Rifabutin has fewer pharmacologic interactions with antiretroviral agents than Rifampicin and can be used in combination with Isoniazid for the treatment of latent tuberculosis infection.
What is the level of evidence provided by this article?
●All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant.
●WHO recommends three tests for screening for LTBI:
1- Tuberculin skin test (TST)
2- and two interferon gamma release assays (IGRAs) namely,
A- QuantiFERON1-TB (QFT) Gold In-Tube
B- and T-SPOT1T
●IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients
●there are likely to be more false positive, false negative and indeterminate results of IGRAs in transplant recipient
○Rahimifard et al., 2018)study showed A higher rate of LTBI in patients undergoing renal transplantation , using IGRA tests
●In low resource settings, TST continues to be used for diagnosing LTBI
Pathogenetic mechanisms of LTBI and active TB occurrence in renal allograft recipients.
D free of TB ==> R free of TB ==> R free of TB
D previous infected==> R free of TB==> R donor drived infection
D free of TB ==> R previous infected==> R indigenous reactivation
D free of TB ==>R free of TB ==> R De novo infection
M.tb bacilli remain dormant within the transplant kidney for months to years.
Case report
□44 year old man
□endogenous reactivation of LTBI
□right open nephrectomy
□ normal functioning solitary left kidney.
□Three years later, he developed pelvi-ureteric junction stricture and mid ureteric stricture of the solitary left kidney
□active TB was diagnosed.
□Anti-TB treatment
□ percutaneous nephrostomy
□A left open nephrectomy was done and the patient was on maintenance HD for 24 months.
□A live related renal transplantation was subsequently done 2 years later
□ Four years after the transplant, there was a mild and gradual worsening of the renal function
□ biopsy showed evidence of epithelioid granuloma with Langhans giant cells in the graft kidney, suggestive of TB in the renal allograft
●The patient had a symptomatic and biochemical improvement after initiation of anti-TB treatment.
●Various meta-analyses guidelines recommend that all renal transplant candidates should be routinely screened for LTBI (Stagg et al., 2014).
●British Thoracic Society guidelines suggest screening for LTBI where tuberculosis incidence rates are high
patients with risk factors for developing tuberculosis (Horne et al., 2013).
1- Previous rejection episodes,
2- high-dose corticosteroids,
3-diabetes mellitus
4-those living in endemic areas
5- close contacts of patients with active tuberculosis,
6drug users,
7- homeless
●Kowada recommends an active TB screening with IGRA for all renal allograft recipients with individualized risk (Kowada, 2018).
●if there is a need to undergo transplantation, it’s worthwhile to temporarily stop TB treatment intake and recommence the treatment schedule to completion once patients were clinically stable.
Treatment of LTBI in donor and recipient
The Treatment of LTBI should follow WHO 2018 guidelines
the following treatment options for LTBI
●Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
●Rifampicin plus Isoniazid daily for 3 months should be offered as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
●Rifapentine and Isoniazid weekly for 3 months may be offered as preventive treatment for both adults and children in countries with a high TB incidence.
◇The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy:
◇9 months of isoniazid,
◇or a 3-month regimen of weekly rifapentine plus isoniazid,
◇ or 3–4 months of isoniazid plus rifampicin,
◇or 3–4 months of rifampicin alone.
●There is a need for well-designed prospective controlled cohort trials of short course LTBI treatment regimens in transplant recipients, (efficacy, safety, hepatotoxicity and adherence to treatment.)
Treatment of active TB
●should follow WHO treatment guidelines
●remains a challenging task.
●Hepatotoxicity is a serious dose limiting side effects of both Isoniazid and Rifampicin.
●Peripheral neuropathy caused by Isoniazid can be prevented by co-administration of pyridoxine.
● Rifampicin interferes with the efficacy of many drugs by interfering with their metabolism.
●It may not be an ideal choice for patients taking oral contraceptives or HIV-infected individuals on protease inhibitors or non-nucleoside reverse transcriptase inhibitors.
●Rifabutin has fewer pharmacologic interactions with antiretroviral agents than Rifampicin and can be used in combination with Isoniazid for the treatment of latent tuberculosis infection
Introduction: Tuberculosis (TB) is the commonest infectious cause of death. Patent TB infection 9ltbi0 is defined as state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens without evidence of clinically manifest active TB disease. 10% of LTBI lead to active TB disease, especially in presence of risk factors like diabetes, malnutrition, HIV, use of immunosuppressive medications like a transplant recipient. Active TB incidence in kidney transplant recipients (KTRs) is higher than the general population leading to morbidity, mortality, and graft loss. Most cases are due to reactivation of LTBI, or could either donor-derived or a de novo infection. The diagnosis can be missed due to atypical presentation, and more extrapulmonary features.
Screening and diagnosis of LTBI: WHO recommends LTBI testing using tuberculin skin test (TST) and interferon gamma release assays (IGRAs) using either QuantiFERON-TB Gold In-Tube or T-SPOT T tests. IGRAs are more sensitive that TST for LTBI. The diagnostic approach involves history (of TB contact or TB treatment), Symptoms (of chronic cough, night sweats, weight loss and anorexia), clinical examination (for both pulmonary and extrapulmonary TB), investigations (CBC, CRP, LFT, RFT, M.tb microscopy and culture, histology of aspirates and biopsy for acid fast bacilli and granuloma, GeneXpert MTB/RIF assay on sputum, urine, or biopsy), and imaging (chest x-ray, renal ultrasound, MRI, CT or PET-CT, when indicated).
Treatment of LTBI in donor and recipient: The regimens used for LTBI treatment include isoniazid monotherapy for 6 months, 3 months of isoniazid with rifampicin, or 3 months of weekly isoniazid with rifapentine in high-endemicity areas; while for low endemicity regions, isoniazid for 6 or 9 months, 3-4 months of rifampicin, 3-4 months of combination of isoniazid and rifampicin, and weekly isoniazid and rifapentine for 3 months have been recommended. Adverse effects, drug interactions, and longer duration of treatment are the challenges faced during LTBI treatment. Rifabutin can be used in place of rifampicin in transplant recipients.
Treatment of active TB: It involves following WHO guidelines with close monitoring of liver enzymes and other adverse effects as well as looking for drug interactions.
Conclusions: Transplant recipients have increased risk of developing TB due to reactivation of LTBI, a donor-derived infection, or a de novo infection. Proactive TB screening with IGRA and individualized risk assessment is important to diagnose TB/ LTBI, and monitoring of adverse reactions as well as drug interactions during treatment is essential for good patient and graft outcomes.
2. What is the level of evidence provided by this article?
The incidence of active TB disease among renal transplant recipients is much higher than in the general population
The authors of this paper have tried to address this very important issue of diagnosing and managing latent tuberculosis in transplant population.
Latent tuberculosis infection is defined by the World Health Organisation (WHO) as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’ (WHO, 2018b). Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime.
SCREENING AND DIAGNOSIS OF LATENT TB
The first step is always to take good history, proper physical exam and then relevant lab investigations and imaging.
There is no gold standard test for diagnosing LTBI accurately. WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T (WHO, 2018b). The TST may be unreliable in patients with advanced chronic kidney disease and in those on
immunosuppressive agents.
IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
Treatment of LTBI in donor and recipient
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month
regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB
Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines (WHO, 2017, 2018c). The most important thing is to consider serious interactions of Rifampicin especially with CNIs. It is mandatory that each center should devise there own policies in this regard according to local guidelines.
Latent tuberculosis infection and renal transplantation – Diagnosis and management Introduction
· Tuberculosis (TB) is the most common cause of death from infectious diseases.
· There are about 1.7 billion people worldwide with latent TB.
· WHO definition of LTB: ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB disease’
· Risk factors of activation of LTB: DM, malnutrition, HIV, and biologic and immunosuppressive drugs.
· In recipients, TB increases mortality, morbidity, and graft loss.
· The commonest cause of TB in recipients is the activation of LTB.
· As LTB is asymptomatic, diagnosis and treatment could be challenging.
· Transplant recipient’s clinical presentation is different from the general population and has more incidence of extrapulmonary TB. Screening and diagnosis of LTBI
· WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon-gamma release assays (IGRAs) namely, QuantiFERON-TB (QFT) Gold In-Tube and T-SPOT T
· TST could be unreliable in advanced CKD and in those immunosuppressed patients.
· IGRAs are more specific to M.tb antigens and are highly specific in LTBI in immunosuppressed patients
· transplant recipients have falser positive, falser negative and indeterminate results of IGRAs
· IGRAs found to be more sensitive than the TST for the diagnosis of LTBI in renal transplant candidates. Treatment of LTBI in donor and recipient
· Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
· Rifampicin plus Isoniazid daily for 3 months is an alternative as preventive treatment for children and adolescents (<15 y) in countries with a high TB incidence.
· Rifapentine and Isoniazid weekly for 3 months is an alternative as preventive treatment for both adults and children in countries with a high TB incidence.
· Treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy:
1) 9 months of isoniazid,
2)or a 3-month regimen of weekly rifapentine plus isoniazid,
3)or 3–4 months of isoniazid plus rifampicin,
4)or 3–4 months of rifampicin alone.
Treatment of active TB
· should follow WHO treatment guidelines (
· Isoniazid and Rifampicin have hepatotoxicity limiting its use.
· Peripheral neuropathy caused by Isoniazid can be prevented by co-administration of pyridoxine
· Rifampicin has many drug-drug interactions, while Rifabutin has fewer interactions Conclusions
· TB is a serious complication in renal transplant recipients and increases morbidity and mortality.
· Immunosuppression increases the risk of activation of LTBI
· All donors and recipients should be screened for LTBI and active TB disease prior to transplant.
· Increasedawareness of the possibility of TB in renal transplant recipients may lead to early diagnosis and treatment, which may reduce graft loss. This is a narrative review with evidence V.
In this article, published in 2019, the authors have used a combination of a single database search (PubMed) in addition to specialist society guidelines in order to evidence a brief overview of the role of latent mycobacterium tuberculosis infection (LTBI) in renal transplant recipients. The authors detail the search terms used but do not provide detailed analysis of their search results/selection process: an assessment of the comprehensiveness of the overview in relation to available published research is not possible and as such the article stands more as an opinion piece aiming to give the reader a broad understanding of the relevant issues.
The authors highlight estimates that globally 1.7 billion people have LTBI. Up to 10% of this LTBI group will develop active TB at some point, with immunosuppression being a significant risk factor for this. This demonstrates how the transplant population are specifically at higher risk of this compared to the general population.
The authors explain the 4 ways in which renal transplant recipients may be affected by TB:
i) transmission of TB from donor kidney
ii) endogenous reactivation of latent TB (LTBI)- commonest
iii) de novo TB infection post transplantation – with risk of quick progression to miliary TB due to immunosuppression
iv) loss of renal allograft due to TB
In the article they then go on to explore TB in renal transplant recipients in relation to 3 areas:
– Prevention
– Diagnosis
– Management
Preventionof TB in renal transplant recipients
· Ideally, all renal transplant recipients and potential donors should undergo screening for LTBI and active TB, although in low TB endemic countries an assessment may be made based upon specific risk factors
· Screening is very important as management at this stage is associated with better outcomes than if the patient develops active TB post transplantation – patients found to have LTBI should complete a course of anti-TB treatment while they are on the waiting list
Diagnosis of LTBI
· Available screening tests: Tuberculin skin test (TST), Quantiferon-TB Gold and T-SPOT (with the latter 2 tests being preferable particularly in those with advanced CKD or on immunosuppression due to higher sensitivity, although TST may be used in lower resource settings)
· Screening tests should be utilised alongside full clinical assessment including history (particularly of contacts with active pulmonary TB or previous TB treatment), symptoms, blood tests and imaging to include CXR and renal ultrasound scan
Management of LTBI and active TB in potential renal transplant recipients
· As above, the recommendation is to diagnose and treat TB prior to transplantation wherever possible
· WHO 2018 guidelines are used to guide the treatment of LTBI. Depending on the incidence rate of TB in the country and age of the patient this could be
– 6 month course isoniazid
– 3 month course of isoniazid + rifampicin
– 6 month course rifapentine and isoniazid
– 4 month course rifampicin alone
· WHO 2018 guidelines should also be used to treat any active TB infection detected in a potential renal transplant recipient
· For those patients in whom active TB is diagnosed post-transplantation the management of this is challenging for several reasons: the patient may develop more widespread/severe disease due to their immunosuppressed state and additionally there are some very significant interactions between anti-TB medications and immunosuppressive agents (particularly rifampicin and CNIs)
Level of evidence:
This article should be considered as level 5 evidence which is usually expert opinion. The authors have referenced relevant guidelines and research throughout the piece but there is no comprehensive search methodology and this could therefore have resulted in significant bias in which references the authors chose to include. Although overall this makes it a lower quality evidence in terms of reliability, it provides a succinct overview of the topic for the reader highlighting key areas and acknowledging gaps in current research in this area.
Summary
Tuberculosis (TB) remained one of the important infectious diseases associated with high mortality with an estimated death rate according to the WHO data of 1.3 million recent data confirm an increasing rate of LTBI in the range of 1.7million latent tuberculosis according to the WHO definition referred to the state of persistent immune response to MTB with no clinical evidence of active disease however over time there is about 10% risk of progression to active TB disease, especially with the impaired immune response with Malnutrition, HIV, immunosuppression therapy with a biological agent after transplantation, post-renal transplantation recipients at risk of reactivation of LTBI and its the most common cause of active TB after SOT, with high mortality rate and lower graft survival. One of the challenges of post-transplantation MTB infection is the nonspecific or atypical presentation and can easily be missed if not keep a high index of clinical suspicion especially if the donor or recipients are from an endemic area or have previous history of TB or LTBI diagnosis with a late intervention, extrapulmonary TB is more common after transplantation, this review article addresses the challenges with the diagnosis, prevention, and treatment of MBT after kidney transplantation.
Screening and diagnosis of LTBI
All renal transplant recipients and donors should undergo screening for LTBI and active TB disease as part of the transplant workup. There is no gold standard test for
diagnosing LTBI accurately.
Screening for LTBI includes TUBERCULIN SKIN TEST ( TST), IGRA test, or QuantiFERON1-TB (QFT)
Gold In-Tube and T-SPOT1 (WHO 2018).
The limitation with TST in CKD, hemodialysis patients and on IS , IGRA test more specific forLTBI screen and sometimes combination of both can increased the sensitivity of the assay.
Diagnosis of LTBI reactivation or active TB after transplantation including denovo MTB or extra pulmonary TB depends on history or previous exposure or close contact , donor from endemic area or treated on line of LTBI or active infection, social history and physical examination for pulmonary and extrapulmonary manifestations , symptoms of wt loss , night sweat and chronic cough, Images including CXR , CT , abdominal images and finally microscopic examination for AFB and cultures for MTB , tissue biopsy to confirm the diagnosis , gen expert for MTB
Treatment of LTBI in Donor and recipient
1 Isoniazid monotherapy for 6 months is recommended for both adults and children in countries with
high and low TB incidence.
2. Rifampicin plus Isoniazid daily for 3 months as an alternative to 6 months of isoniazid monotherapy as
Preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
1. Rifapentine and Isoniazid weekly for 3 months. preventive treatment for both adults and children in countries
with a high TB incidence.
5.9 months of isoniazid, or a 3-month no agreement about the total duration of treatment
Treatment of active MBT
Treatment of drug-sensitive and drug-resistant active TB disease in renal transplant recipients should follow WHO treatment
guidelines (WHO, 2017, 2018c).
What is the level of evidence provided by this article?
Review article, narrative review level V of evidence
Latent tuberculosis infection is defined by the World Health Organisation (WHO) as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB disease.Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime.
The incidence of active TB disease among renal transplant recipients is much higher than in the general population and causes much morbidity and death in these patients . TB is also responsible for loss of the renal allograft (transplanted kidney) in approximately one third of cases.
Screening and diagnosis of LTBI:
WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) , QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1
The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agents . IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
A higher rate of LTBI was found in patients undergoing renal transplantation than those undergoing other organ transplantation, especially when IGRA tests were used compare to the TST. Thus IGRAs (both QFT and T-SPOT) have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
Treatment of LTBI in donor and recipient:
The WHO 2018 guidelines outline the following treatment options for LTBI
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
The highest risk for developing TB disease occurs when a range of risk factors for re-activation LTBI occur when conditions of immunosuppression are present such as diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients
Prior to transplant, all kidney transplant patients and their donors should be screened for LTBI and active TB disease. The Tuberculin Skin Test (TST) and two interferon gamma release assays (IGRAs), QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T, are the three tests that the WHO advises for LTBI screening.
IGRAs have a good specificity for LTBI detection in immunosuppressed patients and are more specific to M.tb antigens.
Treatment of LTBI in donor and recipient
* Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
* Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
* Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
* The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB
Should follow WHO guidelines. Treatment of patients with active tuberculosis detected after renal allograft transplantation remains a challenging task.
Active TB is more common in KT than general population
TB in KT patient causes graft loss in 1/3 cases
Most TB in KT is due to inactivation of latent TB
LTBI is cryptic and diagnosis is difficult so AWARENESS of LTBI is teh key
Recipient and donor should ne screened for LTBI and active TB
DIAGNOSIS OF LTBI
TST – skin test may not be reliable in advanced ESRD and patient on IS
IGRA- interferon gamma release assay – QUANTIFERON TB GOLD , AND T SPOT
LTBI is more common in KT than other SOT
IGRA is more sensitive that TST
who need screening ?
endemic area – all potential recipients and donors ,
non endemic are – those with history of contact , high dose steroid, homeless , drug user , incarcerated person , recently arrived foreign born person
Patients with positive LTBI can be started on treatment while waiting for transplant
how to screen ?
history and physical exam
CXR
Blood test ,CBC WITH ESR , LFT RENAL PROFILE
USG OF KIDNEYS
Sputum AND URINE AFB SMEAR AQND CULTURE
GENXPERT ABD RIF ASSAY ON SPUTUM BIOPSY URINE
TST
IGRA
IMAGING – MRI/CT OR PET SCAN IF INDICATED
MANAGEMNET
LTBI
INH DAILY 6 MONTH
INH AND RIFAMPICIN DAILY 3 MONTHS IN LESS THAN 15 YRS PATINETS
REFAPETINE AND INH WEEKLY FOR 3 MONTHS
IN LOW ENDEMIC AREA – less intense course can be given
ACTIVE TB
follow national guideline or WHO guideline
like general population with TB
Challenges – hepatotoxicity is high
rifampicin causes low level of IS while INH causes high level of IS
GOAL is to adhere to standard regime and complete the course while maintaining adequate IS
CONCLUSION
KT is done globally in area endemic for TB
Aim is identify LTBI and treat adequately
High degree of awareness is the key
Latent tuberculosis infection and renal transplantation Diagnosis and management
The incidence of active TB disease among renal transplant recipients is much higher than in the general population and causes much morbidity and death in these patients .
TB is also responsible for loss of the renal allograft (transplanted kidney) in approximately one third of cases. Most of the TB cases in renal transplant recipients are due to re-activation of LTBI in the recipient or from donor kidney.
The diagnosis and treatment of LTBI and active TB disease in donors and transplant recipients can be quite challenging since the presentation is cryptic with non-specific symptoms and signs, and the diagnosis can easily be missed unless there is a high degree of awareness of the possibility of TB. The clinical presentation of TB occurring in transplant recipients is said to differ from that in the general population and an increased frequency of extrapulmonary TB is seen.
Screening and diagnosis of LTBI
There is no gold standard test for diagnosing LTBI accurately. WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1 -TB (QFT) Gold In-Tube and T-SPOT 1 T (WHO, 2018b). The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agents (Guirao-Arrabal and TorreCisneros, 2018). IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients (Pai et al., 2014; Guirao-Arrabal and Torre-Cisneros, 2018). There are scanty data on the sensitivities and specificities of IGRAs and TST in screening for LBI in renal transplant recipients.
Thus IGRAs (both QFT and T-SPOT) have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
Treatment of LTBI in donor and recipient
Every effort must be made to diagnose and treat LTBI and active tuberculosis in bothlivedonorandrecipientbeforetransplantation.TreatmentofLTBI should follow WHO 2018 guidelines
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB
Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines (WHO, 2017, 2018c). Treatment of patients with active tuberculosis detected after renal allograft transplantation remains a challenging task.
Adherence to one specific standardized regime, completion of the recommended duration of the regime and a close monitoring and early identification of the adverse effects of the drugs would greatly enhance the effectiveness of treatment against LTBI.
Conclusions
Renal transplantation is now widely available globally. TB is a serious complication in renal transplant recipients and causes much morbidity and mortality. Due to immunosuppression, transplant recipients are at a higher risk of re-activating LTBI from within themselves or from the transplanted donor kidney. Several guidelines are available and are consistent in recommending that all donors and recipients are routinely screened for LTBI and active TB disease prior to transplant whenever possible. A high degree of awareness of the possibility of TB is required in all renal transplant patients so that it can be diagnosed and treated early, reducing the risk of loss of allograft.
Estimated 1.7 billion people have LTBI with aprox 10% developing TB in their lifetime.TB estimated to cause graft loss in 1/3 of cases.
SCREENING AND DX OF LTBI.
Who recommendation for LTBI screening ;TST,IGRA(Quantiferon TB and T spot).TST is less sensitive in CKD and Immunosuppressed. IGRAs are more sensitive in immunosuppressed pts and pre transplant pts.
INH -9/12 or 3/12 weekly rifapentine + INH or 3-4/12 INH + rifampicin or 3-4/12 of rifampicin monotherapy – low incidence TB.
TX OF ACTIVE TB.
Who guidelines should be adhered to.SE and DI should be carefully factored in. Each transplant center should develop local guidelines to guide treatment of LTBI and active TB.
● Tuberculosis (TB) is the commonest infectious disease cause of death worldwide
● TB is a serious complication in renal transplant recipients and causes much morbidity and mortality
● Latent tuberculosis infection is defined as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’
● Up to 10% of people with LTBI will progress to developing active TB
● The highest risk for developing TB disease accociated with diabetes,HIV, malnutrition, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients
● The incidence of active TB disease among renal transplant recipients is much higher than in the general population
● Most of the TB cases in renal transplant recipients are due to re-activation of LTBI in the recipient or from donor kidney TB or acquiring new M.tb infection
● Living donors who were born and live in high TB endemic countries and migrated to low TB endemic areas may have higher rates of LTBI.
● Presentations of TB in recipients differs from that in the general population with increased frequency of extrapulmonary TB
Screening and diagnosis of LTBI
● All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant.
● Tests recommended for screening LTBI:
☆ TST
☆ IGRAs
☆ QuantiFERON1-TB (QFT)
● The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agents
● IGRA is more specific to MTB antigens and offer high specificity in detecting LTBI in immunosuppressed patients
● A higher rate of LTBI was found in patients with renal transplantation than those with organ transplantation
● Posttransplant TB was more common in renal recipients than in liver transplant
● The M.tb bacilli remain dormant within the transplant kidney for months to years.
● Reactivation of LTBI to active TB disease occures due to IS therapy
Clinical workup of donors and transplant recipients to screen for LTBI and active TB:
☆ History: contact with patient with active pulmonary TB or previous TB treatment
☆ Symptoms: chronic cough, night sweats,
anorexia, weight loss.
☆ Full clinical examination
☆ Investigations: CBC, CRP, GFR, LFT, microscopy (AFB) and culture for MTB ( sputum , urin )
☆ Histology of biopsy and aspirates
☆ GeneXpert MTB/Rif assay
☆ TST , IGRA test
☆ Chest X ray
☆ Renal ultrasound
☆ MRI or CTscan
☆ PET/CTscan
● All renal transplant candidates should be routinely screened for LTBI
● Risk factors for developing TB in low
incidence areas
☆ History of TB
☆ Previous rejection episodes
☆ High-dose corticosteroids
☆ Diabetes mellitus
☆ Those living in endemic areas
● Risk factors for progression from LTBI to active disease:
☆ Close contacts with active tuberculosis
☆ Recently arrived foreign-born persons
☆ Drug users
☆ Incarcerated persons
☆ Homeless individuals
LTBI screening in immunosuppressed individuals and those undergoing SOT
☆ Chest X-ray
☆ History of previous exposure to patients with TB
☆ Risk factor assessment for travel or migration from endemic areas
Treatment of LTBI in donor and recipient
● Isoniazid monotherapy for 6 months in both adults and children in countries with
high and low TB incidence.
● Alternative therapy in high TB incidence:
☆ Rifampicin plus Isoniazid daily for 3 months In patients aged <15 years
☆ Rifapentine and Isoniazid weekly for 3 months in both adults and children
● Alternative therapy in lowTB incidence:
☆ 9 months of isoniazid
☆ a 3-month of weekly rifapentine plus isoniazid
☆ 3–4 months of isoniazid plus rifampicin
☆ 3–4 months of rifampicin alone.
Treatment of active TB
● Should follow WHO guidelines
● Serious dose limiting side effects
☆ Hepatotoxicity
☆ Peripheral neuropathy
☆ Rifampicin interferes with the efficacy of many drugs
☆ Rifabutin has interactions with antiretroviral agents less than Rifampicin
Summary: Introduction:
Tuberculosis (TB) continues to be the commonest infectious disease cause of death worldwide. Tuberculosis is an important infectious disease cause of morbidity and death in renal transplant recipients. Tuberculosis can also cause loss of kidney allograft. The purpose of this viewpoint is to highlight the issues related to prevention, diagnosis and treatment of tuberculosis in renal transplant recipients.
Methods:
The PubMed database was searched for publications and guidelines on diagnosis and management of LTBI in renal transplantation. Publications on renal allograft recipients with LTBI and TB in post-operative period were also analysed. Specialist Society guidelines were also used.
Findings:
Tuberculosis is one of the most important infectious disease-related causes of morbidity and death in transplant recipients. LTBI in allograft recipients continues to be a clinical management problem. It can occur either from donor kidney or from endogenous reactivation of latent tuberculosis infection or from acquiring new Mycobacterium tuberculosis infection. Tuberculosis can also cause loss of kidney allograft.
Clinical workup of donors and transplant recipients to screen for LTBI and active TB: · History: contact with an index case of TB and previous history of TB treatment. · Symptoms: includes cough, fever, weight loos, drenching night sweat and anorexia. · Examination: to look for signs of active TB and exclude extrapulmonary TB. · Investigations: FBC, CRP, renal function test and liver function test. Microscopy (acid fast bacilli) and culture for MTB (sputum and early morning urine samples). Histology of biopsy and aspirate (acid fast bacilli and granuloma). GeneXpert/RIF assay (on sputum, urine and biopsy) · Test for LTBI includes tuberculin skin testing and or/ IGRA (either TSPOT.TB or QuantiFERON). · Imaging such as chest x ray, renal scan, CT or MRI (where indicated), PET/CT SCAN may also be done as required.
Treatment of LTBI in donor and recipients The WHO 2018 guidelines outline the following treatment options for LTBI (WHO, 2018b). · Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence. · Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence. · Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence. · The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB This should follow the WHO guidelines while paying attention to drug interactions and risk of toxicity. Adherence and completion of treatment should be emphasized.
Conclusions: Kidney transplantation is now universally performed in high and low Tuberculosis endemic countries. A high index of awareness of the possibility of TB disease or LTBI is required prior to renal transplant aligned to reduce renal allograft damage, morbidity and death due to tuberculosis. WHO Management recommendations for LTBI screening and treatment should be followed.
Summary Latent tuberculosis infection and renal transplantation – Diagnosis and management
Latent tuberculosis infection is a state of persistent immune response to stimulation by Mycobacterium tuberculosis (MTB) antigens with no evidence of clinically manifest active TB disease. Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime.
Risk factors for re-activation LTBI are diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients.
Most of the TB cases in renal transplant recipients are due to re-activation of LTBI in the recipient or from donor kidney.
Living donors who were born and lived in high TB endemic countries and migrated to low TB endemic areas may have higher rates of LTBI.
Screening and diagnosis of LTBI
WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T
IGRAs are more specific to MTB antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
A higher rate of LTBI was found in patients undergoing renal transplantation than those undergoing other organ transplantation.
IGRAs (both QFT and T-SPOT) have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
Posttransplant TB was more common in renal recipients than in liver transplant patients.
LTBI in a recipient that has gone undiagnosed during pre-transplant evaluation, which either continues to persist as LTBI or may undergo endogenous reactivation in the post-transplant period and in some cases is a scenario where both the donor and the recipient have been free from disease. The post-transplant period also has been uneventful until the recipient gets exposed to MTB bacilli and develops denovo LTBI
Various meta-analyses and subsequent guidelines recommend that all renal transplant candidates should be routinely screened for LTBI
British Thoracic Society guidelines
Suggest screening for LTBI where tuberculosis incidence rates are high or in patients with risk factors for developing tuberculosis in low incidence areas.
Those with epidemiologic risk factors such as history of TB, previous rejection episodes, high-dose corticosteroids, diabetes mellitus and those living in endemic areas need to be evaluated with chest radiography and other screening tests as part of the screening for latent tuberculosis.
In low TB endemic countries, LTBI screening is recommended for population subgroups with a high prevalence of TB or those with a high likelihood of progression from LTBI to active disease. These include close contacts of patients with active tuberculosis, recently arrived foreign-born persons, drug users, incarcerated persons, and homeless individuals and were advised screening for LTBI
Chest X-ray, detailed background history of previous exposure to patients with TB and risk factor assessment for travel or migration from endemic areas was the most frequent recommendation for LTBI screening in immunosuppressed individuals and those undergoing Solid Organ Transplant (SOT) Treatment of LTBI in donor and recipient
The WHO 2018 guidelines outline the following treatment options for LTBI
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid
Treatment of active TB
Treatment of latent tuberculosis infection. Adherence to one specific standardized regime, completion of the recommended duration of the regime and a close monitoring and early identification of the adverse effects of the drugs would greatly enhance the effectiveness of treatment against LTBI.
Conclusion
A high degree of awareness of the possibility of TB is required in all renal transplant patients so that it can be diagnosed and treated early, reducing the risk of loss of allograft.
TB is the commonest infectious disease cause of death worldwide.
Latent tuberculosis infection is define BY WHO as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’.
10% of people with LTBI will progress to developing active TB.
Immunosuppression RISK:
Diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies.
Most of the TB cases in renal transplant recipients are due to re-activation of LTBI in the recipient or from donors.TB can also occur due to increased susceptibility to acquiring new M.tb infection which rap rapidly progresses to miliary TB because of immunosuppressive therapy.
Screening and diagnosis of LTBI:
WHO recommends three tests for screening for LTBI?
Tuberculin skin test (TST).
Two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube
And T-SPOT1 T.
IGRAs (both QFT and T-SPOT) have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
In low resource settings, TST continues to be used for diagnosing LTBI
All renal transplant candidates should be routinely screened for LTB.
British Thoracic Society guidelines suggest screening for LTBI where tuberculosis incidence rates are high or in patients with risk factors for developing tuberculosis in low incidence areas.
Similarly those with epidemiologic risk factors such as history of TB, previous rejection episodes, high-dose corticosteroids, diabetes mellitus and those living in endemic areas need to be evaluated with chest radiography and other screening tests as part of the screening for latent tuberculosis.
TB endemic countries,
High likelihood of progression from LTBI to active disease:
These include close contacts of patients with active tuberculosis, recently arrived foreign-born persons, drug users, incarcerated persons, and homeless individuals and were advised screening for LTBI (
Chest X-ray, detailed background history of previous exposure to patients with TB and risk factor assessment for travel or migration from endemic areas was the most frequent recommendation for LTBI screening in immunosuppressed individuals and those undergoing Solid Organ Transplant.
Treatment of LTBI in donor and recipient:
The WHO 2018 guidelines outline the following treatment options for LTBI (WHO, 2018b):
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged LESS THAN 15 IN AREA WITH HIGH INCIDENCE.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy:
9 months of isoniazid, or a 3-month
Regimen of weekly Rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB:
Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines (WHO, 2017, 2018c).
Conclusions:
Renal transplantation is now widely available globally.
A high degree of awareness of the possibility of TB is required in all renal transplant patients so that it can be diagnosed and treated early, reducing the risk of loss of allograft.
IV. Latent tuberculosis infection and renal transplantation – Diagnosis and management
Summarise the article
Objectives
– To underscore the issues related to prevention, diagnosis and treatment of TB in kidney transplant recipients
Methods
– literature search on PubMed for publications and guidelines on diagnosis and management of LTBI in kidney transplantation
Introduction
– TB is an important infectious disease in kidney transplant recipients and it is associated with significant morbidity and mortality. It also causes graft loss in approximately 30% of the cases.
– LTBI is defined as a state of persistent immune response stimulation by M.tb antigens without any evidence of clinically manifest active TB disease
– 10% of people with LTBI develop active TB during their lifetime
– reactivation of LTBI portends the highest risk for developing TB
– risk factors for LTBI reactivation include diabetes, HIV, malnutrition, previous history of TB, biologics, immunosuppressive agents including antirejection treatment in SOT recipients
– other risk factors include exposure to active disease, drug users, incarcerated persons, homeless people
– incidence of active TB disease is higher among kidney transplant recipients (KTRs) than in the general population
– most of the cases of TB among KTRs are due to reactivation of LTBI or from the donor kidney
– TB can also occur following de novo acquisition of new M.tb infection which progresses to miliary TB due to exposure to immunosuppressive therapy
– diagnosis and treatment of LTBI and active TB disease in KTRs remains a challenge due to the atypical presentation and an increased frequency of extrapulmonary TB (EPTB)
– a high index of suspicion is thus required in this population of patients
Screening and diagnosis of LTBI
– all kidney transplant recipients and donors should be thoroughly screened for LTBI and active TB disease
– there is no gold standard screening test for LTBI diagnosis
– the WHO recommended screening tests for LTBI include TST and two IGRAs i.e., Quantiferon-TB (QFT) Gold In-Tube and T-SPOT
– TST is not reliable in patients with advanced CKD and in patients on immunosuppressive therapy
– IGRAs offer high specificity in detection of LTBI in immunosuppressed patients and are more specific to the M.tb antigens
– among kidney transplant candidates, IGRAs are more sensitive than TST in the diagnosis of LTBI
– chest radiographs should be part of the screening tools for LTBI
– initiate LTBI treatment prior to kidney transplantation
Treatment of LTBI in the donor and recipient
– Treatment options include: –
Isoniazid monotherapy plus pyridoxine daily for 6 months (for adults and children in countries with high and low TB incidence)
Rifampicin plus isoniazid daily for 3 months (for <15year old in countries with high TB incidence)
Isoniazid plus rifapentine weekly for 12 weeks (for adults and children in countries with a high TB incidence)
Other options in place of isoniazid monotherapy in low incidence countries include 9 months of isoniazid, 3 months of weekly isoniazid plus rifapentine, 3-4 months of isoniazid pus rifampicin or 3-4 months of rifampicin monotherapy
– shorter courses of treatment are preferred to ensure treatment adherence given the adverse events and drug interactions associated with these drugs
Treatment of active TB
– WHO guidelines should be followed
– treatment of active TB post-kidney transplantation remains a challenge
– hepatotoxicity is a major adverse effect associated with rifampicin and isoniazid
– isoniazid should be co-administered with pyridoxine to prevent peripheral neuropathy
– rifampicin is a potent CYP3A4 inducer therefore it interacts with many drugs affecting their metabolism
– rifabutin is a weaker CYP3A4 inducer hence is associated with fewer pharmacologic interactions
Conclusion
– kidney transplantation is now widely available
– TB is a common infectious disease among KTRs an is associated with significant morbidity and mortality
– due to the degree of immunosuppression, KTRs are at a higher risk of endogenous LTBI reactivation (i.e., LTBI reactivation within themselves) or donor-derived TB (from the transplanted donor kidney)
– all transplant recipients and donors should be screened for LTBI and active TB disease prior to kidney transplantation
– a high index of suspicion for active TB or LTBI is required to allow for timely diagnosis and treatment so as to reduce the risk of graft loss, morbidity and mortality associated with TB
Introduction:
10% of LTBI patients will acquire active TB during their lifetime. When immunosuppression is present, such as in diabetes, malnutrition, HIV, and transplant patients using biologics immunosuppressive drugs, TB infection is most possible to occur.
Renal transplant recipients have a significant rate of active TB illness, which can cause graft loss & can spread to miliary TB rapidly. Screening & diagnosis:
Prior to transplant, both recipients and donors of renal transplants should be screened for Latent and active TB.
WHO recommends the Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs), QuantiFERON Gold and T-SPOT TB, for screening for LTBI.
In individuals with severe chronic kidney disease and those using immunosuppressive drugs, the TST may be inaccurate.
IGRAs are more specific to M.tb antigens and have a higher level of specificity for detecting LTBI in immunocompromised patients.
In situations with limited resources, the TST is still used to diagnose LTBI. Clinical workup of donors and transplant recipients to screen for LTBI and active TB:
Hx:
– Hx of previous TB ttt
– Hx of contact to a case of active pulm.TB
Symptoms:
– Fever, night sweets, wt loss or chronic cough
Investigations:
– CBC with differential
– CRP
– RFTs&LFTs
– Microscopy for acid fast bacilli & culture for M.tb in sputum & early morning urine sample
– Histology of aspirate or biopsy (acid fast bacilli & granuloma)
– GeneExpert MTB/Rif assay on urine, sputum or biopsy
Test for LTB:
– TST
– IGRAs (quantiferon/Tspot TB)
Radiological:
– CXR
– US
– CT
– PET CT
Treatment of LTBI in donor and recipient: The WHO 2018 guidelines outline the following treatment options for LTBI
– Isoniazid monotherapy for 6 monthsis recommended for
treatment of LTBI in both adults and children in countries with
high and low TB incidence.
– Rifampicin plus Isoniazid daily for 3 months should be offered as
an alternative to 6 months of isoniazid monotherapy as
preventive treatment for children and adolescents aged
<15 years in countries with a high TB incidence.
– Rifapentine and Isoniazid weekly for 3 months may be offered as
an alternative to 6 months of Isoniazid monotherapy as
preventive treatment for both adults and children in countries
with a high TB incidence.
– The following options are recommended for treatment of LTBI in
countries with a low TB incidence as alternatives to 6 months of
isoniazid monotherapy: 9 months of isoniazid, or a 3-month
regimen of weekly rifapentine plus isoniazid, or 3–4 months of
isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
conclusion:
Renal transplant recipients’ TB complications are serious. Immunosuppression increases the likelihood of LTBI reactivation in transplant recipients or donor.
Many guidelines recommend screening donors and recipients for LTBI and active TB before transplantation. All kidney transplant patients must be aware of TB so it can be recognized and treated early to reduce allograft loss.
IV. Latent tuberculosis infection and renal transplantation – Diagnosis and management:
1. Summarise this article.
2. What is the level of evidence provided by this article?
1) Summary of this article:
Introduction:
Tuberculosis (TB) is the commonest infectious disease worldwide.
WHO (Definition of latent tuberculosis infection):
A state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically active TB disease
The prevalence of active TB is significantly higher in SOT than general population. It is estimated that around 1.7 billion people are suffering from latent TB worldwide.
10 % of patients with latent TB can develop active TB during their lifetime if they are immunosuppressed. Causes of TB in recipients mostly due to re-activation of LTBI or from donor kidney or new infection.
Clinical presentation of TB in renal transplant is differ from that in the general population and needs high degree of awareness of Suspicion.
Risk factors for re-activation LTBI include: DM, malnutrition, HIV, and immunosuppression’s
Active TB in renal transplant recipients is higher than general population and causes morbidity and death with allograft loss.
Mode 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 recipient.
All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant. There is no gold standard test for diagnosing LTBI accurately.
WHO recommends three tests for screening for LTBI:
Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1, both are usually negative in immunosuppressed patients due to their dependence on the host immune response, which is impaired in these sets of patients,
The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agents.
In SOT candidates with ESRD or advanced liver disease, it is preferred to use IGRA over TST due to its higher sensitivity in these sets of patients.
IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
Thus IGRAs (both QFT and T-SPOT) have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
So, all recipients and donors should both be undergoing careful evaluation of the risk, history, examination and CXR, together with test for latent TB.
All transplant recipients and donors should have thorough history taking and CXR. Renal transplant recipients should have no symptoms, CXR should be normal and no evidence of exra-pulmonary TB to settle the diagnosis of latent TB.
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 A Summary of the diagnostic approach for detection of active and latent TB:
History: Contact with patient with active TB, Previous TB treatment Symptoms:Chronic cough, night sweats, weight loss, Hemoptysis Clinical examination: Pulmonary/ extra pulmonary TB Lab: CBC, CRP, ESR, RFT/LFT, Microscopy and culture of TB, Histology of biopsy and aspirate, GeneXpert MTB Tests for LTBI: TST, GRA Imaging: Xray chest, Renal ultrasound, MRI/CT/ PET scan (if indicated)
Risk Factors:
History of TB, DM, previous rejection episodes, high-dose corticosteroids, and those living in endemic areas need to be evaluated with chest radiography and other screening tests as part of the screening for latent tuberculosis. Pathogenesis of LTBI in post-transplant recipients:
No donor or recipient TB: denovo recipient infection LTBI screening: (BTS ):
Areas of high incidence of TB
High risk of TB in low incidence areas (contact with active TB, recently arrived from travel abroad, drug users, incarcerated persons, alcohol abuse or injection drug use, and homeless) In low TB endemic countries, LTBI screening is recommended for population subgroups with a high prevalence of TB or those with a high likelihood of progression from LTBI to active disease. These include close contacts of patients with active tuberculosis, recently arrived foreign-born persons, drug users, incarcerated persons, and homeless individuals and were advised screening for LTBI. Chest X-ray, detailed background history of previous exposure to patients with TB and risk factor assessment for travel or migration from endemic areas was the most frequent recommendation for LTBI screening in immunosuppressed individuals and those undergoing Solid Organ Transplant (SOT). Treatment of LTBI in donor and recipient (WHO 2018 guidelines):
Isoniazid mono-therapy for 6 months is recommended for treatment of LTBI in both adults and children in countries withhigh and low TB incidence.
Patient 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.
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid mono-therapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid mono-therapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid mono-therapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB:
Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guideline.
It is challenging treatment after transplant:
Hepatotoxicity (rifampicin and isoniazid) Peripheral neuropathy (isoniazid) Rifampicin (interactions with oral contraceptives, antiretrovirals)
Enhance effectiveness of treatment: Adherence to one specific regimen
Completion of the recommended duration
Close monitoring and early identification of adverse effects Conclusions:
TB is a serious complication in renal transplant recipients and causes much morbidity and mortality.
Transplant recipients are at a higher risk of re-activating LTBI from within themselves or from the transplanted donor kidney, due to immunosuppression causing mortality and morbidity, in addition to allograft loss.
Several guidelines are available and are consistent in recommending that all donors and recipients are routinely screened for LTBI and active TB disease prior to transplant whenever possible.
A high degree of awareness of the possibility of TB is required in all renal transplant patients so that it can be diagnosed and treated early, reducing the risk of loss of allograft. What is the level of evidence provided by this article?
Summary of Latent tuberculosis infection and renal transplantation – Diagnosis and managementIntroduction
Up to 10% of people with LTBI will progress to develop active T.B diseases, a high risk to develop T.B disease in presence of DM, malnutrition,HIV , biological agent, and immunosuppression agent in transplant patients.
The diagnosis and treatment of LTBI and active TB disease in donors and transplant recipients can be quite challenging since the presentation with non specific symptoms and signs and diagnosis easily be missed unless there is a high degree of awareness of the possibility of T.B . Screening and diagnosis of LTBI:
There is no gold standard test for the diagnosis LTBI accurately.
WHO recommended 3 tests for screening for LTBI : a tuberculin skin test and 2 IGRAs.
TST is unreliable in patients with advanced CKD and in those on immunosuppression agents .IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI immunosuppressed patients .there are scanty data on the sensitivity and specificity of IGRAs and TST in screening for LTBI in the renal transplant recipient.
Guidelines recommended renal transplant candidates should be routinely screened for LTBI .
If the donor has epidemiological risk factors such as DM, previous rejection, high dose steroid needs to be evaluated with CXR and another screening test.
Kowada recommends an active T.B screening with IGRA for all renal allograft recipients with individual risk assessment of each of the patient during LTBI treatment
Diagnosis and treat LTBI and active T.B in both live donor and recipient before transplantation is crucial.
Treatment of LTBI should follow WHO 2018guidlines :
INH for 6 month
Rifampicin plus INH for 3 months
Rifapentine and INH weekly for 3 month Treatment of active T.B
Following WHO 2018 guidelines treatment of patients with active T.B after renal transplant is challenging:
1-hepatotoxicity 2- interference of rifampicin with IS 3- adherence to the anti T.B regimens. Conclusion
High risk of reactivation LTBI from themselves or from transplant donor kidney results from IS.
Guidelines recommended that all donors and recipients are routinely screened for LTBI and active T.B disease prior to transplant whenever possible .high degree of awareness of the possibility of T.B is required in all renal transplant patients so can be diagnosed and treated early reducing the risk of loss of allograft
Latent tuberculosis infection is defined as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (TB) which is the commonest infectious disease cause of death worldwide . Latent Mycobacterium tuberculosis infection (LTBI)affects 1.7 billion people worldwide . The incidence of active TB disease among renal transplant recipients is much higher compared with the general population; it causes increased morbidity and mortality in these patients . Commonly caused by reactivation of LTBI in the recipient or to a lesser extent from donor kidney The diagnosis and treatment of LTBI and active TB disease in donors and transplant recipients is quite challenging and needs a high degree of awareness of the possibility of TB.
There is an increased frequency of extrapulmonary TB in transplant recipients than in the general population
Screening and diagnosis of LTBI:
Screening for LTBI is recommended for all renal transplant candidates and their donors , especially those with history of TB, previous rejection, or other risk factors. LTBI screening is recommended for population subgroups with high prevalence of TB or high likelihood of progression to active disease, including close contacts, foreign-born persons, drug users, incarcerated persons, and homeless individuals WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T .
There limited data on the sensitivities and specificities of TST and IGRAs in screening for LBI in renal transplant recipients,but IGRAs have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients candidates for renal transplantation. Undiagnosed LTBI in a recipient during pretransplant evaluation, either persists as LTBI or may undergo endogenous reactivation in the period of immunosuppression .
Treatment of LTBI in donor and recipient :
The treatment of LTBI should be as recommended by WHO 2018 guideline :
Isoniazid monotherapy for 6 months
Rifampicin plus Isoniazid daily for 3 months
Rifapentine and Isoniazid weekly for 3 months
TB has a direct effect on the allograft function, so transmission of TB infection should be prevented
Treatment of active TB:
Treatment of both drug-sensitive and drug resistant active TB in renal transplant recipients should follow WHO treatment guidelines. adverse events caused by Isoniazid ( hepatotoxicity and peripheral neuropathy)can be prevented by pyridoxine co-administration Rifampicin is a potent enzyme inducer which decrease the level of immunosuppressant and other drugs and may not be an ideal choice for patients taking oral contraceptives or HIV-infected individuals on protease inhibitors or non-nucleoside reverse- transcriptase inhibitors. Proactive TB screening with IGRA is to be recommended for all renal allograft recipients.
Conclusion :
TB is a serious infection in renal transplant recipients because of immunosuppression. All donors and recipients are screened for LTBI and active TB disease prior to transplant to reduce the risk of loss of allograft as recommended by several guidelines .
What is the level of evidence provided by this article?
Latent tuberculosis infection and renal transplantation –
Diagnosis and management
Introduction
· The incidence of active TB disease among renal transplant recipients is much higher than in the general population.
· TB is a cause of increased morbidity and death in renal transplant recipients and is responsible for loss of the renal allograft in approximately one third of cases.
· Most of the TB cases in renal transplant recipients are due to re-activation of LTBI in the recipient or from donor kidney.
· TB can also occur due to increased susceptibility to acquiring new M.tb infection which rapidly progresses to miliary TB because of immunosuppressive therapy.
· The diagnosis and treatment of LTBI and active TB disease in donors and transplant recipients can be challenging since the presentation can be nonspecific.
Screening and diagnosis of LTBI
· Various meta-analyses and guidelines recommend that all renal transplant candidates should be routinely screened for LTBI.
· WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs).
· Regarding sensitivities and specificities of IGRAs and TST in screening for LBI in renal transplant recipients, there are likely to be more false positive, false negative and indetermi- nate results in transplant recipients.
· IGRAs have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
Treatment of LTBI in donor and recipient
· LTBI and active tuberculosis must be diagnosed and treated in both live donor and recipient before transplantation.
· Treatment of LTBI should follow WHO 2018 guidelines
The WHO 2018 guidelines for treatment of LTBI
· Isoniazid monotherapy for 6 months in both adults and children in countries with high and low TB incidence.
· Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy for both adults and children in countries with a high TB incidence
· 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy.
· Hepatotoxicity is a serious dose limiting side effects of both Isoniazid and Rifampicin
· Rifampicin interferes with the efficacy of many drugs by interfering with their metabolism.
· Adherence to one standardized regime and a close monitoring for the adverse effects of the drugs would greatly enhance the effectiveness of treatment.
Introduction TB is the most common infectious diseasecausing death worldwide, about 1.7 billion people worldwide have LTBI. WHO definition of LTBI is ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’ Up to 10% of people with LTBI will progress to active TB disease during life time due to disrupted immune system (ie DM, HIV, immunosuppressive medications… etc). The incidence of active TB disease among renal transplant recipients is higher than in the general population, leading to graft loss in one-third of cases.
Screening and diagnosis of LTBI WHO recommends three tests for screening: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs). IGRAs are more specific to mycobacterium TB antigensand offer high specificity in detecting LTBI in immunosuppressed patients.
Clinical workup of donors and transplant recipients to screen for LTBI and active TB: History:
Contact with a patient with active TB.
Previous TB treatment.
Symptoms of cough, anorexia, weight loss, & night sweats.
Physical examination:
Examine for active pulmonary TB.
Examine for extra-pulmonary TB.
Investigations:
CBC & differential
CRP
RFT,LFT
IGRAS test
Microscopy & culture for AFB
Gene XpertMTB test (on sputum, urine, blood, or biopsy)
Imaging studies:
Chest xray
Ultrasonography
CT,MRI,PET (where indicated ).
The commonest mode of transmission is reactivation of LTBI, followed by exposure to infected subject, and rarely donor derived infection.
Treatment of LTBI in donor and recipient According to WHO 2018 guidelines:
Treatment in countries with high TB incidence:
Isoniazid monotherapy for 6 months recommended for both adults and children.
Rifampicin + INH daily for 3 months should be offered as an alternative for children and adolescents aged <15 years.
Rifapentine + INH weekly for 3 months for both adults and children.
Treatment of LTBI in countries with a low TB incidence:
6-9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines Proactive TB screening with IGRA and monitoring the drug toxicity during LTBI treatment is recommended for all renal allograft recipients.
Conclusions LTBI and active TB infection post transplantation, carry a deleterious effect on patient health and graft function. Better disease understanding, screening, diagnosis and treatment could improve overall patient and graft survival.
What is the level of evidence provided by this article? The level of evidence- V erratic review
Introduction
TB is the leading infectious disease killer worldwide. In 2017 reported 1.3 million TB deaths. New modeling recalculations show 1.7 billion persons globally have latent Mycobacterium TB infection. The WHO defines latent tuberculosis infection as “a state of sustained immunological response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically apparent active TB illness.” 10% of LTBI patients will acquire active TB. When immunosuppression is prevalent, such as in diabetes, malnutrition, HIV, and transplant patients using biologics and immunosuppressive drugs, TB illness is most likely to develop.
Active TB illness is more common in kidney transplant recipients and causes substantial morbidity and death. One-third of kidney allografts are lost due to TB. Reactivation of LTBI in renal transplant patients or donor kidneys causes most TB cases.
Screening and diagnosis of LTBI
All TB-endemic countries practice kidney transplantation.
Renal transplant recipients and donors should be screened for LTBI and active TB before transplant.
Kowada suggests active TB screening with IGRA for renal transplant recipients during LTBI treatment. Patients on the waiting list should start anti-TB treatment and finish it before transplantation. If transplantation is necessary, briefly cease drug intake and resume treatment after clinical stability.
Treatment of LTBI in donor and recipient
The function of the allograft may be adversely affected by tuberculosis, so it is crucial to take every precaution to stop the spread of the infection in this special subgroup of patients.
In both high- and low-TB incidence nations, isoniazid monotherapy for six months is advised for the treatment of LTBI in both adults and children.
In nations with a high incidence of tuberculosis, rifapentine plus isoniazid may be prescribed as an alternative to six months of isoniazid monotherapy as a preventive treatment for both adults and children.
The following alternatives to 6 months of isoniazid monotherapy are advised for the treatment of LTBI in nations with low TB incidence: 9 months of isoniazid, or a 3-month course.
Short course LTBI therapy regimens in transplant recipients require well-designed prospective, controlled cohort trials to evaluate their efficacy, safety, hepatotoxicity, and adherence to treatment.
Treatment of active TB
The WHO treatment recommendations should be followed while treating drug-sensitive and drug-resistant active TB illness in renal transplant recipients.
It is still difficult to treat people who have active TB that was discovered after receiving a kidney allograft.
By interfering with their metabolism, rifampicin reduces the effectiveness of numerous medications.
For patients using oral contraceptives, HIV-positive people taking protease inhibitors, or those receiving non-nucleoside reverse transcriptase inhibitors, it might not be the best option.
Latent tuberculosis infection can be treated with Rifampicin and isoniazid in combination.
For all recipients of renal allografts, proactive TB screening with IGRA is advised, along with individual risk assessments of each patient and monitoring of drug toxicity during LTBI treatment.
Conclusion
In kidney transplant recipients, TB is a significant complication that increases morbidity and mortality. Reactivation of LTBI from within or from the transplanted donor kidney is more likely in transplant recipients.
All donors and recipients should, wherever possible, be routinely checked for LTBI and active TB disease prior to transplant, according to a number of guidelines that are all in agreement with one another.
All kidney transplant recipients must be highly aware of the possibility of TB so that it can be identified and treated early, lowering the risk of allograft loss.
Introduction: Tuberculosis (TB) is one of the most common infectious diseases, and approximately 1.3 million people affected with TB dies in 2017. It is estimated that there are approximately 1.7 billion people worldwide with latent Mycobacterium tuberculosis infection (LTBI). LTBI is defined as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis(M.tb) antigens with no evidence of clinically manifest active TB disease’ by WHO. It has been shown that up to 10% of patients with LTBI will progress to developing active disease and the highest risk factors are conditions that lead to immune suppression, such as diabetes, malnutrition, HVI infection and immune suppression medications for transplant patients. TB can also occur to due to increased susceptibility of acquiring new M.tb infection, in patients with immune suppression. There is a higher incidence of TB among renal transplant patients, compared to the general population and it is associated with higher morbidity and mortality rates and can lead to graft loss. The clinical presentation of LTBI and TB in transplant recipients varies from the general population and they have an increased frequency of extra-pulmonary TB, hence diagnosis and treatment is challenging.
Screening and diagnosis of LTBI: All kidney transplant donor and recipients should undergo screening for LTBI and active TB infection prior to the transplant. As there is no gold standard test for screening for LTBI, WHO recommends the tuberculin skin test (TST), and two interferon gamma release assays (IGRAs) which are Quantiferon-TB (QFT) Gold In-Tube and T-SPOT T. TST may be unreliable in patients with chronic kidney disease and those on immune suppressive medications. IGRAs are more specific to M.tb antigens and have a high specificity in detecting LTBI in immunosuppressed patients. The screening for donors and recipients begin with a history highlighting any contact with a patient with active pulmonary TB or a history of any previous TB treatment, and any symptoms of chronic cough, night sweats, weight loss and anorexia. The full clinical examination should examine for active pulmonary TB and should exclude extra-pulmonary TB. Investigations should include a full blood count with differentials, CRP, renal and liver function tests, microscopy (for acid fast bacilli) and culture for M.tb (sputum and early morning urine samples), histology of biopsy or aspirates (acid fast bacilli and granuloma) and GeneXpert MTB/Rif Assay (on sputum, urine or biopsy). The tests for LTBI include a TST and IGRAs. Imaging include a chest X-ray, renal ultrasound and MRI/CT/PET scan where indicated. These screening measures are especially recommended in high TB endemic areas. In low TB endemic areas, LTBI screening is recommended for population subgroups with high prevalence of TB or those with a high likelihood of progression from LTBI to active disease. These include close contact of patients with active TB, recently arrived foreign-born people, drug users, incarcerated persons, and homeless individuals.
Treatment of LTBI in the donor and recipient: The WHO guidelines for treating LTBI in SOT recipients indicate:
Isoniazid monotherapy for 6 months – for adults and children.
Rifampicin plus isoniazid daily for 3 months, as an alternative to isoniazid monotherapy – preventative therapy for children <15 years in high TB endemic countries
Rifapentin and isoniazid daily for 3 months as an alternative for isoniazid monotherapy – as preventative therapy for adults and children in high TB endemic countries
Treatment of drug sensitive and drug resistant active TB in transplant recipients should follow WHO guidelines. Hepatotoxicity may cause a reduction in the drug dosages. Isoniazid may cause peripheral neuropathy, and it can be prevented by using pyridoxine concurrently. Rifampicin has drug interactions, and should be used with caution.
Conclusion: TB, latent of active, increases the rate of mortality and morbidity for transplant recipients. All donors and recipients should be screened and appropriately treated as per the guidelines, ideally prior to transplantation. Diagnosis of LTBI can be challenging especially in patients with end stage kidneys disease
Summary Some facts
The prevalence of active TB is significantly higher in SOT. Important to realize that estimated of 1.7 billion people suffer from latent TB worldwide. It is estimated that up to 10 % of patients with latent TB can develop active TB during their lifetime.
Active TB in renal transplant recipients is associated with high morbidity and mortality. One third of cases even lose the graft due to Active TB. Mode of transmission
Activation of latent TB.
Acquiring the disease post-transplant (donor derived)
Acquiring new infection because of immunosuppression post-Transplant (not common, it is usually progress to military TB)
Diagnosis of latent TB
Post Transplant Patients having latent TB are at high risk of conversion to active TB. But if the donor has latent TB and did not receive proper treatment it still carries a risk of transmission to the recipient therefore both recipients and donors should be screened carefully, with detail history, examination and CXR, together with test for latent TB. Test which are used to screen for latent TB is tuberculin skin test (TST) and IGRA (Quantiferon, T-SPOT), but both can be negative in immunosuppressed patients due to their dependence on the host immune response which is impaired.
In ESRD or advanced liver disease, preferred test would be IGRA over TST due to its higher sensitivity.
Thorough history taking and CXR must be checked for Donar and recipient both.
If radiology is suspicious for TB like apical fibronodular lesions, calcified solitary nodule, calcified lymph nodes, or pleural thickening, further evaluation should be carried out including microbiological assessment of fluid or secretions.
If Active TB is diagnosed in the recipient, transplantation should be delayed till complete treatment of TB.
Protocol for treatment of latent TB
INH for 6-9 months (the preferred regimen) OR
Rifampin for 3-4 months OR
INH+ rifapentine for 3 months OR
INH + rifampin for 3 months.
oral pyridoxine 50 mg given daily with INH decrease the incidence of peripheral neuropathy.
What is the level of evidence provided by this article?
It is narrative review, therefore level of evidence is V.
Latent tuberculosis infection and renal transplantation – Diagnosis and management. Introduction.
Latent tuberculosis infection is defined by the World Health Organization (WHO) as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB disease, and there is a chance for the LTBI to converts to active TB under special circumstances such as diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients, TB in KTX recipients may be due to reactivation of LTBI, DDI or recent acquired infection, Diagnosis needs a high suspicion as mainly LTBI not manifested clinically and treatment also is challenging in such cases specially with drug resistance and drug interaction with immunosuppression. Screening and diagnosis of LTBI.
WHO recommends three tests for screening for LTBI:
-TST: which is not reliable in CKD patients and in those on immunosuppressive agents.
-Two IGRAs (both QFT and T-SPOT) which are more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
-Approach for diagnosis started with History of previous TB infection or contact with infected case before, clinical examination , basic investigation with specific TB cultures and specific TB testes and PCR. Treatment of LTBI in donor and recipient.
The WHO 2018 guidelines outline the following treatment options for LTBI:
1-Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
2-Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
3-Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
4-The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone. Treatment of active TB.
Is challenging due to many factors such as drug adherence, drug side effects and drug interaction with immunosuppression medications, so still we need well-designed prospective controlled cohort trials of short course LTBI and active TB treatment regimens in transplant recipients. Conclusion:
TB is a serious infection in post kidney transplant which carries morbidity and mortality for transplant recipients and so screening for LTBI and active TB in donor and recipient is challenging and considered better than treatment and LTBI causes should be treated and bear in mind the drug side effects and drug- drug interactions with immunosuppression.
Level of evidence :V.
Tuberculosis alone was reported to be accountable for the death of about 1.3 million people globally and this does not come as a surprise with over 1.7 billion people with latent TB infection without symptoms. Among the factors that could predispose to TB are diabetes, HIV, malnutrition, and immunosuppressive stage like in SOT. The majority of the people that contract TB infection among kidney transplantation are either through reactivation of LTBI or from the donor and unfortunately, they usually don’t present with the classical TB infection like in immunocompetent
Screening and diagnosis of LTBI
Both potential donors and recipients for kindy transplantation are expected to be screened for LTBI and active infection
The WHO recommends TST and IGRA (both QFT & T-SPOT)
IGRA has been shown to be more sensitive than TST in LTBI
The full clinical workup includes; History, Symptoms, Full Clinical Examination, Investigation, Test for LTBI, and imaging test
Treatment of LTBI in donors and recipients
The WHO guidelines for treatments of LTBI are as follows:
INH monotherapy x 6 months in countries with high or low endemicity for TB
Rifampicin +INH for 3 months as a preventive treatment in ages < 15 years in countries with high incidence
Rifampentine + INH weekly x 3 months in countries with a high incidence as an alternative to 6-month duration
Other alternatives for LTBI are INH X 9 months, 3-4 months Rifampicin alone
The treatment of active TB is according to 2017 WHO guidelines and this is frost with challenges like drug-drug interaction with immunosuppressive, antiretroviral, and hepatotoxicity or nephrotoxicity. It is advisable that each transplant centre should have its own protocol that is effective and with fewer attendant drug side effect and that also enhance adherence among transplant patients
Latent tuberculosis infection is as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB disease.
Up to 10% of people with LTBI will progress to developing active TB.
The incidence of active TB disease among renal transplant recipients is much higher than in the general population and causes much morbidity and death in these patients.
Screening and diagnosis of LTBI:
There is no gold standard test for diagnosing LTBI accurately.
WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT.
IGRAs are more specific and offer high specificity in detecting LTBI in immunosuppressed patients.
A diagnostic approach for detection of active and latent tuberculosis included proper history and symptom screening, lab. investigations, screening tests and radiological evaluation when indicated.
Guidelines recommend that all renal transplant candidates should be routinely screened for LTB.
In low TB endemic countries, LTBI screening is recommended for population subgroups with a high prevalence of TB or those with a high likelihood of progression from LTBI to active disease.
Treatment of LTB in donor and recipient: (The WHO 2018 guidelines)
Isoniazid monotherapy for 6 months.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative for adult and children in high endemic area.
In low incidence countries: alternative regimen includes 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone
Treatment of active TB:
The optimal period of treatment 6-24 months (not less than 6-9 months)
The first-line treatment should be a four-drug regimen containing rifampicin used both in severe and non-severe cases.
Consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin.
Challenges during treatment: 1- Drug interaction between rifampicin and IS:
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.
Rifampicin can be replaced by rifabutin.
Rifabutin has fewer pharmacologic interactions with antiretroviral agents than Rifampicin and can be used in combination with Isoniazid for the treatment of latent tuberculosis infection
2- Adverse effect of the drugs:
Hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol): most common
3- Drug adherence 4- Associated graft dysfunction require dose modification 5- Reduction of IS in severe cases
According to EHO 2018 report, Tuberculosis is the most death-related infectious disease worldwide. Organ transplantation is wide and takes place both in areas with low and high incidence. Awareness and clinical suspicion are the most important issues. Latent disease is defined as an immune response to TBC when no evident infection needs to be addressed. Up to %10 of latent cases progress to active disease. Treating suspected and defined cases will help prevent disastrous active infection post-transplantation. TBC is with high mortality and is the main cause of graft loss. Immunosuppression may lead to milliary tuberculosis. As shown in figure 2, TBC infection can evolve as denovo or can be activated due to recipients or donors. Detailed history, questioning about symptoms like cough, night seating is mandatory. İnverstigation in selected cased can b wide basically with CBC, CRP, Acid fast bacilli surveillance, histology or sputum evaluation. İmaging can be done with chest x-ay, CT etc.
Many guidelines suggest routine screening of all candidates. Treatment of latent infection is essential. Treatment should follow WHO 2018 guidelines. In this viewpoint, six-month INH is suggested. Alternatively 3-month IND+RIF combination, especially in areas with high incidence. Rifapentine and INH weekly for 3 months are alternatives to INH+RIF 6-month regimen.
Active TBC treatment should follow the guidelines of WHO (2017, 2018c). Peripheral neuropathy related to INH can be prevented by pyridoxine. Hepatotoxicity and drug interactions should be considered.
TB is the commonest infectious disease cause of death world wide .
1.7 billions people world wide have latent TB.
10% of latent TB progress to active TB in general population.
Because of immunosuppretion ,active TB from latent is higher than general population. Screening and diagnosis of latent TB infection
All renal transplant recipient and donor should be screening for latent TB infection.
WHO recommend three tets:
TST which may be unreliable in CKD and immunosuppressive patients.
IGRA is more specific in detection of latent TB infection.
Tb (QFT). Diagnosis of latent TB infection depend on:
1.History for contact or previous TB.
2.symptoms like:chronic cough ,night sweating,anorexia,feverand weight loss.
3.examination for active pulmonary TB and exclude extra pulmonary TB.
4.investigation by CBC,CRP,RFT,LFT,sputum for AAFB,culture for M TB bacilliiand gne expert test.
5.test for latent TB infection (TST,IGRA).
6. CXR. TRETMENT of latent TB infection in donor and recipient.
Isoniazid monotherapy for 6 month in countries with high and low incidence .
Rifampicin plus isoniazid is alternative daily for 3 month in high incidence countries.
Rifapentine and isoniazid is alternative ,weekly for 3month in countries with high incidence.
Short cource is recommended if high adverse effect Treatment of active tuberculosis
Treatment of drug resistance and drug sensitive active TB in renal transplant recipients should follow WHO treatment guidelines.
Hepatotoxicity is serious dose limiting side effect of both isoniazid and rifampicin .
Peripheral neuropathy by isoniazid.
Rifampicin and drug interactions better don’t take when:HIV treatments and contraceptive pills .
Rifabutin is less pharmaceutical interaction and can be use with isoniazid. Conclusion
All renal transplant recipient or donor should be screen for latent TB infection. What is the level of evidence provided by this article?V
Summarise this article * The risks for developing TB disease are conditions of immunosuppression, such as: diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients. * The incidence of active TB disease among renal transplant recipients is much higher than in the general population * Most of the TB cases in renal transplant recipients are due to re-activation of LTBI in the recipient or from donor kidney * A higher rate of LTBI was found in patients undergoing renal transplantation than those undergoing other organ transplantation. Screening and diagnosis of LTBI * WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT)Gold In-Tube and T-SPOT *Various meta-analyses and subsequent guidelines recommend that all renal transplant candidates should be routinely screened for LTBI 1. Screening for LTBI: a) History: · Contact with patients with active TB. · Previous TB infection and treatment. b) Symptoms: chronic cough, night sweat, anorexia and weight loss. c) Full clinical examination: · To examine for active pulmonary TB. · To exclude extra-pulmonary TB. 2. Investigations: a) General investigations: CBC, CRP, RFT and LFT. b) Specific investigations for TB: · microscopy for AFB and culture for MTB(sputum and early morning urine samples). · Histology of biopsy or aspirates(AFB and granuloma). 3. Imaging: · CXR. · MRI, CT, PET/CT scan Treatment of LTBI in donor and recipient a) Isoniazid monotherapy for 6 months . b) Rifampicin plus Isoniazid daily for 3 months as an alternative to 6 months of isoniazid monotherapy c) Rifapentine and Isoniazid weekly for 3 months may as an alternative to 6 months of Isoniazid monotherapy -Patients may find completing the long course of LTBI treatment difficult due to adverse effects and the interactions with immunosuppressive drugs, hence shorter courses of treatment are recommended. Treatment of active TB -Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines -Hepatotoxicity is a serious dose limiting side effects of both Isoniazid and Rifampicin -Rifampicin interferes with the efficacy of many drugs by interfering with their metabolism. – It may not be an ideal choice for patients taking oral contraceptives or HIV-infected individuals on protease inhibitors or non-nucleoside reverse- transcriptase inhibitors. – Rifabutin has fewer pharmacologic interactions with antiretroviral agents than Rifampicin level of evidence provided by this article Level V
IV. Latent tuberculosis infection and renal transplantation – Diagnosis and management
=================================================================== Summarise this article
Introduction
TB is the most common infectious disease cause of death worldwide, with 1.7 billion people worldwide with latent Mycobacterium tuberculosis infection (LTBI).
Up to 10% of people with LTBI will progress to active TB disease, with the highest risk occurring when conditions of immunosuppression are present.
The incidence of active TB disease among renal transplant recipients is higher than in the general population, causing much morbidity and death, and is responsible for loss of the renal allograft in approximately one-third of cases.
It can also occur due to re-activation of LTBI, increased susceptibility to acquiring new M.tb infections, and an increased frequency of extrapulmonary TB.
Diagnosis and treatment of LTBI and active TB in donors and transplant recipients can be challenging due to crypti with non-specific symptoms and signs.
================================================================= Screening and diagnosis of LTBI
Screening and diagnosis of LTBI is now universally performed in high and low TB endemic countries.
WHO recommends three tests for screening: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs).
IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
However, there is scanty data on the sensitivities and specificities of IGRAs and TST in screening for LBI in renal transplant recipients.
A systematic review and meta-analysis assessed the use of the TST and IGRAs in different organtransplantations including liver, renal and haemopoetic stem cell.
A higher rate of LTBI was found in patients undergoing renal transplantation than those undergoing other organ transplantation, especially when IGRA tests were used.
Post-transplant TB was more common in renal recipients than in liver transplant patients.
A diagnostic approach for detection of active and latent
tuberculosis has been outlined by Demir and Sever (2017). Clinical
workup of donors and transplant recipients to screen for LTBI and
active TB is shown in Figure 1
History:
Contact with a patient with active TB.
Previous TB treatment.
Symptoms of cough, anorexia, weight loss, & night sweats.
Physical examination:
Examine for active pulmonary TB.
Examine for extra-pulmonary TB.
Investigations:
CBC & differential
CRP
RFT,LFT
IGRAS test
Microscopy & culture for AFB
Gene XpertMTB test (on sputum, urine, blood, or biopsy)
The WHO 2018 guidelines outline the treatment options for LTBI, with Isoniazid monotherapy for 6 months recommended for both adults and children in countries with high and low TB incidence.
Rifampicin daily for 3 months should be offered as an alternative for children and adolescents aged <15 years in countries with a high TB incidence.
Short course LTBI treatment regimens should be evaluated for efficacy, safety, hepatotoxicity and adherence to treatment.
Treatment of active TB
Treatment of active TB in renal transplant recipients should follow WHO treatment guidelines.
Hepatotoxicity and peripheral neuropathy can be prevented by co administration of pyridoxine, and Rifampicin inter-feres with the efficacy of many drugs.
Adherence to one standardized regime, completion of the recommended duration of the regime and a close monitoring and early identification of the adverse effects of the drugs would enhance the effectiveness of treatment against LTBI.
Proactive TB screening with IGRA and monitoring the drug toxicity during LTBI treatment is recommended for all renal allograft recipients
1.Summarise this article
Prior to renal transplant, all recipients & their donors should be screened for LTBI & active TB disease.
The following workup is done on donors & recipients to check for LTBI & active TB: History:
Contact with a patient with active TB.
Previous TB treatment.
Symptoms of cough, anorexia, weight loss, & night sweats.
Physical examination:
Signs of active pulmonary TB.
Signs of extra-pulmonary TB.
Investigations:
CBC & differential
CRP
Renal & liver function test
IGRAS test
Microscopy & culture for AFB
Gene XpertMTB test (on sputum, urine, blood, or biopsy)
Imaging studies:
CXR
Ultrasonography
CT/MRI/PET (where indicated for the involved organs)
Screen recipients for LBTI indicated in the following:
Where TB incidence rates are high
Patients with risk factors for developing TB in low incidence areas (close contacts of active TB, recently arrived foreign-born persons, drug users, & homeless individuals).
History of TB
Previous rejection episodes
High-dose corticosteroids
Diabetes mellitus
Those living in endemic areas
Treatment of LTBI in donor & recipient
Prevention of transmission of TB infection is of utmost importance.
The WHO 2018 guidelines outline the following treatment options for LTBI:
Isoniazid monotherapy for 6 months in countries with high & low TB incidence.
Rifampicin + Isoniazid daily for 3 months as an alternative to 6 months of isoniazid monotherapy as for children & adolescents aged <15 years in countries with a high TB incidence.
Rifapentine + Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults & children in countries with a high TB incidence.
Alternatives to 6 months of isoniazid monotherapy in countries with a low TB incidence include:
9 months of isoniazid
a 3-month regimen of weekly rifapentine + isoniazid
3–4 months of isoniazid + rifampicin
3–4 months of rifampicin alone
Treatment of active TB
Treatment of active TB disease in renal transplant recipients should follow WHO treatment guidelines (WHO, 2017, 2018c).
Challenges of treatment of active TB detected after KTX: Hepatotoxicity is a dose limiting A/E of Isoniazid & Rifampicin, especially in patients with pre-existing liver disease & alcoholics.
Peripheral neuropathy caused by Isoniazid can be prevented by co-administration of pyridoxine.
Rifampicin interferes with the efficacy of many drugs.
Rifabutin can be used as an alternative to rifamicin as it has fewer interactions with other agents than Rifampicin.
======================= 2. What is the level of evidence provided by this article?
Introduction
· TB is the most common infectious disease cause of death worldwide, with 1.7 billion people worldwide with latent Mycobacterium tuberculosis infection (LTBI).
· Up to 10% of people with LTBI will progress to active TB disease, with the highest risk occurring when conditions of immunosuppression are present.
· The incidence of active TB disease among renal transplant recipients is much higher than in the general population, causing much morbidity and death and loss of the renal allograft in approximately one-third of cases.
· It is caused by the re-activation of LTBI in the recipient or from the donor’s kidney, increased susceptibility to acquiring new M.tb infection, and an increased frequency of extrapulmonary TB.
· Diagnosis and treatment of LTBI and active TB disease in donors and transplant recipients can be challenging due to cryptic presentation and non-specific symptoms.
Screening and diagnosis of LTBI
· Kidney transplantation is now universally performed in high and low-TB endemic countries. WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon-gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT.
· IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
· However, there are likely to be more false positive, false negative, and indeterminate results of IGRAs in transplant recipients. In low-resource settings, TST continues to be used for diagnosing LTBI.
· Screening for latent tuberculosis should be done prior to transplant for all renal transplant candidates, particularly those with risk factors such as TB, previous rejection episodes, high-dose corticosteroids, diabetes mellitus, and those living in endemic areas.
· Screening for LTBIB in low TB endemic countries is recommended for those with a high risk of progression to active disease, such as close contacts of TB, recently arrived foreign-born persons, drug users, incarcerated persons, and homeless individuals.
· Kowada recommends active TB screening with IGRA for all renal allograft recipients with individualized risk assessment and initiation of anti-TB treatment prior to transplantation.
Treatment of LTBI in donor and recipient
· Treatment of LTBI should follow WHO 2018 guidelines to prevent transmission of TB infection in SOT recipients.
· Isoniazid monotherapy is recommended for LTBI in countries with high TB incidence, while Rifampicin plus Isoniazid daily for 3 months is an alternative for children and adolescents aged <15.
· Short-term LTBI treatment regimens should be evaluated for efficacy, safety, hepatotoxicity, and adherence.
Treatment of active TB
· Treatment of drug-sensitive and drug-resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines.
· Hepatotoxicity and peripheral neuropathy can be prevented by co-administration of pyridoxine, and Rifampicin interferes with the efficacy of many drugs.
· Rifabutin has fewer pharmacologic interactions with antiretroviral agents and can be used in combination with Isoniazid for the treatment of latent tuberculosis infection.
· Proactive TB screening with IGRA and monitoring the drug toxicity during LTBI treatment is recommended for all renal allograft recipients.
Conclusions
· Due to immunosuppression, transplant recipients are at a higher risk of reactivating LTBI
· Screening for LTBI and active TB is recommended to reduce the risk of loss of allograft.
================================================ What is the level of evidence provided by this article?
Latent tuberculosis infection and renal transplantation – Diagnosis and management
LTBI: Latent tuberculosis infection is defined by the World Health Organization (WHO) as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’ (WHO, 2018b).
· 10% of people with LTBI will progress to developing active TB disease during their lifetime.
· The risks for developing TB disease are conditions of immunosuppression, such as: diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients.
· A higher rate of LTBI was found in patients undergoing renal transplantation than those undergoing other organ transplantation.
TB causes in KTRs:
· From donor kidney(DD-transmission).
· Endogenous reactivation of latent infection.
· New infection with MBT.
Screening and diagnosis of LTBI
1. Screening for LTBI:
a) History:
· Contact with patients with active TB.
· Previous TB infection and treatment.
b) Symptoms: chronic cough, night sweat, anorexia and weight loss.
c) Full clinical examination:
· To examine for active pulmonary TB.
· To exclude extra-pulmonary TB.
2. Investigations: there is no gold standard test for diagnosing LTBI accurately:
a) General investigations: CBC, CRP, RFT and LFT.
b) Specific investigations for TB:
· microscopy for AFB and culture for MTB(sputum and early morning urine samples).
· Histology of biopsy or aspirates(AFB and granuloma).
· GeneXpert MTB/Rif assay(on sputum, urine or biopsy).
c) Tests for LTBI: WHO recommends three tests for screening for LTBI:
· Tuberculin skin test (TST).
· Two interferon gamma release assays (IGRAs) namely, QuantiFERONâ-TB (QFT) Gold In-Tube and T-SPOTâ T (WHO, 2018b).
3. Imaging:
· CXR.
· MRI, CT, PET/CT scan (where indicated).
Treatment of LTBI in donor and recipient
The WHO 2018 guidelines outline the following treatment options for LTBI (WHO, 2018b).
a) Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
b) Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
c) Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
d) The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone. Treatment of active TB
Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines (WHO, 2017, 2018c). The level of evidence provided by this article:
This is a narrative review article with level of evidence grade 5.
Latent tuberculosis infection and renal transplantation – Diagnosis and management
Sriram K et al., in this article aims to highlight the issues related to prevention, diagnosis and treatment of tuberculosis in renal transplant recipients.
Methods
The PubMed database was searched for publications and guidelines on diagnosis and management of LTBI in renal transplantation. Publications/Specialist Society guidelines on renal allograft recipients with LTBI and TB in post-operative period were also analyzed for use.
Findings Screening and diagnosis of LTBI
All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant. There is no gold standard test for diagnosing LTBI accurately. WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T (WHO, 2018b).
Clinical workup of donors and transplant recipients to screen for LTBI and active TB.
History – contact with an index case of TB and previous history of TB treatment.
Symptoms – includes cough, fever, weight loos, drenching night sweat and anorexia.
Examination – to look for signs of active TB and exclude extrapulmonary TB.
Investigations – FBC, CRP, renal function test and liver function test. Microscopy (acid fast bacilli) and culture for MTB (sputum and early morning urine samples). Histology of biopsy and aspirate (acid fast bacilli and granuloma).
GeneXpert/RIF assay (on sputum, urine and biopsy)
Test for LTBI includes tuberculin skin testing and or/ IGRA (either TSPOT.TB or QuantiFERON).
Imaging such as chest x ray, renal scan, CT or MRI (where indicated), PET/CT SCAN may also be done as required.
Treatment of LTBI in donor and recipients
The WHO 2018 guidelines outline the following treatment options for LTBI (WHO, 2018b).
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB
This should follow the WHO guidelines while paying attention to drug interactions and risk of toxicity. Adherence and completion of treatment should be emphasized.
Conclusions
TB poses a great threat to immunosuppressed patients including transplant recipients. High index of suspicion with early diagnosis and treatment is essential.
Introduction
TB represents the most common infectious cause of mortality all over the world.
Cases with latent TB infection was estimated as 1.7 billion people.
WHO defines Latent tuberculosis infection LTBI as the persistence of immune response to M .tuberculosis antigens with no active TB disease manifestations.
Reactivation of LTBI can progress to active TB when risk factors are present as immunosuppressive status.
TB infection is more common in transplant recipients occurring due to either re-activation of LTBI in the recipient or from donor
kidney leading to death and graft loss.
Diagnosis of TB in the donor and the recipient is challenging. Screening and diagnosis
Renal transplant recipients and donors must be screened for LTBI and active TB disease before transplant.
Tuberculin skin test (TST) and two interferongamma release assays (IGRAs) ie , QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T are 3 tests recommended by WHO for LTBI screening as there is no gold standard test .
TST is inaccurate in CKD and those on immunosuppressive agents , but IGRAs are more specific to M.TB antigens and is highly specific in detecting LTBI in immunosuppressed patients.
A metanalytical study demonstrated that a higher rate of LTBI was detected in renal transplant recipients compared to other organs recipients when IGRA tests were used rather than the TST.
Ø Clinical workup for active TB screening in donors and transplant recipients include history taking as contact with active TB case, symptoms evaluation as night sweats , cough clinical examination to detect active pulmonary TB and exclude extrapulmonary TB Investigations including M TB microscopic examination culture , histopathological evaluation of biopsies , GeneXpert assay
Ø For LTBI screening TST and IGRA tests
Imaging as chest xray ,renal US ,CT,MRI,CT/PET
Guidelines recommend that all renal transplant candidates should be routinely screened for LTBI.
British Thoracic Society guidelines recommend screening for LTBI where tuberculosis incidence rates are high or in high risk cases for developing tuberculosis in low incidence areas.
In low TB endemic areas, LTBI screening is recommended for
Those having high TB prevalence or those likely to progress from LTBI to active disease.
Kowada advices for an active TB screening with IGRA for all
renal transplant recipients based on individualized risk assessment during LTBI therapy . Treatment of LTBI in donor and recipient
Diagnosing and treating LTBI and active tuberculosis in both live donors and recipients before transplantation is crucial.
WHO 2018 LTBI treatment guidelines
o Isoniazid monotherapy for 6 months for children and adults in low and high TB incidence areas.
o Rifampicin and Isoniazid daily for 3 months as an substitute to 6 months of isoniazid monotherapy for preventive treatment for children till 15 years in countries with a high TB incidence.
o Rifapentine and Isoniazid weekly for 3 months may be offered as a substitute to 6 months of Isoniazid monotherapy as preventive treatment for adults and children in high TB incidence areas.
o isoniazid for 9 months, or a 3-month regimen of weekly rifapentine and isoniazid, or 3–4 months of isoniazid and rifampicin, or 3–4 months of rifampicin alone for treatment of LTBI in low TB incidence areas. Active TB treatment
WHO guidelines have to be applied meanwhile Isoniazid and Rifampicin increases hepatotoxicity risk .
Pyridoxine has to be given with INH to avoid neurotoxicity.
Rifampicin has many drug interactions wit immunosuppressive medications.
Rifabutin having less drug interaction than rifampicin can be taken with INH for latent TB treatment.
Compliance with one specific standardized regimen,
Finishing the duration of the regimen , close monitoring and
early detection of drugs side effects can increase the efficacy of LTBI therapy. Conclusion
Diagnosis and prompt treatment of TB disease or LTBI is essential before renal transplant in order to avoid reduce renal graft loss, morbidity and death . WHO recommendations for LTBI screening and treatment must be applied .
I like your summary, level of evidence, analysis and take home messages. I appreciate your debate regarding the uncertainty on optimal duration of therapy
The prevalence of active TB is significantly higher in SOT than general population
It is estimated that around 1.7 billion people are suffering from latent TB worldwide
10 % 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 graft
Mode 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 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
2 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 patients
In SOT candidates with ESRD or advanced liver disease, it is preferred to use IGRA over TST due to its higher sensitivity in these sets of patients
All transplant recipients and donors should have thorough history taking and CXR
Renal 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 TB
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
Protocol for treatment of latent TB
INH for 6-9 months (the preferred regimen)
Rifampin for 3-4 months
INH+ rifapentine for 3 months
INH + rifampin for 3 months
Patient 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?
I like your summary, level of evidence, analysis and take home messages.I appreciate your debate regarding the uncertainty on optimal duration of therapy
Introduction: Tuberculosis (TB) is the most common infectious cause of death worldwide. Latent tuberculosis infection is defined by the WorldHealth Organization (WHO) as a state of persistent immune response to stimulation with Mycobacterium tuberculosis (M. tb) antigens without evidence of clinically active tuberculosis Presence of tuberculosis active in kidney transplant recipients population is much higher than in the general population. In approximately one-third of cases, TB were the cause of renal allograft loss. Most cases of tuberculosis in kidney transplant recipients are due to reactivation of LTBI in the recipient or donor kidney Screening and diagnosis of LTBI:
All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant.
WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T
IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients
History “
Pervious TB or contact with patient have a disease
Symtoms :
Cough ,night sweat .wegiht loss and anorexia
Full clinical examination
Investigation:
CBC,ESR,CRP,LFT, RFT ,Sputum for culture and sensitivity ,Gene xpert MTB /rif assay .Histology for biopsy or aspirate acid fast bacilli
Test for latent TB infection :
TST and IGRA
Imaging :
Chest x ray
Renal US
CT scan or MRI when indicated .
PET/CT scan when indicated
Treatment of LTBI in donor and recipient:
The WHO 2018 guidelines
_ Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence. _Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
_ Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
_ The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone
Treatment of active TB:
Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines (WHO, 2017, 2018c). Conclusions: Kidney transplantation is now widely practiced in countries with high and low prevalence of tuberculosis. High awareness of the likelihood of tuberculosis or ITL is needed prior to kidney transplantation to reduce kidney allograft-related injury, morbidity, and death level 5
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.
Summarise this article All transplant recipients and donors should undergo TB screening. Latent tuberculosis Definition by the World Health Organisation A state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB disease
There is no standard test to diagnose Latent TB Who Recommendations- · TST · IGRA ( Quantiferon TB Gold test and T Spot) IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients sIGRAs (both QFT and T-SPOT) have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
A diagnostic approach for detection of active and latent tuberculosis
History Contact with TB patient Previous Tb
Symptoms Cough , Night sweats, anorexia, weight loss
Examinations
Investigations Blood CP/ESR CRP Renal and liver functions AFB microscopy and culture Histology Gene Xpert MTB
Tests for Latent TB TST IGRA
Imaging Chest X Ray Renal ultrasound HRCT PET/Ct
Risk Factors for TB- History of TB, previous rejection episodes, high-dose corticosteroids, diabetes mellitus and those living in endemic areas In low TB endemic countries, LTBI screening is recommended for- a high prevalence of TB or those with a high likelihood of progression from LTBI to active disease- (close contacts of patients with active tuberculosis, recently arrived foreign-born persons, drug users, incarcerated persons, and homeless individuals)
Treatment of LTBI in donor and recipient Adults and children in countries with high and low TB incidence- Isoniazid monotherapy for 6 months Children and adolescents aged in countries with high incidence of TB- Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment LTBI in countries with a low TB incidence- 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB It should be as per WHO guidelines
What is the level of evidence provided by this article? Level of Evidence- V
This article concerns itself with latent TB in kidney transplant recipients, particularly the aspects related to prevention, diagnosis and treatment. This is an essential topic to consider because of the intense complications that can arise from active TB in renal transplant recipients, the worst of which involves death of the allograft or even the patient.
Discussion
TB in the recipient can come from increased susceptibility to infection due to immunosuppression, or from live donors born in endemic areas, or from latent TB foci which get reactivated post transplant. WHO recommends three tests for screening recipients for LTBI and active TB disease. These include
Tuberculin skin test (TST)
QuantiFERON-TB which is an IGRA
T-SPOT T which is also an IGRA
IGRAs are highly specific for M.TB antigens and thus lead to more accuracy in identifying LTBI in our immunocompromised patients.Both of the above mentioned types of IGRAs are also more sensitive than TST. However, if resources are low, TST can still be used.
Detailed hisory of both donor and recipient is to be taken to screen for LTBI and active TB prior to transplantation. This includes checking for prior contact with active pulmonary TB and previous TB treatment.
Investigations include
Full and differential blood count
CRP levels
Renal and liver function tests
Microscopy for acid fast bacilli and culture for M.Tb which includes samples from sputum and early morning urine
Histological analysis of biopsy or aspirates
GeneXpert MTB/Rif Assay on sputum, urine, biopsy
Imaging investigations include chest Xray, renal ultrasound, MRI or CT scan where indicated.
Good prevention strategies will include routine screening protocols of all donors and recipients for LTBI and active TB. Chest Xray and further investigations are warranted in cases with prior history of TB, previous rejection episodes, high dose corticosteroids, diabetes mellitus.
LTBI screening is recommended especially in populations with high prevalence of TB. Chest Xray, detailed history, and risk assessment is to be done for travel or migration.
Treatment of LTBI involves the following according to WHO guidelines :
Isonizid mono therapy for 6 months – both adult and children
Rifampicin plus isoniazid for 3 months – children and adolescents below 15 years of age
Rifapentin and ionized weekly for 3 months as an alternative for 6 months isoniazid mono therapy works as preventive therapy for adults and children in high TB incidence countries.
Treatment of active TB involves :
Isoniazid and Rifampicin can be used, however, hepatotoxicity is a concern. Dosage and frequency adjustment would be needed in these patients.
Peripheral neuropathy caused by Isoniazid can be prevented by pyridoxine.
Rifabutin has fewer pharmacologic interactions with antiretroviral agents than Rifampicin and can be used in conjunction with Isoniazid, and thus can be used for HIV patients and patients taking oral contraceptives.
Adherence to treatment of one standardized regime, completion of duration of the regime, and close monitoring and early identification of adverse effects of drugs all enhance the effectiveness of treatment.
Conclusion
TB in kidney recipient is a significant complication because it can lead to loss of allograft or even the patient. The way to deal with this would be intensive screening protocols. In the case of LTBI, patients need to strictly adhere to the regimen that has been created for them, and complete the drug program. This ensures a higher degree of success in eradicating the infection and protecting the allograft.
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.
All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant.
There is no gold standard test for diagnosing LTBI accurately.
WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T
The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agents
IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
Thus IGRAs (both QFT and T-SPOT) have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
A diagnostic approach for detection of active and latent TB:
History:
Contact with patient with active TB
Previous TB treatment
Symptoms
Chronic cough, night sweats, weight loss
Clinical examination
Pulmonary/ extra pulmonary TB
Lab
CBC
CRP
RFT/LFT
Microscopy and culture of TB
Histology of biopsy and aspirate
GeneXpert MTB
Tests for LTBI
TST
IGRA
Imaging
Xray chest
Renal ultrasound
MRI/CT/ PET scan (if indicated)
Epidemiologic risk factors such as history of TB, previous rejection episodes, high-dose corticosteroids, diabetes mellitus and those living in endemic areas need to be evaluated with chest radiography and other screening tests as part of the screening for latent tuberculosis.
In low TB endemic countries, LTBI screening is recommended for population subgroups with a high prevalence of TB or those with a high likelihood of progression from LTBI to active disease.
These include close contacts of patients with active tuberculosis, recently arrived foreign-born persons, drug users, incarcerated persons, and homeless individuals and were advised screening for LTBI
Chest X-ray, detailed background history of previous exposure to patients with TB and risk factor assessment for travel or migration from endemic areas was the most frequent recommendation for LTBI screening in immunosuppressed individuals and those undergoing Solid Organ Transplant (SOT).
Treatment of LTBI in donor and recipient
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB
Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guideline
Introduction
Organisation (WHO) as ‘a state of persistent immune response to stimulation by mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’ (WHO, 2018b). Up to 10% of people with LTBI will progress to developing active TB
Screening and diagnosis of LTBI
Kidney transplantation is universally performed in high and low TB endemic countries.
All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant.
Kowada recommends an active TB screening with IGRA for all renal allograft recipients with individualized risk assessment of each of the patients during LTBI treatment.
Those patients are recommended to initiate anti-TB treatment while they were on the waiting list, aiming at a complete treatment schedule prior to transplantation.
If there is a need to undergo transplantation, it’s worthwhile to temporarily stop the drug intake and recommence the treatment schedule to completion once patients were clinically stable
Treatment of LTBI in donor and recipient
As tuberculosis could directly affect the allograft function, it is extremely important to make the utmost effort to prevent transmission of TB infection in such a select subgroup of patients.
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month.
There is a need for well-designed prospective controlled cohort trials of short course LTBI treatment regimens in transplant recipients, which should assess their efficacy, safety, hepatotoxicity and adherence to treatment Treatment of active TB
Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines (WHO, 2017, 2018c).
Treatment of patients with active tuberculosis detected after renal allograft transplantation remains a challenging task.
Rifampicin interferes with the efficacy of many drugs by interfering with their metabolism
It may not be an ideal choice for patients taking oral contraceptives or HIV-infected individuals on protease inhibitors or non-nucleoside reversetranscriptase inhibitors.
Rifampicin and can be used in combination with Isoniazid for the treatment of latent tuberculosis infection (Matteelli et al, 1999).
Proactive TB screening with IGRA with individualized risk assessment of each of the patients and monitoring the drug toxicity during LTBI treatment is to be recommended for all renal allograft recipients Findings
Up to 10% of people with LTBI will progress to developing active TB Conclusion
TB is a serious complication in renal transplant recipients and causes much morbidity and mortality.
Transplant recipients are at a higher risk of re-activating LTBI from within themselves or from the transplanted donor kidney.
Several guidelines are available and are consistent in recommending that all donors and recipients are routinely screened for LTBI and active TB disease prior to transplant whenever possible.
A high degree of awareness of the possibility of TB is required in all renal transplant patients so that it can be diagnosed and treated early, reducing the risk of loss of allograft.
LTBI Summary of the Article Introduction TB is the most common infection that causes death worldwide. 1.7 billion people were estimated to have latent TB in 2017. LTBI is defined by WHO as a state of persistent immune response to stimulation by M.TB antigen with no evidence of clinically manifested active TB. Up to 10% of people with LTBI are at risk to develop active TB, this risk will be higher with higher morbidity and mortality in patients with other risk factors;
Immunosuppressants medication for any cause.
DM.
Malnutrition.
HIV.
1/3 of kidney trans[lant recipients will lost their allograft due to TB, and most cases of TB infection are due to reactivation of latent infection. Screening and diagnosis History;
Hx of contact with active pulmonary TB.
Previous TB treatment.
Symptoms
Chronic cough.
Night sweats.
weight loss.
Anorexia.
Full clinical examination
Examine for active TB.
Examine for extrapulmonary TB.
Lab
CBC and differentials.
CRP.
RFT and LFT.
Microscopy and culture for M.TB ( spututm and early urine sample).
Histology or biopsy of aspirate.
Gene Xpert MTB.
Tests for LTBI
TST
IGRA
Imaging
Chest x-ray.
Renal US.
MRI or CT scan (if indicated)
PET/CT (if indicated).
Treatment of LTBI in donor and recipient (WHO 2018)
INH monotherapy for 6 months (adult and children) in (low or high endemic areas).
Rif and INH dially for 3 months as an alternative to INH monotherapy as preventive treatment to children and adolescent aged <15 years in countries with high Tb incidence.
RIF and INH weekly fir 3 months offered as alternative to INH montherapy as preventive treatment for both adults and children in countries with high Tb incidence.
In low TB incidence countries; INH mnotherapy for 9 months or a 3 months of weekly RIf and INH or 3-4 month of RIF alone.
Treatment of active TB (WHO 2018)
For many challenges, any centers should design their own protocol
Rifabutin (fewer side effects than RIF) plus INH according to Matteelli et al.
Drug interaction (Hepatotoxivoty, neurotoxicity, reduction of immunotherapy serum level by rifampicin).
Conclusion
TB is a serious complication post-transplant, and can be associated with higher morbidity and mortality.
Highre risk of TB post-transplant due to mostly LTBI reactivation.
A awareness of the TB post transplant is vital in early detection by screening and clinical suspicion to avoid graft and recipient life loss.
Do you think IGRA has a better specificity than tuberculin test, and therefore higher LR ratio? What is your comment on this statement of mine. You may or may not agree with me.
Hi Prof
The TST is not sensitive in advance CKD and as well as in immunocompromised patient, while IGRA is more sensitive and specific exactly in detecting latent TB
Introduction
o Tuberculosis (TB) is the commonest infectious disease worldwide
o Definition of latent tuberculosis infection (WHO): a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically active TB disease
o 10% will develop active TB
o Risk factors for re-activation LTBI include diabetes, malnutrition, HIV, and immunosppressions
o Active TB in renal transplant recipients is higher than general population and causes morbidity and death with allograft loss
o Causes of TB in recipients mostly due to re-activation of LTBI or from donor kidney (also acquiring new infection)
o Clinical presentation of TB in renal transplant is differ from that in the general population and needs high degree of awareness of suspicion
Screening and diagnosis of LTBI and active TB History
o Previous TB infection
o Contact with active TB patient Symptoms:
o Chronic cough, weight loss, night sweats, and anorexia Clinical examination:
o Examine for active pulmonary tuberculosis
o Exclude extra pulmonary TB Investigations
o CBC, CRP, RFT, LFT, microscopy for AFB and culture, biopsy or aspirate histology (AFB or granuloma), and genXpert MTB/Ris Assay (on sputum, urine or biopsy) Tests for LTBI
1. Tuberculin skin test (TST): unreliable in advanced CKD/immunosuppressive patients
2. IGRA test (TSPOT.TB or QuantiFeron): more sensitive and specific for diagnosing LTBI Imaging
o Chest x ray, renal ultrasound, MRI or CT scan (where indicated), and PET/CT scan (where indicated)
Pathogenesis of LTBI in post transplant recipients:
1. No donor or recipient TB: allograft free of TB
2. Donor TB/recipient free: donor derived TB
3. Recipient TB/donor free: endogenous recipient re-activation
4. No donor or recipient TB: denovo recipient infection
BTS screening for LTBI:
1. Areas of high incidence of TB
2. High risk of TB in low incidence areas (contact with active TB, recently arrived from travel abroad, drug users, incarcerated persons, alcohol abuse or injection drug use, and homeless)
Treatment of LTBI in donor and recipient (WHO 2018 guidelines)
1. Isoniazid monotherapy for 6 months (both adults and children) in countries with high and low TB incidence
2. Rifampicin and Isoniazid daily for 3 months (children and adolescents aged <15 ) in countries with a high TB incidence
3. Rifapentine and Isoniazid weekly for 3 months (both adults and children) ) in countries with a high TB incidence
4. In countries of low TB incidence: 9 months of Isoniazid, Rifapentine and Isoniazid weekly for 3 months, Rifampicin and Isoniazid for 3-4 months, and rifampicin alone for 3 months
Treatment of active TB
After transplant is challenging:
1. Hepatotoxicity (rifampicin and isoniazid)
2. Peripheral neuropathy (isoniazid)
3. Rifampicin (interactions with oral contraceptives, antiretrovirals)
Enhance effectiveness of treatment:
1. Adherence to one specific regimen
2. Completion of the recommended duration
3. Close monitoring and early identification of adverse effects
Conclusions
o Transplant recipients are at high risk of re-activating LTBI due to immunosuppression causing mortality and morbidity, in addition to allograft loss
o Routine screening of all donors and recipients for LTBI is required and active TB prior transplant
o A high degree of awareness of the possibility of TB is required
What is the level of evidence provided by this article?
Level V (narrative review)
Introduction:
-TB is the commonest infectious disease cause of death worldwide.
-WHO defined LTBI as a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease.
-10% of people with LTBI will progress to active TB disease. – In KTRs, TB is highly prevalent, and it is associated with significant morbidity and mortality. – The diagnosis and treatment of TB donors and transplant recipients is challenging. Screening and diagnosis of LTBI
-There is no gold standard test. WHO recommended the following:
* Tuberculin skin test (TST) :
– Unreliable advanced CKD and immunosuppressed individuals.
– still used in low resource setting.
* IGRAs; (QuantiFERON-TB and T-SPOT ):
– High specificity in detecting LTBI in immunocompromised.
– IGRAs more sensitive than the TST for the diagnosis of LTBI in KTRs.
– British Thoracic Society guidelines suggest screening for LTBI where TB is endemic or having risk factor for TB while living in low incidence area.
– CXR is part of the screening.
– Detailed background history of previous exposure to patients with TB and risk factor assessment
Treatment of LTBI:
WHO 2018 guidelines for LTBI treatment; – Treatment of choice; Isoniazid INH monotherapy for 6 months ( both adult and children).
– Alternative to 6 months monotherapy:
– Rifampicin + INH daily for 3 months (for children in high TB incidence ).
– Rifapentine + INH weekly for 3 months (for both adults and children in high TB incidence).
– In low TB incidence; INH for 9 months of isoniazid, or regimen of weekly rifapentine +INH for 3 months, or INH + rifampicin for 3–4 months, or 3–4 months of rifampicin alone
Treatment of active TB:
– It is challenging task and should follow WHO treatment guidelines.
– Hepatotoxicity is a serious side effects of TB medications.
– Rifampicin interact with many immunosuppressive drugs reducing its level and antiretroviral treatment.
– Rifabutin has fewer pharmacologic interactions with antiretroviral agents
– treatment effectiveness enhanced by close monitoring and early identification of the adverse effects Level of evidence : 5 narrative review.
Summary Introduction
TB is the commonest infectious cause of death worldwide.
WHO defines LTBI as a state of persistent immune response to stimulation by MTB antigens with no clinical symptoms.
Persons with LTBI, 10% of them in their lifetime will develop active TB disease.
Incidence of TB in kidney transplant recipients is higher than general population, and it’s associated with allograft loss in a third of the patients.
TB in the kidney transplant recipient could be due to reactivation of the LTBI or due to new infection that rapidly progresses to milliary TB.
Clinical presentation of TB in kidney transplant recipients differs from that of the general population.
Screening and diagnosis
All kidney transplant recipients and their donors should be screened for TB prior to transplantation.
No gold standard test.
WHO approves three test: tuberculin skin test and IGRA (Quantiferon and T spot).
Tuberculin skin test not reliable in CKD and in patients on immunosuppressants.
IGRA more sensitive and specific than tuberculin skin test, however limited studies on specificity and sensitivity of IGRA and TST in organ recipients.
CXR and a detailed history is essential in screening.
Treatment of LTBI
Recommended LTBI treatment as per WHO 2018 guidelines
Isoniazid mono therapy for 6 months recommended in both adults and children in high and low endemic areas
Rifampicin + isoniazid daily for 3 months in children and adolescent <15 years in high endemic areas.
Rifapentine + isoniazid weekly for 3 months in children and adults in high endemic areas
Low TB incidence alternatives to 6 months INH
9 months isoniazid
Rifapentine + isoniazid weekly for 3 months
3-4 months of rifampicin alone
3-4 isoniazid + rifampicin
Treatment of active disease
Treatment in renal transplant recipient should follow WHO guidelines.
Caution:
Isoniazid and rifampicin are hepatotoxic
Isoniazid causes peripheral neuropathy prevented by co-administering pyridoxine
Rifampiccin interacts with various drugs
Level of evidence
This was a review of articles making it level V.
Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime.
The authors wrote nice work up for LTBI from clinical assessment to radiograph, cultures and look for LTBI with TST and or IGRA. IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients The article explores treatment of both latent and active TB infections and pointed to drug side effects like liver, neuro toxicity. Rifampicin alter metabolism of CNI and it is important to monitor the levels closely
TB is the leading infectious disease killer globally (WHO, 2018a). 2017 had 1.3 million TB deaths. The latest modeling recalculations show that 1.7 billion persons globally have latent Mycobacterium tuberculosis infection (LTBI). The WHO defines latent tuberculosis infection as a condition of sustained immunological response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no indication of clinically apparent active TB illness’ (WHO, 2018b). 10% of LTBI patients will acquire active TB.
Methods:
A search was conducted in the PubMed database to locate papers and recommendations pertaining to the diagnosis and treatment of LTBI in renal transplantation. Articles on renal transplant patients who were diagnosed with LTBI and TB during the postoperative period were also examined. Guidelines provided by specialized societies were also taken into consideration.
Testing for LTBI:
All TB-endemic nations do kidney transplants. Renal transplant patients and donors should be screened for LTBI and active TB before transplant. No LTBI test is definitive. WHO recommends three tests for LTBI screening: TST, QuantiFERON-1-TB (QFT) Gold In-Tube, and T-SPOT1. Advanced chronic renal disease and immunosuppression may render the TST unreliable. IGRAs are highly specific to M. TB antigens and may identify LTBI in immunosuppressed individuals. IGRAs and TST screening for LBI in renal transplant patients have little evidence of their sensitivities and specificities.
Treatment of LTBI in donor and recipient:
LTBI treatment for adults and children in high- and low-TB countries is 6-month isoniazid monotherapy.
In high-TB nations, children and adolescents under 15 should be treated with rifampicin and isoniazid daily for 3 months instead of 6 months of isoniazid monotherapy.
Rifapentine and isoniazid given weekly for 3 months may be used as a preventative treatment for adults and children in high-TB nations instead of 6 months of monotherapy.
Alternatives to 6-month isoniazid monotherapy for LTBI treatment in low-TB countries include 9 months of isoniazid.
Treatment of active TB:
In active cases of tuberculosis, treatment in accordance with WHO standards
INH and rifampicin both have a number of potential adverse effects, but one of the most serious is hepatotoxicity.
As compared to rifampicin, the antiviral drug rifabutin showed a much lower potential for adverse drug interactions.
Pyridoxine, when given in conjunction with INH, has the ability to ward against peripheral neuropathy.
I like your summary, level of evidence, and analysis.
You mentioned TB antigen test. Do you think GeneXpert in comparison to IGRA has a better specificity and therefore higher LR ratio?
Name of the study:Latent tuberculosis infection and renal transplantation Diagnosis and management Year of the study:(2019) Journal: International Journal of Infectious Diseases 2021 Impact Factor 9.022 Summery
Definition: Latent tuberculosis infection is defined by the World Health Organisation (WHO) as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens( in the form of positive skin test in non-vaccinated population or positive IGRA test with no evidence of clinically manifest active TB disease(in the form of negative symptoms and normal radiology)
Screening and diagnosis of LTBI
There is no gold standard test for diagnosing LTBI accurately.
WHO recommendations are
1-Diagnosis of persistent immunological response by Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) which include (QuantiFERON1-TB (QFT)
Gold In-Tube and T-SPOT1).
2-Then exclude active TB disease by :History of exposure and symptoms then confirmed by radiology and laboratory investigations like acid fast bacilli. Treatment of LTBI in donor and recipient
Same regimen of general population with special consideration of drug-drug interaction especially rifampicine and CNI (better to be replaced by refaputine)
Latent TBI showed be treated in both donor (risk of transmission and cause also expose him to risk of ESRD) and recipient(risk of activation to active TB disease around 20-75%)
· Reactivation of latent TB to active disease is common among KT.
· It has greater burden to increase morbidity and mortality.
· Risk factors as strong induction and immunosuppressive therapy, plus comorbidities as DM, HIV, CMV.
· Screening by TST and IGRA tests. IGRA has better sensitivity in immunocompromised patients and can differentiate between MTB and other MOTT (mycobacteria other than TB).
· While in active disease;search for AFB in either sputum or morning urine sample, GeneXpert is rapid and sensitive method in diagnosis, in sputum, urine or biopsy samples.
· Treatment of latent TB in recipients:
o INH + pyridoxine for 6-9 months.
o Oral rifampin for 4 months
· Treatment of active TB in recipients:
· Start immediately after diagnosis.
· 2 Regimens:
· 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.
· 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.
· Monitoring of adverse effects as hepatotoxicity as 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
I like your summary, level of evidence, and analysis. Do you think GeneXpert in comparison to IGRA has a better specificity and therefore higher LR ratio?
Thanks dear professor. I think IGRA has accepted sensitivity and specificity in case of latent TB as it represents sustained immune response to MTB. While geneXpert is highly sensitive in case of active TB disease.
IGRA (QFT, T-SPOT): more specific to MBT antigen & high specificity for LTBI in immunosuppressed patients.
IGRA test is more sensitive than TST in diagnosis of LTBI in renal transplant candidates.
TST still used in low resources sitting.
British Thoracic Society guidelines suggest screening of LTBI if TB incidence rate are high or patients with risk factors for developing TB in low incidence area.
CXR recommended during LTBI screening.
LTBI treatment in donor & recipient:
According WHO 2018 treatment guidelines:
Isonizide (INH) mono therapy for 6 months is the first line treatment for all patients (adult & children).
INH + rifampicin daily for 3 months(alternative to mono-therapy) as prevention in patients <18 years of age in high TB incidence area.
Rifapentin & INH weekly for 3 months (alternative to mono-therapy) as prevention in high endemic area.
In low endemic area, different regime for treatment: 9 months of INH, 3 months of weekly INH+rifapentin or 3-4 months of INH+rifampicin or 3-4 months of rifampicin alone.
Adverse events can limit long term use of anti-TB drugs, so shorter course of treatment can overcome this problem.
Treatment of active TB:
Treatment of active TB according WHO guidelines
Hepatotoxicity is a major side effect of INH & rifampicin that can limit its use.
Co-administration of pyridoxine with INH can prevent peripheral neuropathy.
Rifabutin had fewer pharmocolgical interaction with antiviral than rifampicin.
I like your summary, level of evidence, and analysis. 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.
I like your summary, level of evidence, and analysis. Do you think IGRA has a better specificity and therefore higher LR ratio? I like your summary, level of evidence, and analysis. Do you think IGRA has a better specificity and therefore higher LR ratio?
1-Summarise this article; Introduction;
-There are 1.7 billion people worldwide with latent Mycobacterium tuberculosis infection (LTBI).
-World Health Organisation (WHO) defined Latent tuberculosis infection (LTBI); as a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease.
-Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime. Risk factors for re-activation LTBI;
-Occur when conditions of immunosuppression are present such as diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients. Screening and diagnosis of LTBI;
-There is no gold standard test for diagnosing LTBI accurately.
-WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs); (QFT & T-SPOT).
-The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agents.
-IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients & more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
-British Thoracic Society guidelines suggest screening for LTBI where tuberculosis incidence rates are high or in patients with risk factors for developing tuberculosis in low incidence areas: need to be evaluated with chest radiography and other screening tests as part of the screening for latent tuberculosis. Treatment of LTBI in donor and recipient;
-The WHO 2018 guidelines for treatment options for LTBI;
-Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
-Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy.
-Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy. Treatment of active TB;
-Treatment of patients with active tuberculosis detected after renal allograft transplantation remains a challenging task.
-Hepatotoxicity is a serious dose limiting side effects of both Isoniazid and Rifampicin and this risk is further accentuated in patients with pre-existing liver disease and alcoholics.
-Peripheral neuropathy caused by Isoniazid can be prevented by co-administration of pyridoxine.
-Rifampicin interferes with the efficacy of many drugs by interfering with their metabolism.
-Rifabutin has fewer pharmacologic interactions than Rifampicin and can be used in combination with Isoniazid for the treatment of latent tuberculosis infection. Limitation;
-There is a need for well-designed prospective controlled cohort trials of short course LTBI treatment regimens in transplant recipients, which should also assess their efficacy, safety, hepatotoxicity and adherence to treatment.
-Patients may find completing the long course of LTBI treatment difficult due to adverse effects and the interactions with immunosuppressive drugs, hence shorter courses of treatment are recommended. Conclusions;
-Due to immunosuppression, transplant recipients are at a higher risk of re-activating LTBI from within themselves or from the transplanted donor kidney.
-Kidney transplantation is now universally performed in high and low Tuberculosis endemic countries.
– A high degree of awareness of the possibility of TB is required in all renal transplant patients so that it can be diagnosed and treated early, reducing the risk of loss of allograft.
-WHO Management recommendations for LTBI screening and treatment should be followed. 2-What is the level of evidence provided by this article?
This systematic review and meta-analysis (LOE V).
I like your summary, level of evidence, and analysis.
You mention 3 possible options for prophylaxis against latent TB in recipients. Which one would you choose for your patients?
TB is the commonest infection leading to death throughout the globe
Immune suppression is important risk factor for the development of TB
10% of people with latent infection may progress to active infection
The incidence of active TB in renal transplant is higher than the general population
Transmission is commonly from reactivation of the latent infection or not frequently donor-drive and de novo
In kidney transplant recipient , it is associated with risk of rejection, allograft loss, & mortality
The diagnosis is difficult due to atypical presentation and frequent extra-pulmonary disease
Screening & diagnosis of active & LTBI:
1.History:
Contact
Previous treatment
2.Symptoms:
Chronic cough, night sweats, weight loss, anorexia
3.Full Clinical Examination
Look for both active pulmonary & extra-pulmonary disease
4.Work up
Routine lab work : FBC, CRP, UECs, LFTs
Microscopy & early morning sputum culture
Biopsy or aspirate
Gene Xpert
5.Test for LTBI
TST
IGRA
6.Imaging
CXR, renal U/S, MRI/CT, PET/CT (if they are indicated)
Treatment of LTBI
INH mono therapy for 6 months or
Rifampicin + INH daily for 3 months or Rifabutin + INH weekly for 3 months
Treatment of active tuberculosis
Based on WHO guidelines 2017,2018
Challenging due to toxicities, side effects of the drugs , adherence issues & drug -drug interactions
Conclusion
TB in renal transplant recipients is a risk factor for rejection and mortality. Transmission is commonly due to reactivation of latent infection or donor drive. Diagnosis is challenging due to atypical presentation and the treatment is more challenging due to significant drug drug interactions & side effects. Further studies to assess the need for short course of treatment and the safety and efficacy for LBTI are required.
Adherence issues; as the number of tablets may go up 3 to 5 folds particularly tacrolimus. The prednisone dose is doubled .This may also have cost implications
A part from rejection, graft loss may be due to direct effect of TB on the allograft or the sepsis mediated by TB
WHO- as ‘a state of persistent immune response to stimulation by mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB disease’ (WHO, 2018b). Up to 10% of individuals with LTBI will develop active TB.
LTBI screening and diagnosis
In both high and low TB-endemic nations, kidney transplantation is routinely performed.
Prior to transplant, all recipients and donors of renal transplants should be screened for LTBI and active TB disease.
Kowada suggests an active TB screening with IGRA for all renal allograft recipients, as well as an individual risk assessment for each patient during LTBI treatment.
It is recommended that these patients begin anti-TB treatment while on the transplant waiting list, with the goal of completing their treatment regimen prior to transplantation.
If transplantation is necessary, it is beneficial to temporarily suspend drug consumption and resume the treatment schedule to completion once patients are clinically stable.
LTBI treatment for both donors and recipients
Due to the fact that tuberculosis could directly affect allograft function, it is of the uttermost importance to prevent transmission of TB infection in this select subgroup of patients.
In both countries with a high and low incidence of tuberculosis, a 6-month course of isoniazid monotherapy is suggested for the treatment of LTBI in both adults and children.
In countries with a high incidence of tuberculosis, Rifapentine and Isoniazid may be administered weekly for 3 months as an alternative to 6 months of Isoniazid monotherapy as a preventive treatment for both adults and children.
Alternatives to six months of isoniazid monotherapy for the treatment of LTBI in countries with a low incidence of tuberculosis include nine months of isoniazid or a three-month course.
There is a need for well-designed prospective controlled cohort trials evaluating the efficacy, tolerability, hepatotoxicity, and adherence of short course LTBI treatment regimens in transplant recipients.
The therapy for active TB
The treatment of drug-sensitive and drug-resistant active tuberculosis in kidney transplant recipients should adhere to WHO treatment guidelines (WHO, 2017, 2018c).
The treatment of patients diagnosed with active tuberculosis after renal allograft transplantation remains a difficult endeavour.
Rifampicin reduces the efficacy of numerous medications by interfering with their metabolism.
Patients taking oral contraceptives or HIV-infected individuals taking protease inhibitors or non-nucleoside reversetranscriptase inhibitors may not be optimal candidates.
Rifampicin and isoniazid can be used in conjunction to treat latent tuberculosis infection (Matteelli et al., 1999).
All renal allograft recipients should undergo proactive TB screening with IGRA, with individualised risk assessment for each patient, and monitoring of drug toxicity during LTBI treatment.
Findings
Up to 10% of individuals with LTBI will develop active TB.
Conclusion
In renal transplant recipients, tuberculosis is a serious complication that causes a great deal of morbidity and mortality.
Transplant recipients are at a greater risk of reactivating latent tuberculosis infection (LTBI) from within themselves or from the donor kidney.
Several available guidelines recommend that, whenever practicable, all donors and recipients be screened routinely for LTBI and active TB disease prior to transplantation.
All renal transplant patients must have a high level of awareness of the prospect of tuberculosis so that it can be diagnosed and treated early, thereby reducing the risk of allograft loss.
Tuberculosis is the commonest infectious cause of death worldwide. About 1.3 million people died of TB in 2017. About 1.7 billion people have latent TB worldwide.
Latent TB is a state of immune persistent response to mycobacterium TB antigens without evidence of clinically manifest active TB. About 10% of latent TB progress to active TB.
Reactivation of latent TB occurs in cases of immunosuppression as diabetes, malnutrition, HIV and prescription of biological and Immunosuppressive agents including anti-rejection therapy in transplant recipients.
Active TB is much higher among kidney recipients and can cause loss of allograft in one third of cases.
TB in renal transplant recipients occurs due to reactivation of latent TB in the recipient or from the donor or increased susceptibility to acquire new TB infection
Screening and diagnosis of latent TB
History: contact with patient with active pulmonary TB, previous TB treatment.
Symptoms: chronic cough, night sweats, weight loss and anorexia.
Full clinical examination: examine for active pulmonary TB and exclude extrapulmonary TB.
Investigation: CBC,CRP,LFT,KFT,microscopy for acid fast bacilli and culture for M.tb in sputum and early morning samples
Histology of biopsy or aspirate ( acid fast bacilli and granuloma)
Test for latent TB
,,, Tuberculin skin test but may be unreliable in patients with advanced CKD and those on Immunosuppressive agents.
,,,, Interferon gamma release assays(IGRA) test either TSPOT.TB or QuantiFERON). They are more sensitive than TST in patients with renal transplantation
Pathogenetic mechanism of latent TB
TB free transplant or denovo infection : if the pre transplant recipient and donor are free of TB infection
Donor derived TB: if the donor has previous TB infection and the recipient free of TB infection
Endogenous reactivation: if the donor free of TB infection and the recipient has previous TB infection
Guidelines recommend that all kidney transplant candidates should be routinely screened for latent TB
Treatment of latent TB
Isoniazide monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Rifampcin plus Isoniazide daily for 3months for children and adults less than 15 years as a preventive treatment in countries with a high TB incidence
Rifapentine and Isoniazide weekly for three months as preventive treatment for adults and children in countries with a high incidence TB
The following options can be used in countries with a low incidence of TB: 9 months of Isoniazide or 3 months of weekly rifapentine plus Isoniazide, 3 to 4 months of Isoniazide plus Rifampcin or 3 to 4 months Rifampcin alone
Conclusion
Due to immunosuppression, transplant recipients are at higher risk of reactivation of LTBI from within themselves or from the donor kidney
Routine Screening for LTBI should be done in donors and recipients prior to transplant
All kidney recipients are liable to TB , early diagnosis and early treatment can save the allograft
Level of evidence 5
Tb is an important cause of morbidity and death in renal transplant recipients which may end with loss of kidney allograft. This is a review of the prevention, diagnosis and treatment of tuberculosis in renal transplant recipients which was done through research of PubMed database.
screening for LTBI and active TB disease should be applied to all renal transplant recipients and their donors prior to transplant. There is no gold standard test for diagnosing LTBI accurately but the WHO recommends three tests for screening for LTBI: Tuberculin skin test and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T.
prevention is important to prevent Tb affection of the graft. it is extremely important to make the utmost effort to prevent transmission of TB infection in such a select subgroup of patients.
Treatment of LTBI should follow WHO 2018 guidelines.
– Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
– Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15
– Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
– The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-mont regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone
level of evidence is 5
Screening and diagnosis of latent tuberculosis infection (LTBI):
Clinical workup for donors and transplant recipients to screen for LTBI and active TB:
Tests for LTBI:
Treatment of LTBI in donors and recipients:
Treatment of active TB:
Conclusions:
Level of evidence: Level V.
Summarise this article
Latent TB diagnosis and management
Diagnosis of LTBI
Management
What is the level of evidence provided by this article?
Level 5 evidence – a review
Level 5 evidence
TB is the most common infectious disease causing death worldwide.
Screening and diagnosis of LTBI as recommended by the WHO:
-Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs).
-Treatment of active TB :Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines
Proactive TB screening with IGRA and monitoring the drug toxicity during LTBI treatment is recommended for all renal allograft recipients.
-LTBI and active TB infection post transplantation leads to high morbidity and mortality.
1- Sumarise this article.
Introduction
Who said, Tuberculosis (TB) is the commonest infectious disease cause of
death worldwide .
Recent epidemiology studies report that there are 1.7 billion people worldwide with latent
Mycobacterium tuberculosis infection (LTBI)
About 10% of LTBI will progress to active TB during lifetime.
risk factors for re-activation LTBI
1- Diabetes.
2- Malnutrition.
3- HIV.
4- prescription of biologics and immunosuppressive agents.
The incidence of active TB disease among renal transplant recipients is much higher than in the general population and causes much morbidity and death in these patients . TB is also responsible for loss of the renal allograft in approximately one third of cases.
The clinical presentation of TB occurring in transplant recipients is said to differ from that in the general population and an increased frequency of extra pulmonary TB is seen.
Screening and diagnosis of LTBI:
All renal transplant recipients and their donors should undergo screening for LTBI and active TB
disease prior to transplant.
There is no gold standard test for diagnosing LTBI accurately.
WHO recommends three tests for screening for LTBI:
A- Tuberculin skin test (TST) .
B- two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT T.
diagnostic approach:
A. history.
Ø Contact with TB patient.
Ø Old TB treatment.
B. symptoms.
Chronic cough, fever, night sweat, weight loss, anorexia.
C. Full clinical examination.
Ø For active pulmonary TB.
Ø For extra pulmonary TB.
D. Investigation.
Ø CBC
Ø CRP
Ø Renal and liver function.
Ø AFB and culture for mycobacterium TB.
Ø Tissue biopsy .
Ø geneXpert MTB assay.
E. Investigation for LTBI
Ø Tuberculin skin test.
Ø IGRA test.
F. Imaging.
Ø CXR.
Ø Renal ultrasound.
Ø MRI or CT scan.
ØPET/CT scan.
Treatment of LTBI in donor and recipient:
tuberculosis could directly affect the allograft function.
Every effort
must be made to diagnose and treat LTBI and active tuberculosis in
both live donor and recipient before transplantation.
Treatment of LTBI should follow WHO 2018 guidelines
Ø Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Ø Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment .
Ø Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment.
Ø The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-monthregimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB
Treatment follow WHO treatment guidelines . Treatment of patients with active
tuberculosis post transplantation is a challenging task.
Hepatotoxicity and Peripheral neuropathy should be kept in mind.
Drug interaction with oral contraceptives and anti-retro viral medication.
Proactive TB screening with IGRA with individualized risk assessment of each of the patients and monitoring the drug toxicity during LTBI treatment is to be recommended for all renal allograft recipients.
2- What is the level of evidence provided by this article
Level of evidence is 5.
Latent tuberculosis infection is defined by the World Health Organisation (WHO) as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’ (WHO, 2018b). Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime. The highest risk for developing TB disease occurs when a range of risk factors for re-activation LTBI .occur when conditions of immunosuppression are present such as diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients. Most of the TB cases in renal transplant recipients are due to re-activation of LTBI in the recipient .
Screening and diagnosis of LTB
All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant. There is no gold standard test for diagnosing LTBI accurately. WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT T.
The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agents.IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients., There are likely to be more false positive, false negative and indeterminate results of IGRAs in transplant recipients.. A higher rate of LTBI was found in patients undergoing renal transplantation than those undergoing other organ transplantation, especially when IGRA tests were used compare to the TST. Thus IGRAs (both QFT and T-SPOT) have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation
Treatment of LTBI in donor and recipient
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone
Introduction
Tuberculosis (TB) is the commonest infectious disease cause of death worldwide (WHO, 2018a). An estimated 1.3 million people died of tuberculosis in 2017. Recent modelling re-calculations indicate that there are 1.7 billion people worldwide with latent Mycobacterium tuberculosis infection (LTBI) (Houben and Dodd 2016). Latent tuberculosis infection is defined by the World Health Organisation (WHO) as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’ (WHO, 2018b). Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime.
Screening and diagnosis of LTBI
Kidney transplantation is now universally performed in high and low TB endemic countries. All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant. There is no gold standard test for diagnosing LTBI accurately. WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T (WHO, 2018b). The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agents (Guirao-Arrabal and Torre- Cisneros, 2018). IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients (Pai et al., 2014; Guirao-Arrabal and Torre-Cisneros, 2018).
A diagnostic approach for detection of active and latent tuberculosis has been outlined by Demir and Sever (2017). Clinical workup of donors and transplant recipients to screen for LTBI and active TB The TBNET consensus group has summarized pathogenesis of LTBI in post-transplant patients (Bumbacea et al., 2012).
In low TB endemic countries, LTBI screening is recommended for
population subgroups with a high prevalence of TB or those with a high likelihood of progression from LTBI to active disease. These include close contacts of patients with active tuberculosis, recently arrived foreign-born persons, drug users, incarcerated persons, and homeless individuals and were advised screening for LTBI (Horsburgh, 2004). Chest X-ray, detailed background history of previous exposure to patients with TB and risk factor assessment for travel or migration from endemic areas was the most frequent recommendation for LTBI screening in immunosuppressed individuals and those undergoing Solid Organ Transplant
Treatment of LTBI in donor and recipient As tuberculosis could directly affect the allograft function, it is
extremely important to make the utmost effort to prevent transmission of TB infection in such a select subgroup of patients. Every effort must be made to diagnose and treat LTBI and active tuberculosis in bothlivedonorandrecipientbeforetransplantation.TreatmentofLTBI should follow WHO 2018 guidelines (WHO, 2018b). The Consensus Statement from the Spanish Group for the Study of
Infectious DiseasesinTransplant Recipients defines the indications for treatment of LTBI in SOT recipients (Aguado et al., 2009). The WHO 2018 guidelines outline the following treatment options for LTBI (WHO, 2018b).
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month
regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Renal transplantation is now widely available globally. TB is a
serious complication in renal transplant recipients and causes much morbidity and mortality. Due to immunosuppression, transplant recipients are at a higher risk of re-activating LTBI from within themselves or from the transplanted donor kidney. Several guidelines are available and are consistent in recommending that all donors and recipients are routinely screened for LTBI and active TB disease prior to transplant whenever possible. A high degree of awareness of the possibility of TB is required in all renal transplant patients so that it can be diagnosed and treated early, reducing the risk of loss of allograft
level 5
Introduction :
Latent tuberculosis infection is defined as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (TB) which is the commonest infectious disease cause of death worldwide . Latent Mycobacterium tuberculosis infection (LTBI)affects 1.7 billion people worldwide
.
The incidence of active TB disease among renal transplant recipients is much higher compared with the general population; it causes increased morbidity and mortality in these patients .
Commonly caused by reactivation of LTBI in the recipient or to a lesser extent from donor kidney
The diagnosis and treatment of LTBI and active TB disease in donors and transplant recipients is quite challenging and needs a high degree of awareness of the possibility of TB.
There is an increased frequency of extrapulmonary TB in transplant recipients than in the general population
Screening and diagnosis of LTBI:
Screening for LTBI is recommended for all renal transplant candidates and their donors , especially those with history of TB, previous rejection, or other risk factors. LTBI screening is recommended for population subgroups with high prevalence of TB or high likelihood of progression to active disease, including close contacts, foreign-born persons, drug users, incarcerated persons, and homeless individuals
WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T .
There limited data on the sensitivities and specificities of TST and IGRAs in screening for LBI in renal transplant recipients,but IGRAs have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients candidates for renal transplantation.
Undiagnosed LTBI in a recipient during pretransplant evaluation, either persists as LTBI or may undergo endogenous reactivation in the period of immunosuppression .
Treatment of LTBI in donor and recipient :
The treatment of LTBI should be as recommended by WHO 2018 guideline :
TB has a direct effect on the allograft function, so transmission of TB infection should be prevented
Treatment of active TB:
Treatment of both drug-sensitive and drug resistant active TB in renal transplant recipients should follow WHO treatment guidelines. adverse events caused by Isoniazid ( hepatotoxicity and peripheral neuropathy )can be prevented by pyridoxine co-administration
Rifampicin is a potent enzyme inducer which decrease the level of immunosuppressant and other drugs and may not be an ideal choice for patients taking oral contraceptives or HIV-infected individuals on protease inhibitors or non-nucleoside reverse- transcriptase inhibitors.
Proactive TB screening with IGRA is to be recommended for all renal allograft recipients.
Conclusion :
TB is a serious infection in renal transplant recipients because of immunosuppression. All donors and recipients are screened for LTBI and active TB disease prior to transplant to reduce the risk of loss of allograft as recommended by several guidelines .
Level V
The incidence of active TB in renal transplant recipients is much higher than in the general population
The authors highlighted the very important issue of diagnosis and management of latent TB in transplant population.
Latent TB infection ; by the World Health Organization (WHO) definition is ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (MTB) antigens without evidence of clinically manifest active TB disease’ (WHO, 2018b). Up to 10% of people with LTBI will develop active TB disease during their lifetime.
-Screening and diagnosis of latent TB:
The first step is to take history, proper physical examination and relevant lab investigations including radiology.
No gold standard test for diagnosing LTBI accurately. WHO recommends 3 tests for screening for LTBI: TST and two interferon gamma release assays (IGRAs) :QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T (WHO, 2018b). The TST may be inaccurate in patients with advanced CKD and in those on immunosuppressive medications.
IGRAs are more specific to M.TB antigens and has high specificity in detection of LTBI in immunosuppressed patients.
-Treatment of LTBI in donor and recipient
INH monotherapy for 6 months is recommended for ttt of LTBI in adults and children in areas with high and low TB incidence.
Rifampicin plus INH daily for 3 months must be offered as an alternative to 6 months of INH monotherapy as preventive measure for children and adolescents aged less than15 years in areas with a high TB prevalence.
Rifapentine &INH every week for 3 months may be given as alternative to 6 months of INH monotherapy as preventive measure for adults and children in areas with high TB prevalence.
The following regimens are recommended for treatment of LTBI in areas with low TB incidence as alternatives to 6 months of INH monotherapy: 9 months of INH, or a 3-month regimen of weekly rifapentine plus INH, or 3–4 months of INH plus rifampicin, or 3 to 4 months of rifampicin only.
Treatment of active TB:
Treatment of both drug-sensitive and drug resistant active TB in renal transplant recipients must follow WHO treatment guidelines (WHO, 2017, 2018c). The most important issue is to avoid serious drug interactions of Rifampicin . It is essential that all centers must revise there policies in this aspect based on local guidelines.
Level of evidence V ; narrative review.
Introduction:
Tuberculosis (TB) is the commonest infectious cause of death worldwide – WHO estimated 1.3 million people died of tuberculosis in 2017, and 1.7 billion people worldwide harbour latent Mycobacterium tuberculosis infection (LTBI).
LTBI is defined by WHO as ‘a state of persistent immune response to stimulation by M.tb antigens with no clinical manifestation of active TB disease’.
10% of them progress to active TB disease during lifetime, high risk reactivation occur in presence of diabetes, malnutrition, HIV, immunosuppressive medications, post-transplant.
Active TB incidence in kidney transplant recipients (KTRs) is higher than the general population, associated with high morbidity, graft loss and mortality.
Most cases are due to reactivation of LTBI; but can also be donor-derived or a de novo infection. The diagnosis can be challenging due to atypical presentation, and more extrapulmonary features.
Screening and diagnosis of LTBI:
· There is no gold standard test for diagnosing LTBI accurately.
· WHO recommends screening by tuberculin skin test (TST) and interferon gamma release assays (IGRAs) using either QuantiFERON-TB Gold In-Tube or T-SPOT TB tests. IGRAs are more sensitive that TST for LTBI.
· IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in CKD and immunosuppressed patients.
· IGRAs (both QFT and T-SPOT) have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation
· In low resource settings, TST continues to be used for diagnosing LTBI.
Diagnostic approach for detection of active and latent tuberculosis involves
· history – TB treatment / contact with TB patient
· Symptoms – chronic cough, night sweats, weight loss, anorexia
· clinical examination – pulmonary and extrapulmonary
· investigations – CBC, CRP, LFT, RFT, M.tb microscopy and culture histology of aspirates and biopsy for AFB and granuloma
· Gene X-pert MTB / RIF assay on sputum, urine, or biopsy
· imaging – CXR, renal ultrasound, MRI, CT or PET-CT
Treatment of LTBI in donor and recipient: (WHO 2018 guidelines)
high-endemicity areas
v INH monotherapy x 6 months for both children and adults
v INH + Rifampicin daily x 3months should be offered for children n adolescent <15 years
v INH + Rifampicin weekly x 3months may be offered for adults and older children (>15 years)
low endemicity regions – recommended for treatment of LTBI in countries with a low TB incidence
Ø 6-9 months of isoniazid monotherapy
Ø 3–4 months of INH + Rifampicin
Ø 3-month regimen of weekly Rifampicin + INH
Ø 3–4 months of Rifampicin alone
Adverse effects, drug interactions, and longer duration of treatment are the challenges faced during LTBI treatment. Rifabutin can be used in place of rifampicin in case of high drug reactions in transplant recipients.
Treatment of active TB:
To follow local / WHO guidelines – intensive phase 4 drug regimen, maintenance phase 2drugs (Rifampicin based preferable), Total duration of 9-12 months.
Close monitoring of liver enzymes, other adverse effects, and looking for drug interactions.
Conclusions:
v TB is a serious complication in renal transplant recipients and increases morbidity and mortality.
Transplant recipients have increased risk of developing TB due to reactivation of LTBI, a donor-derived infection, or a de novo infection.
v All donors and recipients should be screened for LTBI and active TB disease prior to transplant – screening with IGRA and individualized risk assessment is important to diagnose TB / LTBI.
v Increased awareness in patients regarding possibility of TB post-transplant may lead to early diagnosis and treatment, which may reduce graft loss.
v Monitoring of adverse reactions as well as drug interactions during treatment is essential for good patient and graft outcomes.
2. What is the level of evidence provided by this article?
Level of evidence: level 5 – Narrative review.
Latent tuberculosis infection and renal transplantation – Diagnosis and management
Introduction
· Tuberculosis (TB) is the most common cause of death from infectious diseases.
· There are about 1.7 billion people worldwide with latent TB.
· WHO definition of LTB: ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB disease’
· Risk factors of activation of LTB: DM, malnutrition, HIV, and biologic and immunosuppressive drugs.
· In recipients, TB increases mortality, morbidity, and graft loss.
· The commonest cause of TB in recipients is the activation of LTB.
· As LTB is asymptomatic, diagnosis and treatment could be challenging.
· Transplant recipient’s clinical presentation is different from the general population and has more incidence of extrapulmonary TB.
Screening and diagnosis of LTBI
· WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon-gamma release assays (IGRAs) namely, QuantiFERON-TB (QFT) Gold In-Tube and T-SPOT T
· TST could be unreliable in advanced CKD and in those immunosuppressed patients.
· IGRAs are more specific to M.tb antigens and are highly specific in LTBI in immunosuppressed patients
· transplant recipients have falser positive, falser negative and indeterminate results of IGRAs
· IGRAs found to be more sensitive than the TST for the diagnosis of LTBI in renal transplant candidates.
Treatment of LTBI in donor and recipient
· Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
· Rifampicin plus Isoniazid daily for 3 months is an alternative as preventive treatment for children and adolescents (<15 y) in countries with a high TB incidence.
· Rifapentine and Isoniazid weekly for 3 months is an alternative as preventive treatment for both adults and children in countries with a high TB incidence.
· Treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy:
1) 9 months of isoniazid,
2)or a 3-month regimen of weekly rifapentine plus isoniazid,
3)or 3–4 months of isoniazid plus rifampicin,
4)or 3–4 months of rifampicin alone.
Treatment of active TB
· should follow WHO treatment guidelines (
· Isoniazid and Rifampicin have hepatotoxicity limiting its use.
· Peripheral neuropathy caused by Isoniazid can be prevented by co-administration of pyridoxine
· Rifampicin has many drug-drug interactions, while Rifabutin has fewer interactions
Conclusions
· TB is a serious complication in renal transplant recipients and increases morbidity and mortality.
· Immunosuppression increases the risk of activation of LTBI
· All donors and recipients should be screened for LTBI and active TB disease prior to transplant.
· Increased awareness of the possibility of TB in renal transplant recipients may lead to early diagnosis and treatment, which may reduce graft loss.
This is a narrative review with evidence V.
One of the commonest disease which has increased mortality rate globally is Tuberculosis. And immunocompromised patients like renal transplant have even more chances of acquiring T.B compared to general population.Latent T.B is the presence of Mycobacterium organism in the patient with no symptoms and around 10% of such patients have chances to progress to full blown active T.B during their lifetime.
Screening and diagnosis of LTBI
Both donor and recipient should be screened for LTBI and there is no gold standard test available. BTS recommends LTBI screening should be done for patients having risk factors like patients having past history of T.B, diabetes ,history of rejection and taking steroids .However, in areas with low incidence of TB , patients having close contacts with active tuberculosis patients, recent history of travel,drug users, incarcerated persons, and homeless individuals should be screened..According To WHO , : three tests are available: Tuberculin skin test (TST) and interferon gamma release assays (IGRAs) i.e., QuantiFERON1-TB (QFT) Gold Test and T-SPOT .Reliable test in renal transplant patient is IGRA assays. After detailed history and examination, following investigations should be carried out to rule out active T.B and LTBI .Tests include:CBC,CRP,RFTs,LFTs, LTBI test(Quantiferon T.B gold test, TSPOT ),for ruling out active infection -sputum and urine for microscopy for AFB, Gen-expert MTB-RIF assay and culture for M.T.B, Tissue sample for histology and Genexpert-RIF, followed by X-Ray Chest and Ultrasound Abdomen .CT scan ,MRI Abdomen ,PET scan as per requirement.
Treatment of LTBI in donor and recipient
Various treatment options available as mentioned in the WHO 2018 guidelines
1- Isoniazid monotherapy for 6 months
2- Rifampicin plus Isoniazid daily for 3 month
3- Rifapentine and Isoniazid weekly for 3 months
4- For low TB incidence areas: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB
Drug-sensitive and drug resistant active TB disease treatment –similar as in general population and should follow WHO guidelines ,but should be cautious of the drug-drug interactions with the immunosuppression as can have drastic consequences.
Conclusions
In short, renal or any solid organ transplant patients should be thoroughly screened for T.B as timely detection and management can help in reducing the morbidity . mortality and also allograft loss.
level of evidence V-narrative review.
Introduction;
According to WHO 2018 it was estimated more than 1.3 million people,
LTBI 1.7million, up-to 10% develop active TB,
TB is risk is much higher than general population, most of the cases are re-activation of LTBI.
The clinical presentation of TB occurring in transplant recipient is to differ from that in the general population and an increased frequency of extrapulmonary TB is seen.
Screening and diagnosis of LTBI;
There is no gold standard test for diagnosis LTBI, however, WHO recommends these tests,
1. TST, may be unreliable in CKD, and immunocompromissed,
2. IGRA, (QFT, T-SPOT) more specific and high specific in detection.
3. Clinical approach and workup,
A good history,
Constitutional symptoms,
Baseline investigation, microscopy, GeneXpert MTB/Rif Assay.
Imaging.
In low TB endemic countries LTBI screening is recommended with high prevalence of TB, and those with close contacts, drug users, and homeless individuals.
It’s recommended an active TB screening with IGRA for all renal allograft recipient.
Aiming at complete treatment schedule prior to transplantation.
Treatment of LTBI in donor and recipient;
Isoniazid immunotherapy for six months with high and low TB incidence.
Rifampicin plus Isoniazid daily for 3 months as alternate to immunotherapy with age <15 years.
As a preventive RIF + INH weekly for three months in high TB incidence,
Other options with LTBI in countries with low TB incidence as alternatives 6 months INH, or 9 month INH, or 3 months regimen of weekly RIF + INH, or 3 months INH + RIF, or RIF alone.
Treatment of active TB;
According to 2018 guidelines showed be followed for drug sensitive and drug resistant TB disease.
Drug induced toxicity has been major issue in treatment of recipient.
To prevent peripheral neuropathy co-administration of pyridoxine.
Drug interaction with RIF, rifabutin has fewer side effects.
Conclusion;
Transplant recipient has high morbidity and mortality with TB disease.
Due to immunosuppression there is high risk of re-activation of LTBI.
It is highly recommended to screen donor and recipient prior to transplantation.
level of evidence V
Latent tuberculosis infection is defined by the World Health Organisation (WHO) as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB disease’. Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime. The highest risk for developing TB disease occurs when a range of risk factors for re-activation LTBI occur when conditions of immunosuppression are present such as diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients.
The incidence of active TB disease among renal transplant recipients is much higher than in the general population and causes much morbidity and death in these patients. TB is also responsible for loss of the renal allograft (transplanted kidney) in approximately one third of cases. Most of the TB cases in renal transplant recipients are due to re-activation of LTBI in the recipient or from donor kidney.
All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant. There is no gold standard test for diagnosing LTBI accurately. WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs). The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agentes and IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
British Thoracic Society guidelines suggest screening for LTBI where tuberculosis incidence rates are high or in patients with risk factors for developing tuberculosis in low incidence áreas. Various meta-analyses and subsequent guidelines recommend that all renal transplant candidates should be routinely screened for LTBI.
Treatment of LTBI in donor and recipiente
The Consensus Statement from the Spanish Group for the Study of InfectiousDiseases inTransplantRecipientsdefines the indications for treatment of LTBI in SOT recipients and the WHO 2018 guidelines outline the following treatment options for LTBI:
– Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
– Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged < 15 years in countries with a high TB incidence.
– Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
– The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone
Treatment of active TB
Treatment of patients with active tuberculosis detected after renal allograft transplantation remains a challenging task. Hepatotoxicity is a serious dose limiting side effects of both Isoniazid and Rifampicin and this risk is further accentuated in patients with pre-existing liver disease and alcoholics. Peripheral neuropathy caused by Isoniazid can be prevented by co-administration of pyridoxine. Rifampicin interferes with the efficacy of many drugs by interfering with their metabolism. It may not be an ideal choice for patients taking oral contraceptives or HIV-infected individuals on protease inhibitors or non-nucleoside reverse- transcriptase inhibitors. Rifabutin has fewer pharmacologic interactions with antiretroviral agents than Rifampicin and can be used in combination with Isoniazid for the treatment of latent tuberculosis infection.
This is a level 05 – Narrative review.
●All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant.
●WHO recommends three tests for screening for LTBI:
1- Tuberculin skin test (TST)
2- and two interferon gamma release assays (IGRAs) namely,
A- QuantiFERON1-TB (QFT) Gold In-Tube
B- and T-SPOT1T
●IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients
●there are likely to be more false positive, false negative and indeterminate results of IGRAs in transplant recipient
○Rahimifard et al., 2018)study showed A higher rate of LTBI in patients undergoing renal transplantation , using IGRA tests
●In low resource settings, TST continues to be used for diagnosing LTBI
Pathogenetic mechanisms of LTBI and active TB occurrence in renal allograft recipients.
D free of TB ==> R free of TB ==> R free of TB
D previous infected==> R free of TB==> R donor drived infection
D free of TB ==> R previous infected==> R indigenous reactivation
D free of TB ==>R free of TB ==> R De novo infection
M.tb bacilli remain dormant within the transplant kidney for months to years.
Case report
□44 year old man
□endogenous reactivation of LTBI
□right open nephrectomy
□ normal functioning solitary left kidney.
□Three years later, he developed pelvi-ureteric junction stricture and mid ureteric stricture of the solitary left kidney
□active TB was diagnosed.
□Anti-TB treatment
□ percutaneous nephrostomy
□A left open nephrectomy was done and the patient was on maintenance HD for 24 months.
□A live related renal transplantation was subsequently done 2 years later
□ Four years after the transplant, there was a mild and gradual worsening of the renal function
□ biopsy showed evidence of epithelioid granuloma with Langhans giant cells in the graft kidney, suggestive of TB in the renal allograft
●The patient had a symptomatic and biochemical improvement after initiation of anti-TB treatment.
●Various meta-analyses guidelines recommend that all renal transplant candidates should be routinely screened for LTBI (Stagg et al., 2014).
●British Thoracic Society guidelines suggest screening for LTBI where tuberculosis incidence rates are high
patients with risk factors for developing tuberculosis (Horne et al., 2013).
1- Previous rejection episodes,
2- high-dose corticosteroids,
3-diabetes mellitus
4-those living in endemic areas
5- close contacts of patients with active tuberculosis,
6drug users,
7- homeless
●Kowada recommends an active TB screening with IGRA for all renal allograft recipients with individualized risk (Kowada, 2018).
●if there is a need to undergo transplantation, it’s worthwhile to temporarily stop TB treatment intake and recommence the treatment schedule to completion once patients were clinically stable.
Treatment of LTBI in donor and recipient
The Treatment of LTBI should follow WHO 2018 guidelines
the following treatment options for LTBI
●Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
●Rifampicin plus Isoniazid daily for 3 months should be offered as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
●Rifapentine and Isoniazid weekly for 3 months may be offered as preventive treatment for both adults and children in countries with a high TB incidence.
◇The following options are recommended for treatment of LTBI in countries with a low TB incidence
as alternatives to 6 months of isoniazid monotherapy:
◇9 months of isoniazid,
◇or a 3-month regimen of weekly rifapentine plus isoniazid,
◇ or 3–4 months of isoniazid plus rifampicin,
◇or 3–4 months of rifampicin alone.
●There is a need for well-designed prospective controlled cohort trials of short course LTBI treatment regimens in transplant recipients, (efficacy, safety, hepatotoxicity and adherence to treatment.)
Treatment of active TB
●should follow WHO treatment guidelines
●remains a challenging task.
●Hepatotoxicity is a serious dose limiting side effects of both Isoniazid and Rifampicin.
●Peripheral neuropathy caused by Isoniazid can be prevented by co-administration of pyridoxine.
● Rifampicin interferes with the efficacy of many drugs by interfering with their metabolism.
●It may not be an ideal choice for patients taking oral contraceptives or HIV-infected individuals on protease inhibitors or non-nucleoside reverse transcriptase inhibitors.
●Rifabutin has fewer pharmacologic interactions with antiretroviral agents than Rifampicin and can be used in combination with Isoniazid for the treatment of latent tuberculosis infection
Level of evidence V
Introduction: Tuberculosis (TB) is the commonest infectious cause of death. Patent TB infection 9ltbi0 is defined as state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens without evidence of clinically manifest active TB disease. 10% of LTBI lead to active TB disease, especially in presence of risk factors like diabetes, malnutrition, HIV, use of immunosuppressive medications like a transplant recipient. Active TB incidence in kidney transplant recipients (KTRs) is higher than the general population leading to morbidity, mortality, and graft loss. Most cases are due to reactivation of LTBI, or could either donor-derived or a de novo infection. The diagnosis can be missed due to atypical presentation, and more extrapulmonary features.
Screening and diagnosis of LTBI: WHO recommends LTBI testing using tuberculin skin test (TST) and interferon gamma release assays (IGRAs) using either QuantiFERON-TB Gold In-Tube or T-SPOT T tests. IGRAs are more sensitive that TST for LTBI. The diagnostic approach involves history (of TB contact or TB treatment), Symptoms (of chronic cough, night sweats, weight loss and anorexia), clinical examination (for both pulmonary and extrapulmonary TB), investigations (CBC, CRP, LFT, RFT, M.tb microscopy and culture, histology of aspirates and biopsy for acid fast bacilli and granuloma, GeneXpert MTB/RIF assay on sputum, urine, or biopsy), and imaging (chest x-ray, renal ultrasound, MRI, CT or PET-CT, when indicated).
Treatment of LTBI in donor and recipient: The regimens used for LTBI treatment include isoniazid monotherapy for 6 months, 3 months of isoniazid with rifampicin, or 3 months of weekly isoniazid with rifapentine in high-endemicity areas; while for low endemicity regions, isoniazid for 6 or 9 months, 3-4 months of rifampicin, 3-4 months of combination of isoniazid and rifampicin, and weekly isoniazid and rifapentine for 3 months have been recommended. Adverse effects, drug interactions, and longer duration of treatment are the challenges faced during LTBI treatment. Rifabutin can be used in place of rifampicin in transplant recipients.
Treatment of active TB: It involves following WHO guidelines with close monitoring of liver enzymes and other adverse effects as well as looking for drug interactions.
Conclusions: Transplant recipients have increased risk of developing TB due to reactivation of LTBI, a donor-derived infection, or a de novo infection. Proactive TB screening with IGRA and individualized risk assessment is important to diagnose TB/ LTBI, and monitoring of adverse reactions as well as drug interactions during treatment is essential for good patient and graft outcomes.
2. What is the level of evidence provided by this article?
Level of evidence: level 5 – Narrative review.
The incidence of active TB disease among renal transplant recipients is much higher than in the general population
The authors of this paper have tried to address this very important issue of diagnosing and managing latent tuberculosis in transplant population.
Latent tuberculosis infection is defined by the World Health Organisation (WHO) as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’ (WHO, 2018b). Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime.
SCREENING AND DIAGNOSIS OF LATENT TB
The first step is always to take good history, proper physical exam and then relevant lab investigations and imaging.
There is no gold standard test for diagnosing LTBI accurately. WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T (WHO, 2018b). The TST may be unreliable in patients with advanced chronic kidney disease and in those on
immunosuppressive agents.
IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
Treatment of LTBI in donor and recipient
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month
regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB
Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines (WHO, 2017, 2018c). The most important thing is to consider serious interactions of Rifampicin especially with CNIs. It is mandatory that each center should devise there own policies in this regard according to local guidelines.
Narrative review
level of evidence is V
Latent tuberculosis infection and renal transplantation – Diagnosis and management
Introduction
· Tuberculosis (TB) is the most common cause of death from infectious diseases.
· There are about 1.7 billion people worldwide with latent TB.
· WHO definition of LTB: ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB disease’
· Risk factors of activation of LTB: DM, malnutrition, HIV, and biologic and immunosuppressive drugs.
· In recipients, TB increases mortality, morbidity, and graft loss.
· The commonest cause of TB in recipients is the activation of LTB.
· As LTB is asymptomatic, diagnosis and treatment could be challenging.
· Transplant recipient’s clinical presentation is different from the general population and has more incidence of extrapulmonary TB.
Screening and diagnosis of LTBI
· WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon-gamma release assays (IGRAs) namely, QuantiFERON-TB (QFT) Gold In-Tube and T-SPOT T
· TST could be unreliable in advanced CKD and in those immunosuppressed patients.
· IGRAs are more specific to M.tb antigens and are highly specific in LTBI in immunosuppressed patients
· transplant recipients have falser positive, falser negative and indeterminate results of IGRAs
· IGRAs found to be more sensitive than the TST for the diagnosis of LTBI in renal transplant candidates.
Treatment of LTBI in donor and recipient
· Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
· Rifampicin plus Isoniazid daily for 3 months is an alternative as preventive treatment for children and adolescents (<15 y) in countries with a high TB incidence.
· Rifapentine and Isoniazid weekly for 3 months is an alternative as preventive treatment for both adults and children in countries with a high TB incidence.
· Treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy:
1) 9 months of isoniazid,
2)or a 3-month regimen of weekly rifapentine plus isoniazid,
3)or 3–4 months of isoniazid plus rifampicin,
4)or 3–4 months of rifampicin alone.
Treatment of active TB
· should follow WHO treatment guidelines (
· Isoniazid and Rifampicin have hepatotoxicity limiting its use.
· Peripheral neuropathy caused by Isoniazid can be prevented by co-administration of pyridoxine
· Rifampicin has many drug-drug interactions, while Rifabutin has fewer interactions
Conclusions
· TB is a serious complication in renal transplant recipients and increases morbidity and mortality.
· Immunosuppression increases the risk of activation of LTBI
· All donors and recipients should be screened for LTBI and active TB disease prior to transplant.
· Increased awareness of the possibility of TB in renal transplant recipients may lead to early diagnosis and treatment, which may reduce graft loss.
This is a narrative review with evidence V.
In this article, published in 2019, the authors have used a combination of a single database search (PubMed) in addition to specialist society guidelines in order to evidence a brief overview of the role of latent mycobacterium tuberculosis infection (LTBI) in renal transplant recipients. The authors detail the search terms used but do not provide detailed analysis of their search results/selection process: an assessment of the comprehensiveness of the overview in relation to available published research is not possible and as such the article stands more as an opinion piece aiming to give the reader a broad understanding of the relevant issues.
The authors highlight estimates that globally 1.7 billion people have LTBI. Up to 10% of this LTBI group will develop active TB at some point, with immunosuppression being a significant risk factor for this. This demonstrates how the transplant population are specifically at higher risk of this compared to the general population.
The authors explain the 4 ways in which renal transplant recipients may be affected by TB:
i) transmission of TB from donor kidney
ii) endogenous reactivation of latent TB (LTBI)- commonest
iii) de novo TB infection post transplantation – with risk of quick progression to miliary TB due to immunosuppression
iv) loss of renal allograft due to TB
In the article they then go on to explore TB in renal transplant recipients in relation to 3 areas:
– Prevention
– Diagnosis
– Management
Prevention of TB in renal transplant recipients
· Ideally, all renal transplant recipients and potential donors should undergo screening for LTBI and active TB, although in low TB endemic countries an assessment may be made based upon specific risk factors
· Screening is very important as management at this stage is associated with better outcomes than if the patient develops active TB post transplantation – patients found to have LTBI should complete a course of anti-TB treatment while they are on the waiting list
Diagnosis of LTBI
· Available screening tests: Tuberculin skin test (TST), Quantiferon-TB Gold and T-SPOT (with the latter 2 tests being preferable particularly in those with advanced CKD or on immunosuppression due to higher sensitivity, although TST may be used in lower resource settings)
· Screening tests should be utilised alongside full clinical assessment including history (particularly of contacts with active pulmonary TB or previous TB treatment), symptoms, blood tests and imaging to include CXR and renal ultrasound scan
Management of LTBI and active TB in potential renal transplant recipients
· As above, the recommendation is to diagnose and treat TB prior to transplantation wherever possible
· WHO 2018 guidelines are used to guide the treatment of LTBI. Depending on the incidence rate of TB in the country and age of the patient this could be
– 6 month course isoniazid
– 3 month course of isoniazid + rifampicin
– 6 month course rifapentine and isoniazid
– 4 month course rifampicin alone
· WHO 2018 guidelines should also be used to treat any active TB infection detected in a potential renal transplant recipient
· For those patients in whom active TB is diagnosed post-transplantation the management of this is challenging for several reasons: the patient may develop more widespread/severe disease due to their immunosuppressed state and additionally there are some very significant interactions between anti-TB medications and immunosuppressive agents (particularly rifampicin and CNIs)
Level of evidence:
This article should be considered as level 5 evidence which is usually expert opinion. The authors have referenced relevant guidelines and research throughout the piece but there is no comprehensive search methodology and this could therefore have resulted in significant bias in which references the authors chose to include. Although overall this makes it a lower quality evidence in terms of reliability, it provides a succinct overview of the topic for the reader highlighting key areas and acknowledging gaps in current research in this area.
Summary
Tuberculosis (TB) remained one of the important infectious diseases associated with high mortality with an estimated death rate according to the WHO data of 1.3 million recent data confirm an increasing rate of LTBI in the range of 1.7million latent tuberculosis according to the WHO definition referred to the state of persistent immune response to MTB with no clinical evidence of active disease however over time there is about 10% risk of progression to active TB disease, especially with the impaired immune response with Malnutrition, HIV, immunosuppression therapy with a biological agent after transplantation, post-renal transplantation recipients at risk of reactivation of LTBI and its the most common cause of active TB after SOT, with high mortality rate and lower graft survival. One of the challenges of post-transplantation MTB infection is the nonspecific or atypical presentation and can easily be missed if not keep a high index of clinical suspicion especially if the donor or recipients are from an endemic area or have previous history of TB or LTBI diagnosis with a late intervention, extrapulmonary TB is more common after transplantation, this review article addresses the challenges with the diagnosis, prevention, and treatment of MBT after kidney transplantation.
Screening and diagnosis of LTBI
All renal transplant recipients and donors should undergo screening for LTBI and active TB disease as part of the transplant workup. There is no gold standard test for
diagnosing LTBI accurately.
Screening for LTBI includes TUBERCULIN SKIN TEST ( TST), IGRA test, or QuantiFERON1-TB (QFT)
Gold In-Tube and T-SPOT1 (WHO 2018).
The limitation with TST in CKD, hemodialysis patients and on IS , IGRA test more specific forLTBI screen and sometimes combination of both can increased the sensitivity of the assay.
Diagnosis of LTBI reactivation or active TB after transplantation including denovo MTB or extra pulmonary TB depends on history or previous exposure or close contact , donor from endemic area or treated on line of LTBI or active infection, social history and physical examination for pulmonary and extrapulmonary manifestations , symptoms of wt loss , night sweat and chronic cough, Images including CXR , CT , abdominal images and finally microscopic examination for AFB and cultures for MTB , tissue biopsy to confirm the diagnosis , gen expert for MTB
Treatment of LTBI in Donor and recipient
1 Isoniazid monotherapy for 6 months is recommended for both adults and children in countries with
high and low TB incidence.
2. Rifampicin plus Isoniazid daily for 3 months as an alternative to 6 months of isoniazid monotherapy as
Preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
1. Rifapentine and Isoniazid weekly for 3 months. preventive treatment for both adults and children in countries
with a high TB incidence.
5.9 months of isoniazid, or a 3-month no agreement about the total duration of treatment
Treatment of active MBT
Treatment of drug-sensitive and drug-resistant active TB disease in renal transplant recipients should follow WHO treatment
guidelines (WHO, 2017, 2018c).
What is the level of evidence provided by this article?
Review article, narrative review level V of evidence
Latent tuberculosis infection is defined by the World Health Organisation (WHO) as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB disease.Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime.
The incidence of active TB disease among renal transplant recipients is much higher than in the general population and causes much morbidity and death in these patients . TB is also responsible for loss of the renal allograft (transplanted kidney) in approximately one third of cases.
Screening and diagnosis of LTBI:
WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) , QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1
The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agents . IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
A higher rate of LTBI was found in patients undergoing renal transplantation than those undergoing other organ transplantation, especially when IGRA tests were used compare to the TST. Thus IGRAs (both QFT and T-SPOT) have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
Treatment of LTBI in donor and recipient:
The WHO 2018 guidelines outline the following treatment options for LTBI
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Level of Evidence V
The highest risk for developing TB disease occurs when a range of risk factors for re-activation LTBI occur when conditions of immunosuppression are present such as diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients
Prior to transplant, all kidney transplant patients and their donors should be screened for LTBI and active TB disease. The Tuberculin Skin Test (TST) and two interferon gamma release assays (IGRAs), QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T, are the three tests that the WHO advises for LTBI screening.
IGRAs have a good specificity for LTBI detection in immunosuppressed patients and are more specific to M.tb antigens.
Treatment of LTBI in donor and recipient
* Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
* Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
* Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
* The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB
Should follow WHO guidelines. Treatment of patients with active tuberculosis detected after renal allograft transplantation remains a challenging task.
Level of Evidence V
LTBI
Active TB is more common in KT than general population
TB in KT patient causes graft loss in 1/3 cases
Most TB in KT is due to inactivation of latent TB
LTBI is cryptic and diagnosis is difficult so AWARENESS of LTBI is teh key
Recipient and donor should ne screened for LTBI and active TB
DIAGNOSIS OF LTBI
TST – skin test may not be reliable in advanced ESRD and patient on IS
IGRA- interferon gamma release assay – QUANTIFERON TB GOLD , AND T SPOT
LTBI is more common in KT than other SOT
IGRA is more sensitive that TST
who need screening ?
endemic area – all potential recipients and donors ,
non endemic are – those with history of contact , high dose steroid, homeless , drug user , incarcerated person , recently arrived foreign born person
Patients with positive LTBI can be started on treatment while waiting for transplant
how to screen ?
history and physical exam
CXR
Blood test ,CBC WITH ESR , LFT RENAL PROFILE
USG OF KIDNEYS
Sputum AND URINE AFB SMEAR AQND CULTURE
GENXPERT ABD RIF ASSAY ON SPUTUM BIOPSY URINE
TST
IGRA
IMAGING – MRI/CT OR PET SCAN IF INDICATED
MANAGEMNET
LTBI
INH DAILY 6 MONTH
INH AND RIFAMPICIN DAILY 3 MONTHS IN LESS THAN 15 YRS PATINETS
REFAPETINE AND INH WEEKLY FOR 3 MONTHS
IN LOW ENDEMIC AREA – less intense course can be given
ACTIVE TB
follow national guideline or WHO guideline
like general population with TB
Challenges – hepatotoxicity is high
rifampicin causes low level of IS while INH causes high level of IS
GOAL is to adhere to standard regime and complete the course while maintaining adequate IS
CONCLUSION
KT is done globally in area endemic for TB
Aim is identify LTBI and treat adequately
High degree of awareness is the key
Latent tuberculosis infection and renal transplantation Diagnosis and management
The incidence of active TB disease among renal transplant recipients is much higher than in the general population and causes much morbidity and death in these patients .
TB is also responsible for loss of the renal allograft (transplanted kidney) in approximately one third of cases. Most of the TB cases in renal transplant recipients are due to re-activation of LTBI in the recipient or from donor kidney.
The diagnosis and treatment of LTBI and active TB disease in donors and transplant recipients can be quite challenging since the presentation is cryptic with non-specific symptoms and signs, and the diagnosis can easily be missed unless there is a high degree of awareness of the possibility of TB. The clinical presentation of TB occurring in transplant recipients is said to differ from that in the general population and an increased frequency of extrapulmonary TB is seen.
Screening and diagnosis of LTBI
There is no gold standard test for diagnosing LTBI accurately. WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1 -TB (QFT) Gold In-Tube and T-SPOT 1 T (WHO, 2018b). The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agents (Guirao-Arrabal and TorreCisneros, 2018). IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients (Pai et al., 2014; Guirao-Arrabal and Torre-Cisneros, 2018). There are scanty data on the sensitivities and specificities of IGRAs and TST in screening for LBI in renal transplant recipients.
Thus IGRAs (both QFT and T-SPOT) have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
Treatment of LTBI in donor and recipient
Every effort must be made to diagnose and treat LTBI and active tuberculosis in bothlivedonorandrecipientbeforetransplantation.TreatmentofLTBI should follow WHO 2018 guidelines
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB
Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines (WHO, 2017, 2018c). Treatment of patients with active tuberculosis detected after renal allograft transplantation remains a challenging task.
Adherence to one specific standardized regime, completion of the recommended duration of the regime and a close monitoring and early identification of the adverse effects of the drugs would greatly enhance the effectiveness of treatment against LTBI.
Conclusions
Renal transplantation is now widely available globally. TB is a serious complication in renal transplant recipients and causes much morbidity and mortality. Due to immunosuppression, transplant recipients are at a higher risk of re-activating LTBI from within themselves or from the transplanted donor kidney. Several guidelines are available and are consistent in recommending that all donors and recipients are routinely screened for LTBI and active TB disease prior to transplant whenever possible. A high degree of awareness of the possibility of TB is required in all renal transplant patients so that it can be diagnosed and treated early, reducing the risk of loss of allograft.
Level of evidence V
LTBI AND RENAL TRANSPLANTATION – DX AND MGT.
INTRODUCTION.
Estimated 1.7 billion people have LTBI with aprox 10% developing TB in their lifetime.TB estimated to cause graft loss in 1/3 of cases.
SCREENING AND DX OF LTBI.
Who recommendation for LTBI screening ;TST,IGRA(Quantiferon TB and T spot).TST is less sensitive in CKD and Immunosuppressed. IGRAs are more sensitive in immunosuppressed pts and pre transplant pts.
TX OF LTBI IN DONOR AND RECIPIENTS.
WHO 2018 Guidelines recommended;
TX OF ACTIVE TB.
Who guidelines should be adhered to.SE and DI should be carefully factored in. Each transplant center should develop local guidelines to guide treatment of LTBI and active TB.
LEVEL OF EVIDENCE – V
Introduction
● Tuberculosis (TB) is the commonest infectious disease cause of death worldwide
● TB is a serious complication in renal transplant recipients and causes much morbidity and mortality
● Latent tuberculosis infection is defined as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’
● Up to 10% of people with LTBI will progress to developing active TB
● The highest risk for developing TB disease accociated with diabetes,HIV, malnutrition, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients
● The incidence of active TB disease among renal transplant recipients is much higher than in the general population
● Most of the TB cases in renal transplant recipients are due to re-activation of LTBI in the recipient or from donor kidney TB or acquiring new M.tb infection
● Living donors who were born and live in high TB endemic countries and migrated to low TB endemic areas may have higher rates of LTBI.
● Presentations of TB in recipients differs from that in the general population with increased frequency of extrapulmonary TB
Screening and diagnosis of LTBI
● All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant.
● Tests recommended for screening LTBI:
☆ TST
☆ IGRAs
☆ QuantiFERON1-TB (QFT)
● The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agents
● IGRA is more specific to MTB antigens and offer high specificity in detecting LTBI in immunosuppressed patients
● A higher rate of LTBI was found in patients with renal transplantation than those with organ transplantation
● Posttransplant TB was more common in renal recipients than in liver transplant
● The M.tb bacilli remain dormant within the transplant kidney for months to years.
● Reactivation of LTBI to active TB disease occures due to IS therapy
Clinical workup of donors and transplant recipients to screen for LTBI and active TB:
☆ History: contact with patient with active pulmonary TB or previous TB treatment
☆ Symptoms: chronic cough, night sweats,
anorexia, weight loss.
☆ Full clinical examination
☆ Investigations: CBC, CRP, GFR, LFT, microscopy (AFB) and culture for MTB ( sputum , urin )
☆ Histology of biopsy and aspirates
☆ GeneXpert MTB/Rif assay
☆ TST , IGRA test
☆ Chest X ray
☆ Renal ultrasound
☆ MRI or CTscan
☆ PET/CTscan
● All renal transplant candidates should be routinely screened for LTBI
● Risk factors for developing TB in low
incidence areas
☆ History of TB
☆ Previous rejection episodes
☆ High-dose corticosteroids
☆ Diabetes mellitus
☆ Those living in endemic areas
● Risk factors for progression from LTBI to active disease:
☆ Close contacts with active tuberculosis
☆ Recently arrived foreign-born persons
☆ Drug users
☆ Incarcerated persons
☆ Homeless individuals
LTBI screening in immunosuppressed individuals and those undergoing SOT
☆ Chest X-ray
☆ History of previous exposure to patients with TB
☆ Risk factor assessment for travel or migration from endemic areas
Treatment of LTBI in donor and recipient
● Isoniazid monotherapy for 6 months in both adults and children in countries with
high and low TB incidence.
● Alternative therapy in high TB incidence:
☆ Rifampicin plus Isoniazid daily for 3 months In patients aged <15 years
☆ Rifapentine and Isoniazid weekly for 3 months in both adults and children
● Alternative therapy in lowTB incidence:
☆ 9 months of isoniazid
☆ a 3-month of weekly rifapentine plus isoniazid
☆ 3–4 months of isoniazid plus rifampicin
☆ 3–4 months of rifampicin alone.
Treatment of active TB
● Should follow WHO guidelines
● Serious dose limiting side effects
☆ Hepatotoxicity
☆ Peripheral neuropathy
☆ Rifampicin interferes with the efficacy of many drugs
☆ Rifabutin has interactions with antiretroviral agents less than Rifampicin
● Level : 5
Summary:
Introduction:
Tuberculosis (TB) continues to be the commonest infectious disease cause of death worldwide. Tuberculosis is an important infectious disease cause of morbidity and death in renal transplant recipients. Tuberculosis can also cause loss of kidney allograft. The purpose of this viewpoint is to highlight the issues related to prevention, diagnosis and treatment of tuberculosis in renal transplant recipients.
Methods:
The PubMed database was searched for publications and guidelines on diagnosis and management of LTBI in renal transplantation. Publications on renal allograft recipients with LTBI and TB in post-operative period were also analysed. Specialist Society guidelines were also used.
Findings:
Tuberculosis is one of the most important infectious disease-related causes of morbidity and death in transplant recipients. LTBI in allograft recipients continues to be a clinical management problem. It can occur either from donor kidney or from endogenous reactivation of latent tuberculosis infection or from acquiring new Mycobacterium tuberculosis infection. Tuberculosis can also cause loss of kidney allograft.
Clinical workup of donors and transplant recipients to screen for LTBI and active TB:
· History: contact with an index case of TB and previous history of TB treatment.
· Symptoms: includes cough, fever, weight loos, drenching night sweat and anorexia.
· Examination: to look for signs of active TB and exclude extrapulmonary TB.
· Investigations: FBC, CRP, renal function test and liver function test. Microscopy (acid fast bacilli) and culture for MTB (sputum and early morning urine samples). Histology of biopsy and aspirate (acid fast bacilli and granuloma).
GeneXpert/RIF assay (on sputum, urine and biopsy)
· Test for LTBI includes tuberculin skin testing and or/ IGRA (either TSPOT.TB or QuantiFERON).
· Imaging such as chest x ray, renal scan, CT or MRI (where indicated), PET/CT SCAN may also be done as required.
Treatment of LTBI in donor and recipients
The WHO 2018 guidelines outline the following treatment options for LTBI (WHO, 2018b).
· Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
· Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
· Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
· The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB
This should follow the WHO guidelines while paying attention to drug interactions and risk of toxicity. Adherence and completion of treatment should be emphasized.
Conclusions: Kidney transplantation is now universally performed in high and low Tuberculosis endemic countries. A high index of awareness of the possibility of TB disease or LTBI is required prior to renal transplant aligned to reduce renal allograft damage, morbidity and death due to tuberculosis. WHO Management recommendations for LTBI screening and treatment should be followed.
Level of evidence – Level V
Summary
Latent tuberculosis infection and renal transplantation – Diagnosis and management
Latent tuberculosis infection is a state of persistent immune response to stimulation by Mycobacterium tuberculosis (MTB) antigens with no evidence of clinically manifest active TB disease. Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime.
Risk factors for re-activation LTBI are diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients.
Most of the TB cases in renal transplant recipients are due to re-activation of LTBI in the recipient or from donor kidney.
Living donors who were born and lived in high TB endemic countries and migrated to low TB endemic areas may have higher rates of LTBI.
Screening and diagnosis of LTBI
WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T
IGRAs are more specific to MTB antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
A higher rate of LTBI was found in patients undergoing renal transplantation than those undergoing other organ transplantation.
IGRAs (both QFT and T-SPOT) have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
Posttransplant TB was more common in renal recipients than in liver transplant patients.
LTBI in a recipient that has gone undiagnosed during pre-transplant evaluation, which either continues to persist as LTBI or may undergo endogenous reactivation in the post-transplant period and in some cases is a scenario where both the donor and the recipient have been free from disease. The post-transplant period also has been uneventful until the recipient gets exposed to MTB bacilli and develops denovo LTBI
Various meta-analyses and subsequent guidelines recommend that all renal transplant candidates should be routinely screened for LTBI
British Thoracic Society guidelines
Suggest screening for LTBI where tuberculosis incidence rates are high or in patients with risk factors for developing tuberculosis in low incidence areas.
Those with epidemiologic risk factors such as history of TB, previous rejection episodes, high-dose corticosteroids, diabetes mellitus and those living in endemic areas need to be evaluated with chest radiography and other screening tests as part of the screening for latent tuberculosis.
In low TB endemic countries, LTBI screening is recommended for population subgroups with a high prevalence of TB or those with a high likelihood of progression from LTBI to active disease. These include close contacts of patients with active tuberculosis, recently arrived foreign-born persons, drug users, incarcerated persons, and homeless individuals and were advised screening for LTBI
Chest X-ray, detailed background history of previous exposure to patients with TB and risk factor assessment for travel or migration from endemic areas was the most frequent recommendation for LTBI screening in immunosuppressed individuals and those undergoing Solid Organ Transplant (SOT)
Treatment of LTBI in donor and recipient
The WHO 2018 guidelines outline the following treatment options for LTBI
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid
Treatment of active TB
Treatment of latent tuberculosis infection. Adherence to one specific standardized regime, completion of the recommended duration of the regime and a close monitoring and early identification of the adverse effects of the drugs would greatly enhance the effectiveness of treatment against LTBI.
Conclusion
A high degree of awareness of the possibility of TB is required in all renal transplant patients so that it can be diagnosed and treated early, reducing the risk of loss of allograft.
Level of evidence is – level 5 review
Introduction:
TB is the commonest infectious disease cause of death worldwide.
Latent tuberculosis infection is define BY WHO as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’.
10% of people with LTBI will progress to developing active TB.
Immunosuppression RISK:
Diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies.
Most of the TB cases in renal transplant recipients are due to re-activation of LTBI in the recipient or from donors.TB can also occur due to increased susceptibility to acquiring new M.tb infection which rap rapidly progresses to miliary TB because of immunosuppressive therapy.
Screening and diagnosis of LTBI:
WHO recommends three tests for screening for LTBI?
Tuberculin skin test (TST).
Two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube
And T-SPOT1 T.
IGRAs (both QFT and T-SPOT) have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
In low resource settings, TST continues to be used for diagnosing LTBI
All renal transplant candidates should be routinely screened for LTB.
British Thoracic Society guidelines suggest screening for LTBI where tuberculosis incidence rates are high or in patients with risk factors for developing tuberculosis in low incidence areas.
Similarly those with epidemiologic risk factors such as history of TB, previous rejection episodes, high-dose corticosteroids, diabetes mellitus and those living in endemic areas need to be evaluated with chest radiography and other screening tests as part of the screening for latent tuberculosis.
TB endemic countries,
High likelihood of progression from LTBI to active disease:
These include close contacts of patients with active tuberculosis, recently arrived foreign-born persons, drug users, incarcerated persons, and homeless individuals and were advised screening for LTBI (
Chest X-ray, detailed background history of previous exposure to patients with TB and risk factor assessment for travel or migration from endemic areas was the most frequent recommendation for LTBI screening in immunosuppressed individuals and those undergoing Solid Organ Transplant.
Treatment of LTBI in donor and recipient:
The WHO 2018 guidelines outline the following treatment options for LTBI (WHO, 2018b):
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged LESS THAN 15 IN AREA WITH HIGH INCIDENCE.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy:
9 months of isoniazid, or a 3-month
Regimen of weekly Rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB:
Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines (WHO, 2017, 2018c).
Conclusions:
Renal transplantation is now widely available globally.
A high degree of awareness of the possibility of TB is required in all renal transplant patients so that it can be diagnosed and treated early, reducing the risk of loss of allograft.
Level of evidence V.
IV. Latent tuberculosis infection and renal transplantation – Diagnosis and management
Summarise the article
Objectives
– To underscore the issues related to prevention, diagnosis and treatment of TB in kidney transplant recipients
Methods
– literature search on PubMed for publications and guidelines on diagnosis and management of LTBI in kidney transplantation
Introduction
– TB is an important infectious disease in kidney transplant recipients and it is associated with significant morbidity and mortality. It also causes graft loss in approximately 30% of the cases.
– LTBI is defined as a state of persistent immune response stimulation by M.tb antigens without any evidence of clinically manifest active TB disease
– 10% of people with LTBI develop active TB during their lifetime
– reactivation of LTBI portends the highest risk for developing TB
– risk factors for LTBI reactivation include diabetes, HIV, malnutrition, previous history of TB, biologics, immunosuppressive agents including antirejection treatment in SOT recipients
– other risk factors include exposure to active disease, drug users, incarcerated persons, homeless people
– incidence of active TB disease is higher among kidney transplant recipients (KTRs) than in the general population
– most of the cases of TB among KTRs are due to reactivation of LTBI or from the donor kidney
– TB can also occur following de novo acquisition of new M.tb infection which progresses to miliary TB due to exposure to immunosuppressive therapy
– diagnosis and treatment of LTBI and active TB disease in KTRs remains a challenge due to the atypical presentation and an increased frequency of extrapulmonary TB (EPTB)
– a high index of suspicion is thus required in this population of patients
Screening and diagnosis of LTBI
– all kidney transplant recipients and donors should be thoroughly screened for LTBI and active TB disease
– there is no gold standard screening test for LTBI diagnosis
– the WHO recommended screening tests for LTBI include TST and two IGRAs i.e., Quantiferon-TB (QFT) Gold In-Tube and T-SPOT
– TST is not reliable in patients with advanced CKD and in patients on immunosuppressive therapy
– IGRAs offer high specificity in detection of LTBI in immunosuppressed patients and are more specific to the M.tb antigens
– among kidney transplant candidates, IGRAs are more sensitive than TST in the diagnosis of LTBI
– chest radiographs should be part of the screening tools for LTBI
– initiate LTBI treatment prior to kidney transplantation
Treatment of LTBI in the donor and recipient
– Treatment options include: –
– shorter courses of treatment are preferred to ensure treatment adherence given the adverse events and drug interactions associated with these drugs
Treatment of active TB
– WHO guidelines should be followed
– treatment of active TB post-kidney transplantation remains a challenge
– hepatotoxicity is a major adverse effect associated with rifampicin and isoniazid
– isoniazid should be co-administered with pyridoxine to prevent peripheral neuropathy
– rifampicin is a potent CYP3A4 inducer therefore it interacts with many drugs affecting their metabolism
– rifabutin is a weaker CYP3A4 inducer hence is associated with fewer pharmacologic interactions
Conclusion
– kidney transplantation is now widely available
– TB is a common infectious disease among KTRs an is associated with significant morbidity and mortality
– due to the degree of immunosuppression, KTRs are at a higher risk of endogenous LTBI reactivation (i.e., LTBI reactivation within themselves) or donor-derived TB (from the transplanted donor kidney)
– all transplant recipients and donors should be screened for LTBI and active TB disease prior to kidney transplantation
– a high index of suspicion for active TB or LTBI is required to allow for timely diagnosis and treatment so as to reduce the risk of graft loss, morbidity and mortality associated with TB
Level of evidence provided by this article
– Level V
Introduction:
10% of LTBI patients will acquire active TB during their lifetime. When immunosuppression is present, such as in diabetes, malnutrition, HIV, and transplant patients using biologics immunosuppressive drugs, TB infection is most possible to occur.
Renal transplant recipients have a significant rate of active TB illness, which can cause graft loss & can spread to miliary TB rapidly.
Screening & diagnosis:
Prior to transplant, both recipients and donors of renal transplants should be screened for Latent and active TB.
WHO recommends the Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs), QuantiFERON Gold and T-SPOT TB, for screening for LTBI.
In individuals with severe chronic kidney disease and those using immunosuppressive drugs, the TST may be inaccurate.
IGRAs are more specific to M.tb antigens and have a higher level of specificity for detecting LTBI in immunocompromised patients.
In situations with limited resources, the TST is still used to diagnose LTBI.
Clinical workup of donors and transplant recipients to screen for LTBI and active TB:
Hx:
– Hx of previous TB ttt
– Hx of contact to a case of active pulm.TB
Symptoms:
– Fever, night sweets, wt loss or chronic cough
Investigations:
– CBC with differential
– CRP
– RFTs&LFTs
– Microscopy for acid fast bacilli & culture for M.tb in sputum & early morning urine sample
– Histology of aspirate or biopsy (acid fast bacilli & granuloma)
– GeneExpert MTB/Rif assay on urine, sputum or biopsy
Test for LTB:
– TST
– IGRAs (quantiferon/Tspot TB)
Radiological:
– CXR
– US
– CT
– PET CT
Treatment of LTBI in donor and recipient:
The WHO 2018 guidelines outline the following treatment options for LTBI
– Isoniazid monotherapy for 6 months is recommended for
treatment of LTBI in both adults and children in countries with
high and low TB incidence.
– Rifampicin plus Isoniazid daily for 3 months should be offered as
an alternative to 6 months of isoniazid monotherapy as
preventive treatment for children and adolescents aged
<15 years in countries with a high TB incidence.
– Rifapentine and Isoniazid weekly for 3 months may be offered as
an alternative to 6 months of Isoniazid monotherapy as
preventive treatment for both adults and children in countries
with a high TB incidence.
– The following options are recommended for treatment of LTBI in
countries with a low TB incidence as alternatives to 6 months of
isoniazid monotherapy: 9 months of isoniazid, or a 3-month
regimen of weekly rifapentine plus isoniazid, or 3–4 months of
isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
conclusion:
Renal transplant recipients’ TB complications are serious. Immunosuppression increases the likelihood of LTBI reactivation in transplant recipients or donor.
Many guidelines recommend screening donors and recipients for LTBI and active TB before transplantation. All kidney transplant patients must be aware of TB so it can be recognized and treated early to reduce allograft loss.
> level of evidence:
level 5, a narrative review
IV. Latent tuberculosis infection and renal transplantation – Diagnosis and management:
1. Summarise this article.
2. What is the level of evidence provided by this article?
1) Summary of this article:
Introduction:
Tuberculosis (TB) is the commonest infectious disease worldwide.
WHO (Definition of latent tuberculosis infection):
A state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically active TB disease
The prevalence of active TB is significantly higher in SOT than general population.
It is estimated that around 1.7 billion people are suffering from latent TB worldwide.
10 % of patients with latent TB can develop active TB during their lifetime if they are immunosuppressed.
Causes of TB in recipients mostly due to re-activation of LTBI or from donor kidney or new infection.
Clinical presentation of TB in renal transplant is differ from that in the general population and needs high degree of awareness of Suspicion.
Risk factors for re-activation LTBI include:
DM, malnutrition, HIV, and immunosuppression’s
Active TB in renal transplant recipients is higher than general population and causes morbidity and death with allograft loss.
Mode 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 recipient.
All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant.
There is no gold standard test for diagnosing LTBI accurately.
WHO recommends three tests for screening for LTBI:
Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1, both are usually negative in immunosuppressed patients due to their dependence on the host immune response, which is impaired in these sets of patients,
The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agents.
In SOT candidates with ESRD or advanced liver disease, it is preferred to use IGRA over TST due to its higher sensitivity in these sets of patients.
IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
Thus IGRAs (both QFT and T-SPOT) have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
So, all recipients and donors should both be undergoing careful evaluation of the risk, history, examination and CXR, together with test for latent TB.
All transplant recipients and donors should have thorough history taking and CXR.
Renal transplant recipients should have no symptoms, CXR should be normal and no evidence of exra-pulmonary TB to settle the diagnosis of latent TB.
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
A Summary of the diagnostic approach for detection of active and latent TB:
History: Contact with patient with active TB, Previous TB treatment
Symptoms: Chronic cough, night sweats, weight loss, Hemoptysis
Clinical examination: Pulmonary/ extra pulmonary TB
Lab: CBC, CRP, ESR, RFT/LFT, Microscopy and culture of TB, Histology of biopsy and aspirate, GeneXpert MTB
Tests for LTBI: TST, GRA
Imaging: Xray chest, Renal ultrasound, MRI/CT/ PET scan (if indicated)
Risk Factors:
History of TB, DM, previous rejection episodes, high-dose corticosteroids, and those living in endemic areas need to be evaluated with chest radiography and other screening tests as part of the screening for latent tuberculosis.
Pathogenesis of LTBI in post-transplant recipients:
No donor or recipient TB: allograft free of TB
Donor TB/recipient free: donor derived TB
Recipient TB/donor free: endogenous recipient re-activation
No donor or recipient TB: denovo recipient infection
LTBI screening: (BTS ):
Areas of high incidence of TB
High risk of TB in low incidence areas (contact with active TB, recently arrived from travel abroad, drug users, incarcerated persons, alcohol abuse or injection drug use, and homeless)
In low TB endemic countries, LTBI screening is recommended for population subgroups with a high prevalence of TB or those with a high likelihood of progression from LTBI to active disease.
These include close contacts of patients with active tuberculosis, recently arrived foreign-born persons, drug users, incarcerated persons, and homeless individuals and were advised screening for LTBI.
Chest X-ray, detailed background history of previous exposure to patients with TB and risk factor assessment for travel or migration from endemic areas was the most frequent recommendation for LTBI screening in immunosuppressed individuals and those undergoing Solid Organ Transplant (SOT).
Treatment of LTBI in donor and recipient (WHO 2018 guidelines):
Isoniazid mono-therapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Patient 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.
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid mono-therapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid mono-therapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid mono-therapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB:
Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guideline.
It is challenging treatment after transplant:
Hepatotoxicity (rifampicin and isoniazid)
Peripheral neuropathy (isoniazid)
Rifampicin (interactions with oral contraceptives, antiretrovirals)
Enhance effectiveness of treatment:
Adherence to one specific regimen
Completion of the recommended duration
Close monitoring and early identification of adverse effects
Conclusions:
TB is a serious complication in renal transplant recipients and causes much morbidity and mortality.
Transplant recipients are at a higher risk of re-activating LTBI from within themselves or from the transplanted donor kidney, due to immunosuppression causing mortality and morbidity, in addition to allograft loss.
Several guidelines are available and are consistent in recommending that all donors and recipients are routinely screened for LTBI and active TB disease prior to transplant whenever possible.
A high degree of awareness of the possibility of TB is required in all renal transplant patients so that it can be diagnosed and treated early, reducing the risk of loss of allograft.
What is the level of evidence provided by this article?
A narrative review ==> level of evidence V
Summary of Latent tuberculosis infection and renal transplantation – Diagnosis and managementIntroduction
Up to 10% of people with LTBI will progress to develop active T.B diseases, a high risk to develop T.B disease in presence of DM, malnutrition,HIV , biological agent, and immunosuppression agent in transplant patients.
The diagnosis and treatment of LTBI and active TB disease in donors and transplant recipients can be quite challenging since the presentation with non specific symptoms and signs and diagnosis easily be missed unless there is a high degree of awareness of the possibility of T.B .
Screening and diagnosis of LTBI:
There is no gold standard test for the diagnosis LTBI accurately.
WHO recommended 3 tests for screening for LTBI : a tuberculin skin test and 2 IGRAs.
TST is unreliable in patients with advanced CKD and in those on immunosuppression agents .IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI immunosuppressed patients .there are scanty data on the sensitivity and specificity of IGRAs and TST in screening for LTBI in the renal transplant recipient.
Guidelines recommended renal transplant candidates should be routinely screened for LTBI .
If the donor has epidemiological risk factors such as DM, previous rejection, high dose steroid needs to be evaluated with CXR and another screening test.
Kowada recommends an active T.B screening with IGRA for all renal allograft recipients with individual risk assessment of each of the patient during LTBI treatment
Diagnosis and treat LTBI and active T.B in both live donor and recipient before transplantation is crucial.
Treatment of LTBI should follow WHO 2018guidlines :
INH for 6 month
Rifampicin plus INH for 3 months
Rifapentine and INH weekly for 3 month
Treatment of active T.B
Following WHO 2018 guidelines treatment of patients with active T.B after renal transplant is challenging:
1-hepatotoxicity 2- interference of rifampicin with IS 3- adherence to the anti T.B regimens.
Conclusion
High risk of reactivation LTBI from themselves or from transplant donor kidney results from IS.
Guidelines recommended that all donors and recipients are routinely screened for LTBI and active T.B disease prior to transplant whenever possible .high degree of awareness of the possibility of T.B is required in all renal transplant patients so can be diagnosed and treated early reducing the risk of loss of allograft
level evidence 5
Introduction Tuberculosis:
Latent tuberculosis infection is defined as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (TB) which is the commonest infectious disease cause of death worldwide . Latent Mycobacterium tuberculosis infection (LTBI)affects 1.7 billion people worldwide
.
The incidence of active TB disease among renal transplant recipients is much higher compared with the general population; it causes increased morbidity and mortality in these patients .
Commonly caused by reactivation of LTBI in the recipient or to a lesser extent from donor kidney
The diagnosis and treatment of LTBI and active TB disease in donors and transplant recipients is quite challenging and needs a high degree of awareness of the possibility of TB.
There is an increased frequency of extrapulmonary TB in transplant recipients than in the general population
Screening and diagnosis of LTBI:
Screening for LTBI is recommended for all renal transplant candidates and their donors , especially those with history of TB, previous rejection, or other risk factors. LTBI screening is recommended for population subgroups with high prevalence of TB or high likelihood of progression to active disease, including close contacts, foreign-born persons, drug users, incarcerated persons, and homeless individuals
WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T .
There limited data on the sensitivities and specificities of TST and IGRAs in screening for LBI in renal transplant recipients,but IGRAs have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients candidates for renal transplantation.
Undiagnosed LTBI in a recipient during pretransplant evaluation, either persists as LTBI or may undergo endogenous reactivation in the period of immunosuppression .
Treatment of LTBI in donor and recipient :
The treatment of LTBI should be as recommended by WHO 2018 guideline :
TB has a direct effect on the allograft function, so transmission of TB infection should be prevented
Treatment of active TB:
Treatment of both drug-sensitive and drug resistant active TB in renal transplant recipients should follow WHO treatment guidelines. adverse events caused by Isoniazid ( hepatotoxicity and peripheral neuropathy )can be prevented by pyridoxine co-administration
Rifampicin is a potent enzyme inducer which decrease the level of immunosuppressant and other drugs and may not be an ideal choice for patients taking oral contraceptives or HIV-infected individuals on protease inhibitors or non-nucleoside reverse- transcriptase inhibitors.
Proactive TB screening with IGRA is to be recommended for all renal allograft recipients.
Conclusion :
TB is a serious infection in renal transplant recipients because of immunosuppression. All donors and recipients are screened for LTBI and active TB disease prior to transplant to reduce the risk of loss of allograft as recommended by several guidelines .
level V
Latent tuberculosis infection and renal transplantation –
Diagnosis and management
Introduction
· The incidence of active TB disease among renal transplant recipients is much higher than in the general population.
· TB is a cause of increased morbidity and death in renal transplant recipients and is responsible for loss of the renal allograft in approximately one third of cases.
· Most of the TB cases in renal transplant recipients are due to re-activation of LTBI in the recipient or from donor kidney.
· TB can also occur due to increased susceptibility to acquiring new M.tb infection which rapidly progresses to miliary TB because of immunosuppressive therapy.
· The diagnosis and treatment of LTBI and active TB disease in donors and transplant recipients can be challenging since the presentation can be nonspecific.
Screening and diagnosis of LTBI
· Various meta-analyses and guidelines recommend that all renal transplant candidates should be routinely screened for LTBI.
· WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs).
· Regarding sensitivities and specificities of IGRAs and TST in screening for LBI in renal transplant recipients, there are likely to be more false positive, false negative and indetermi- nate results in transplant recipients.
· IGRAs have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
Treatment of LTBI in donor and recipient
· LTBI and active tuberculosis must be diagnosed and treated in both live donor and recipient before transplantation.
· Treatment of LTBI should follow WHO 2018 guidelines
The WHO 2018 guidelines for treatment of LTBI
· Isoniazid monotherapy for 6 months in both adults and children in countries with high and low TB incidence.
· Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy for both adults and children in countries with a high TB incidence
· 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy.
· Hepatotoxicity is a serious dose limiting side effects of both Isoniazid and Rifampicin
· Rifampicin interferes with the efficacy of many drugs by interfering with their metabolism.
· Adherence to one standardized regime and a close monitoring for the adverse effects of the drugs would greatly enhance the effectiveness of treatment.
I appreciate your debate regarding the uncertainty on optimal duration of therapy
Summarise this article
Introduction
TB is the most common infectious disease causing death worldwide, about 1.7 billion people worldwide have LTBI.
WHO definition of LTBI is ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’
Up to 10% of people with LTBI will progress to active TB disease during life time due to disrupted immune system (ie DM, HIV, immunosuppressive medications… etc).
The incidence of active TB disease among renal transplant recipients is higher than in the general population, leading to graft loss in one-third of cases.
Screening and diagnosis of LTBI
WHO recommends three tests for screening: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs).
IGRAs are more specific to mycobacterium TB antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
Clinical workup of donors and transplant recipients to screen for LTBI and active TB:
History:
Physical examination:
Investigations:
Imaging studies:
The commonest mode of transmission is reactivation of LTBI, followed by exposure to infected subject, and rarely donor derived infection.
Treatment of LTBI in donor and recipient
According to WHO 2018 guidelines:
6-9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB
Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines
Proactive TB screening with IGRA and monitoring the drug toxicity during LTBI treatment is recommended for all renal allograft recipients.
Conclusions
LTBI and active TB infection post transplantation, carry a deleterious effect on patient health and graft function.
Better disease understanding, screening, diagnosis and treatment could improve overall patient and graft survival.
What is the level of evidence provided by this article?
The level of evidence- V erratic review
I appreciate your debate regarding the uncertainty on optimal duration of therapy
I like your summary, level of evidence, analysis and take home messages.
Introduction
TB is the leading infectious disease killer worldwide. In 2017 reported 1.3 million TB deaths. New modeling recalculations show 1.7 billion persons globally have latent Mycobacterium TB infection. The WHO defines latent tuberculosis infection as “a state of sustained immunological response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically apparent active TB illness.” 10% of LTBI patients will acquire active TB. When immunosuppression is prevalent, such as in diabetes, malnutrition, HIV, and transplant patients using biologics and immunosuppressive drugs, TB illness is most likely to develop.
Active TB illness is more common in kidney transplant recipients and causes substantial morbidity and death. One-third of kidney allografts are lost due to TB. Reactivation of LTBI in renal transplant patients or donor kidneys causes most TB cases.
Screening and diagnosis of LTBI
All TB-endemic countries practice kidney transplantation.
Renal transplant recipients and donors should be screened for LTBI and active TB before transplant.
Kowada suggests active TB screening with IGRA for renal transplant recipients during LTBI treatment. Patients on the waiting list should start anti-TB treatment and finish it before transplantation. If transplantation is necessary, briefly cease drug intake and resume treatment after clinical stability.
Treatment of LTBI in donor and recipient
The function of the allograft may be adversely affected by tuberculosis, so it is crucial to take every precaution to stop the spread of the infection in this special subgroup of patients.
In both high- and low-TB incidence nations, isoniazid monotherapy for six months is advised for the treatment of LTBI in both adults and children.
In nations with a high incidence of tuberculosis, rifapentine plus isoniazid may be prescribed as an alternative to six months of isoniazid monotherapy as a preventive treatment for both adults and children.
The following alternatives to 6 months of isoniazid monotherapy are advised for the treatment of LTBI in nations with low TB incidence: 9 months of isoniazid, or a 3-month course.
Short course LTBI therapy regimens in transplant recipients require well-designed prospective, controlled cohort trials to evaluate their efficacy, safety, hepatotoxicity, and adherence to treatment.
Treatment of active TB
The WHO treatment recommendations should be followed while treating drug-sensitive and drug-resistant active TB illness in renal transplant recipients.
It is still difficult to treat people who have active TB that was discovered after receiving a kidney allograft.
By interfering with their metabolism, rifampicin reduces the effectiveness of numerous medications.
For patients using oral contraceptives, HIV-positive people taking protease inhibitors, or those receiving non-nucleoside reverse transcriptase inhibitors, it might not be the best option.
Latent tuberculosis infection can be treated with Rifampicin and isoniazid in combination.
For all recipients of renal allografts, proactive TB screening with IGRA is advised, along with individual risk assessments of each patient and monitoring of drug toxicity during LTBI treatment.
Conclusion
In kidney transplant recipients, TB is a significant complication that increases morbidity and mortality. Reactivation of LTBI from within or from the transplanted donor kidney is more likely in transplant recipients.
All donors and recipients should, wherever possible, be routinely checked for LTBI and active TB disease prior to transplant, according to a number of guidelines that are all in agreement with one another.
All kidney transplant recipients must be highly aware of the possibility of TB so that it can be identified and treated early, lowering the risk of allograft loss.
Level of evidence
Level V
I like your summary, level of evidence, analysis and take home messages.
Introduction:
Tuberculosis (TB) is one of the most common infectious diseases, and approximately 1.3 million people affected with TB dies in 2017. It is estimated that there are approximately 1.7 billion people worldwide with latent Mycobacterium tuberculosis infection (LTBI). LTBI is defined as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’ by WHO. It has been shown that up to 10% of patients with LTBI will progress to developing active disease and the highest risk factors are conditions that lead to immune suppression, such as diabetes, malnutrition, HVI infection and immune suppression medications for transplant patients. TB can also occur to due to increased susceptibility of acquiring new M.tb infection, in patients with immune suppression. There is a higher incidence of TB among renal transplant patients, compared to the general population and it is associated with higher morbidity and mortality rates and can lead to graft loss. The clinical presentation of LTBI and TB in transplant recipients varies from the general population and they have an increased frequency of extra-pulmonary TB, hence diagnosis and treatment is challenging.
Screening and diagnosis of LTBI:
All kidney transplant donor and recipients should undergo screening for LTBI and active TB infection prior to the transplant. As there is no gold standard test for screening for LTBI, WHO recommends the tuberculin skin test (TST), and two interferon gamma release assays (IGRAs) which are Quantiferon-TB (QFT) Gold In-Tube and T-SPOT T. TST may be unreliable in patients with chronic kidney disease and those on immune suppressive medications. IGRAs are more specific to M.tb antigens and have a high specificity in detecting LTBI in immunosuppressed patients. The screening for donors and recipients begin with a history highlighting any contact with a patient with active pulmonary TB or a history of any previous TB treatment, and any symptoms of chronic cough, night sweats, weight loss and anorexia. The full clinical examination should examine for active pulmonary TB and should exclude extra-pulmonary TB. Investigations should include a full blood count with differentials, CRP, renal and liver function tests, microscopy (for acid fast bacilli) and culture for M.tb (sputum and early morning urine samples), histology of biopsy or aspirates (acid fast bacilli and granuloma) and GeneXpert MTB/Rif Assay (on sputum, urine or biopsy). The tests for LTBI include a TST and IGRAs. Imaging include a chest X-ray, renal ultrasound and MRI/CT/PET scan where indicated. These screening measures are especially recommended in high TB endemic areas. In low TB endemic areas, LTBI screening is recommended for population subgroups with high prevalence of TB or those with a high likelihood of progression from LTBI to active disease. These include close contact of patients with active TB, recently arrived foreign-born people, drug users, incarcerated persons, and homeless individuals.
Treatment of LTBI in the donor and recipient:
The WHO guidelines for treating LTBI in SOT recipients indicate:
Treatment of drug sensitive and drug resistant active TB in transplant recipients should follow WHO guidelines. Hepatotoxicity may cause a reduction in the drug dosages. Isoniazid may cause peripheral neuropathy, and it can be prevented by using pyridoxine concurrently. Rifampicin has drug interactions, and should be used with caution.
Conclusion:
TB, latent of active, increases the rate of mortality and morbidity for transplant recipients. All donors and recipients should be screened and appropriately treated as per the guidelines, ideally prior to transplantation. Diagnosis of LTBI can be challenging especially in patients with end stage kidneys disease
This is a narrative review: LOE V
I like your summary, level of evidence, analysis and take home messages.
Thank you Professor Sharma
Summary
Some facts
The prevalence of active TB is significantly higher in SOT. Important to realize that estimated of 1.7 billion people suffer from latent TB worldwide. It is estimated that up to 10 % of patients with latent TB can develop active TB during their lifetime.
Active TB in renal transplant recipients is associated with high morbidity and mortality. One third of cases even lose the graft due to Active TB.
Mode of transmission
Diagnosis of latent TB
Post Transplant Patients having latent TB are at high risk of conversion to active TB. But if the donor has latent TB and did not receive proper treatment it still carries a risk of transmission to the recipient therefore both recipients and donors should be screened carefully, with detail history, examination and CXR, together with test for latent TB. Test which are used to screen for latent TB is tuberculin skin test (TST) and IGRA (Quantiferon, T-SPOT), but both can be negative in immunosuppressed patients due to their dependence on the host immune response which is impaired.
Protocol for treatment of latent TB
oral pyridoxine 50 mg given daily with INH decrease the incidence of peripheral neuropathy.
What is the level of evidence provided by this article?
It is narrative review, therefore level of evidence is V.
I like your detailed summary. I appreciate your debate regarding the uncertainty on optimal duration of therapy
I like your summary, level of evidence, analysis and take home messages.
Latent tuberculosis infection and renal transplantation – Diagnosis and management.
Introduction.
Latent tuberculosis infection is defined by the World Health Organization (WHO) as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB disease, and there is a chance for the LTBI to converts to active TB under special circumstances such as diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients, TB in KTX recipients may be due to reactivation of LTBI, DDI or recent acquired infection, Diagnosis needs a high suspicion as mainly LTBI not manifested clinically and treatment also is challenging in such cases specially with drug resistance and drug interaction with immunosuppression.
Screening and diagnosis of LTBI.
WHO recommends three tests for screening for LTBI:
-TST: which is not reliable in CKD patients and in those on immunosuppressive agents.
-Two IGRAs (both QFT and T-SPOT) which are more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
-Approach for diagnosis started with History of previous TB infection or contact with infected case before, clinical examination , basic investigation with specific TB cultures and specific TB testes and PCR.
Treatment of LTBI in donor and recipient.
The WHO 2018 guidelines outline the following treatment options for LTBI:
1-Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
2-Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
3-Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
4-The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB.
Is challenging due to many factors such as drug adherence, drug side effects and drug interaction with immunosuppression medications, so still we need well-designed prospective controlled cohort trials of short course LTBI and active TB treatment regimens in transplant recipients.
Conclusion:
TB is a serious infection in post kidney transplant which carries morbidity and mortality for transplant recipients and so screening for LTBI and active TB in donor and recipient is challenging and considered better than treatment and LTBI causes should be treated and bear in mind the drug side effects and drug- drug interactions with immunosuppression.
Level of evidence :V.
I appreciate your debate regarding the uncertainty on optimal duration of therapy
I like your summary, level of evidence, analysis and take home messages.
SUMMARY
Introduction
Tuberculosis alone was reported to be accountable for the death of about 1.3 million people globally and this does not come as a surprise with over 1.7 billion people with latent TB infection without symptoms. Among the factors that could predispose to TB are diabetes, HIV, malnutrition, and immunosuppressive stage like in SOT. The majority of the people that contract TB infection among kidney transplantation are either through reactivation of LTBI or from the donor and unfortunately, they usually don’t present with the classical TB infection like in immunocompetent
Screening and diagnosis of LTBI
Treatment of LTBI in donors and recipients
The WHO guidelines for treatments of LTBI are as follows:
The treatment of active TB is according to 2017 WHO guidelines and this is frost with challenges like drug-drug interaction with immunosuppressive, antiretroviral, and hepatotoxicity or nephrotoxicity. It is advisable that each transplant centre should have its own protocol that is effective and with fewer attendant drug side effect and that also enhance adherence among transplant patients
The level of evidence is 5
I appreciate your debate regarding the uncertainty on optimal duration of therapy
I like your summary, level of evidence, analysis and take home messages.
Summary:
Screening and diagnosis of LTBI:
Treatment of LTB in donor and recipient: (The WHO 2018 guidelines)
Treatment of active TB:
Challenges during treatment:
1- Drug interaction between rifampicin and IS:
2- Adverse effect of the drugs:
3- Drug adherence
4- Associated graft dysfunction require dose modification
5- Reduction of IS in severe cases
II- level of evidence: V
I like your summary, level of evidence, analysis and a list of challenges
According to EHO 2018 report, Tuberculosis is the most death-related infectious disease worldwide. Organ transplantation is wide and takes place both in areas with low and high incidence. Awareness and clinical suspicion are the most important issues. Latent disease is defined as an immune response to TBC when no evident infection needs to be addressed. Up to %10 of latent cases progress to active disease. Treating suspected and defined cases will help prevent disastrous active infection post-transplantation. TBC is with high mortality and is the main cause of graft loss. Immunosuppression may lead to milliary tuberculosis. As shown in figure 2, TBC infection can evolve as denovo or can be activated due to recipients or donors. Detailed history, questioning about symptoms like cough, night seating is mandatory. İnverstigation in selected cased can b wide basically with CBC, CRP, Acid fast bacilli surveillance, histology or sputum evaluation. İmaging can be done with chest x-ay, CT etc.
Many guidelines suggest routine screening of all candidates. Treatment of latent infection is essential. Treatment should follow WHO 2018 guidelines. In this viewpoint, six-month INH is suggested. Alternatively 3-month IND+RIF combination, especially in areas with high incidence. Rifapentine and INH weekly for 3 months are alternatives to INH+RIF 6-month regimen.
Active TBC treatment should follow the guidelines of WHO (2017, 2018c). Peripheral neuropathy related to INH can be prevented by pyridoxine. Hepatotoxicity and drug interactions should be considered.
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.
I like your detailed summary.
Summarise this article
Introduction
TB is the commonest infectious disease cause of death world wide .
1.7 billions people world wide have latent TB.
10% of latent TB progress to active TB in general population.
Because of immunosuppretion ,active TB from latent is higher than general population.
Screening and diagnosis of latent TB infection
All renal transplant recipient and donor should be screening for latent TB infection.
WHO recommend three tets:
TST which may be unreliable in CKD and immunosuppressive patients.
IGRA is more specific in detection of latent TB infection.
Tb (QFT).
Diagnosis of latent TB infection depend on:
1.History for contact or previous TB.
2.symptoms like:chronic cough ,night sweating,anorexia,feverand weight loss.
3.examination for active pulmonary TB and exclude extra pulmonary TB.
4.investigation by CBC,CRP,RFT,LFT,sputum for AAFB,culture for M TB bacilliiand gne expert test.
5.test for latent TB infection (TST,IGRA).
6. CXR.
TRETMENT of latent TB infection in donor and recipient.
Isoniazid monotherapy for 6 month in countries with high and low incidence .
Rifampicin plus isoniazid is alternative daily for 3 month in high incidence countries.
Rifapentine and isoniazid is alternative ,weekly for 3month in countries with high incidence.
Short cource is recommended if high adverse effect
Treatment of active tuberculosis
Treatment of drug resistance and drug sensitive active TB in renal transplant recipients should follow WHO treatment guidelines.
Hepatotoxicity is serious dose limiting side effect of both isoniazid and rifampicin .
Peripheral neuropathy by isoniazid.
Rifampicin and drug interactions better don’t take when:HIV treatments and contraceptive pills .
Rifabutin is less pharmaceutical interaction and can be use with isoniazid.
Conclusion
All renal transplant recipient or donor should be screen for latent TB infection.
What is the level of evidence provided by this article?V
I like your summary, level of evidence, and analysis.
Summarise this article
* The risks for developing TB disease are conditions of immunosuppression, such as: diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients.
* The incidence of active TB disease among renal transplant recipients is much higher than in the general population
* Most of the TB cases in renal transplant recipients are due to re-activation of LTBI in the recipient or from donor
kidney
* A higher rate of LTBI was found in patients undergoing renal transplantation than those undergoing other organ transplantation.
Screening and diagnosis of LTBI
* WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon
gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT)Gold In-Tube and T-SPOT
*Various meta-analyses and subsequent guidelines recommend that all renal transplant candidates should be routinely screened for LTBI
1. Screening for LTBI:
a) History:
· Contact with patients with active TB.
· Previous TB infection and treatment.
b) Symptoms: chronic cough, night sweat, anorexia and weight loss.
c) Full clinical examination:
· To examine for active pulmonary TB.
· To exclude extra-pulmonary TB.
2. Investigations:
a) General investigations: CBC, CRP, RFT and LFT.
b) Specific investigations for TB:
· microscopy for AFB and culture for MTB(sputum and early morning urine samples).
· Histology of biopsy or aspirates(AFB and granuloma).
3. Imaging:
· CXR.
· MRI, CT, PET/CT scan
Treatment of LTBI in donor and recipient
a) Isoniazid monotherapy for 6 months .
b) Rifampicin plus Isoniazid daily for 3 months as an alternative to 6 months of isoniazid monotherapy
c) Rifapentine and Isoniazid weekly for 3 months may as an alternative to 6 months of Isoniazid monotherapy
-Patients may find completing the long course of LTBI treatment difficult due to adverse effects and the interactions with immunosuppressive drugs, hence shorter courses of treatment are recommended.
Treatment of active TB
-Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines
-Hepatotoxicity is a serious dose limiting side effects of both Isoniazid and Rifampicin
-Rifampicin interferes with the efficacy of many drugs by interfering with their metabolism.
– It may not be an ideal choice for patients taking oral contraceptives or HIV-infected individuals on protease inhibitors or non-nucleoside reverse- transcriptase inhibitors.
– Rifabutin has fewer pharmacologic interactions with antiretroviral agents than Rifampicin
level of evidence provided by this article
Level V
I like your summary, level of evidence, and analysis.
Do you think IGRA has a better specificity and therefore higher LR ratio?
IV. Latent tuberculosis infection and renal transplantation – Diagnosis and management
===================================================================
Summarise this article
Introduction
=================================================================
Screening and diagnosis of LTBI
A diagnostic approach for detection of active and latent
tuberculosis has been outlined by Demir and Sever (2017). Clinical
workup of donors and transplant recipients to screen for LTBI and
active TB is shown in Figure 1
History:
Physical examination:
Investigations:
Imaging studies:
==================================================================
Treatment of LTBI in donor and recipient
Treatment of active TB
================================================================
Conclusions
====================================================================
What is the level of evidence provided by this article?
The level of evidence is 5
=======================
I like your summary, level of evidence, analysis and take home messages. Typing whole sentence in bold amounts to shouting.
1.Summarise this article
Prior to renal transplant, all recipients & their donors should be screened for LTBI & active TB disease.
The following workup is done on donors & recipients to check for LTBI & active TB:
History:
Physical examination:
Investigations:
Imaging studies:
Screen recipients for LBTI indicated in the following:
Treatment of LTBI in donor & recipient
Alternatives to 6 months of isoniazid monotherapy in countries with a low TB incidence include:
Treatment of active TB
=======================
2. What is the level of evidence provided by this article?
I like your summary, level of evidence, and analysis. I appreciate your debate regarding the uncertainty on optimal duration of therapy
Summarise this article
Introduction
· TB is the most common infectious disease cause of death worldwide, with 1.7 billion people worldwide with latent Mycobacterium tuberculosis infection (LTBI).
· Up to 10% of people with LTBI will progress to active TB disease, with the highest risk occurring when conditions of immunosuppression are present.
· The incidence of active TB disease among renal transplant recipients is much higher than in the general population, causing much morbidity and death and loss of the renal allograft in approximately one-third of cases.
· It is caused by the re-activation of LTBI in the recipient or from the donor’s kidney, increased susceptibility to acquiring new M.tb infection, and an increased frequency of extrapulmonary TB.
· Diagnosis and treatment of LTBI and active TB disease in donors and transplant recipients can be challenging due to cryptic presentation and non-specific symptoms.
Screening and diagnosis of LTBI
· Kidney transplantation is now universally performed in high and low-TB endemic countries. WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon-gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT.
· IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
· However, there are likely to be more false positive, false negative, and indeterminate results of IGRAs in transplant recipients. In low-resource settings, TST continues to be used for diagnosing LTBI.
· Screening for latent tuberculosis should be done prior to transplant for all renal transplant candidates, particularly those with risk factors such as TB, previous rejection episodes, high-dose corticosteroids, diabetes mellitus, and those living in endemic areas.
· Screening for LTBIB in low TB endemic countries is recommended for those with a high risk of progression to active disease, such as close contacts of TB, recently arrived foreign-born persons, drug users, incarcerated persons, and homeless individuals.
· Kowada recommends active TB screening with IGRA for all renal allograft recipients with individualized risk assessment and initiation of anti-TB treatment prior to transplantation.
Treatment of LTBI in donor and recipient
· Treatment of LTBI should follow WHO 2018 guidelines to prevent transmission of TB infection in SOT recipients.
· Isoniazid monotherapy is recommended for LTBI in countries with high TB incidence, while Rifampicin plus Isoniazid daily for 3 months is an alternative for children and adolescents aged <15.
· Short-term LTBI treatment regimens should be evaluated for efficacy, safety, hepatotoxicity, and adherence.
Treatment of active TB
· Treatment of drug-sensitive and drug-resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines.
· Hepatotoxicity and peripheral neuropathy can be prevented by co-administration of pyridoxine, and Rifampicin interferes with the efficacy of many drugs.
· Rifabutin has fewer pharmacologic interactions with antiretroviral agents and can be used in combination with Isoniazid for the treatment of latent tuberculosis infection.
· Proactive TB screening with IGRA and monitoring the drug toxicity during LTBI treatment is recommended for all renal allograft recipients.
Conclusions
· Due to immunosuppression, transplant recipients are at a higher risk of reactivating LTBI
· Screening for LTBI and active TB is recommended to reduce the risk of loss of allograft.
================================================
What is the level of evidence provided by this article?
Level V
I like your summary, level of evidence, and analysis.
Do you think IGRA has a better specificity and therefore higher LR ratio?
Summary of the article
Latent tuberculosis infection and renal transplantation – Diagnosis and management
LTBI: Latent tuberculosis infection is defined by the World Health Organization (WHO) as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’ (WHO, 2018b).
· 10% of people with LTBI will progress to developing active TB disease during their lifetime.
· The risks for developing TB disease are conditions of immunosuppression, such as: diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients.
· A higher rate of LTBI was found in patients undergoing renal transplantation than those undergoing other organ transplantation.
TB causes in KTRs:
· From donor kidney(DD-transmission).
· Endogenous reactivation of latent infection.
· New infection with MBT.
Screening and diagnosis of LTBI
1. Screening for LTBI:
a) History:
· Contact with patients with active TB.
· Previous TB infection and treatment.
b) Symptoms: chronic cough, night sweat, anorexia and weight loss.
c) Full clinical examination:
· To examine for active pulmonary TB.
· To exclude extra-pulmonary TB.
2. Investigations: there is no gold standard test for diagnosing LTBI accurately:
a) General investigations: CBC, CRP, RFT and LFT.
b) Specific investigations for TB:
· microscopy for AFB and culture for MTB(sputum and early morning urine samples).
· Histology of biopsy or aspirates(AFB and granuloma).
· GeneXpert MTB/Rif assay(on sputum, urine or biopsy).
c) Tests for LTBI: WHO recommends three tests for screening for LTBI:
· Tuberculin skin test (TST).
· Two interferon gamma release assays (IGRAs) namely, QuantiFERONâ-TB (QFT) Gold In-Tube and T-SPOTâ T (WHO, 2018b).
3. Imaging:
· CXR.
· MRI, CT, PET/CT scan (where indicated).
Treatment of LTBI in donor and recipient
The WHO 2018 guidelines outline the following treatment options for LTBI (WHO, 2018b).
a) Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
b) Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
c) Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
d) The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB
Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines (WHO, 2017, 2018c).
The level of evidence provided by this article:
This is a narrative review article with level of evidence grade 5.
I like your summary, level of evidence, and analysis. I appreciate your debate regarding the uncertainty on optimal duration of therapy
Latent tuberculosis infection and renal transplantation – Diagnosis and management
Sriram K et al., in this article aims to highlight the issues related to prevention, diagnosis and treatment of tuberculosis in renal transplant recipients.
Methods
The PubMed database was searched for publications and guidelines on diagnosis and management of LTBI in renal transplantation. Publications/Specialist Society guidelines on renal allograft recipients with LTBI and TB in post-operative period were also analyzed for use.
Findings
Screening and diagnosis of LTBI
All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant. There is no gold standard test for diagnosing LTBI accurately. WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T (WHO, 2018b).
Clinical workup of donors and transplant recipients to screen for LTBI and active TB.
History – contact with an index case of TB and previous history of TB treatment.
Symptoms – includes cough, fever, weight loos, drenching night sweat and anorexia.
Examination – to look for signs of active TB and exclude extrapulmonary TB.
Investigations – FBC, CRP, renal function test and liver function test. Microscopy (acid fast bacilli) and culture for MTB (sputum and early morning urine samples). Histology of biopsy and aspirate (acid fast bacilli and granuloma).
GeneXpert/RIF assay (on sputum, urine and biopsy)
Test for LTBI includes tuberculin skin testing and or/ IGRA (either TSPOT.TB or QuantiFERON).
Imaging such as chest x ray, renal scan, CT or MRI (where indicated), PET/CT SCAN may also be done as required.
Treatment of LTBI in donor and recipients
The WHO 2018 guidelines outline the following treatment options for LTBI (WHO, 2018b).
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB
This should follow the WHO guidelines while paying attention to drug interactions and risk of toxicity. Adherence and completion of treatment should be emphasized.
Conclusions
TB poses a great threat to immunosuppressed patients including transplant recipients. High index of suspicion with early diagnosis and treatment is essential.
Level of evidence – Level V
I appreciate your debate regarding the uncertainty on optimal duration of therapy
Introduction
TB represents the most common infectious cause of mortality all over the world.
Cases with latent TB infection was estimated as 1.7 billion people.
WHO defines Latent tuberculosis infection LTBI as the persistence of immune response to M .tuberculosis antigens with no active TB disease manifestations.
Reactivation of LTBI can progress to active TB when risk factors are present as immunosuppressive status.
TB infection is more common in transplant recipients occurring due to either re-activation of LTBI in the recipient or from donor
kidney leading to death and graft loss.
Diagnosis of TB in the donor and the recipient is challenging.
Screening and diagnosis
Renal transplant recipients and donors must be screened for LTBI and active TB disease before transplant.
Tuberculin skin test (TST) and two interferongamma release assays (IGRAs) ie , QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T are 3 tests recommended by WHO for LTBI screening as there is no gold standard test .
TST is inaccurate in CKD and those on immunosuppressive agents , but IGRAs are more specific to M.TB antigens and is highly specific in detecting LTBI in immunosuppressed patients.
A metanalytical study demonstrated that a higher rate of LTBI was detected in renal transplant recipients compared to other organs recipients when IGRA tests were used rather than the TST.
Ø Clinical workup for active TB screening in donors and transplant recipients include
history taking as contact with active TB case,
symptoms evaluation as night sweats , cough
clinical examination to detect active pulmonary TB and exclude extrapulmonary TB
Investigations including M TB microscopic examination culture , histopathological evaluation of biopsies , GeneXpert assay
Ø For LTBI screening TST and IGRA tests
Imaging as chest xray ,renal US ,CT,MRI,CT/PET
Guidelines recommend that all renal transplant candidates should be routinely screened for LTBI.
British Thoracic Society guidelines recommend screening for LTBI where tuberculosis incidence rates are high or in high risk cases for developing tuberculosis in low incidence areas.
In low TB endemic areas, LTBI screening is recommended for
Those having high TB prevalence or those likely to progress from LTBI to active disease.
Kowada advices for an active TB screening with IGRA for all
renal transplant recipients based on individualized risk assessment during LTBI therapy .
Treatment of LTBI in donor and recipient
Diagnosing and treating LTBI and active tuberculosis in both live donors and recipients before transplantation is crucial.
WHO 2018 LTBI treatment guidelines
o Isoniazid monotherapy for 6 months for children and adults in low and high TB incidence areas.
o Rifampicin and Isoniazid daily for 3 months as an substitute to 6 months of isoniazid monotherapy for preventive treatment for children till 15 years in countries with a high TB incidence.
o Rifapentine and Isoniazid weekly for 3 months may be offered as a substitute to 6 months of Isoniazid monotherapy as preventive treatment for adults and children in high TB incidence areas.
o isoniazid for 9 months, or a 3-month regimen of weekly rifapentine and isoniazid, or 3–4 months of isoniazid and rifampicin, or 3–4 months of rifampicin alone for treatment of LTBI in low TB incidence areas.
Active TB treatment
WHO guidelines have to be applied meanwhile Isoniazid and Rifampicin increases hepatotoxicity risk .
Pyridoxine has to be given with INH to avoid neurotoxicity.
Rifampicin has many drug interactions wit immunosuppressive medications.
Rifabutin having less drug interaction than rifampicin can be taken with INH for latent TB treatment.
Compliance with one specific standardized regimen,
Finishing the duration of the regimen , close monitoring and
early detection of drugs side effects can increase the efficacy of LTBI therapy.
Conclusion
Diagnosis and prompt treatment of TB disease or LTBI is essential before renal transplant in order to avoid reduce renal graft loss, morbidity and death . WHO recommendations for LTBI screening and treatment must be applied .
-level of evidence is V
I like your summary, level of evidence, analysis and take home messages. I appreciate your debate regarding the uncertainty on optimal duration of therapy
Summarise this article
Some facts
Mode of transmission
Diagnosis of latent TB
Protocol for treatment of latent TB
Patient 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?
I like your summary, level of evidence, analysis and take home messages.I appreciate your debate regarding the uncertainty on optimal duration of therapy
Introduction:
Tuberculosis (TB) is the most common infectious cause of death worldwide.
Latent tuberculosis infection is defined by the WorldHealth Organization (WHO) as a state of persistent immune response to stimulation with Mycobacterium tuberculosis (M. tb) antigens without evidence of clinically active tuberculosis
Presence of tuberculosis active in kidney transplant recipients population is much higher than in the general population. In approximately one-third of cases,
TB were the cause of renal allograft loss.
Most cases of tuberculosis in kidney transplant recipients are due to reactivation of LTBI in the recipient or donor kidney
Screening and diagnosis of LTBI:
All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant.
WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) namely, QuantiFERON1-TB (QFT) Gold In-Tube and T-SPOT1 T
IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients
History “
Pervious TB or contact with patient have a disease
Symtoms :
Cough ,night sweat .wegiht loss and anorexia
Full clinical examination
Investigation:
CBC,ESR,CRP,LFT, RFT ,Sputum for culture and sensitivity ,Gene xpert MTB /rif assay .Histology for biopsy or aspirate acid fast bacilli
Test for latent TB infection :
TST and IGRA
Imaging :
Chest x ray
Renal US
CT scan or MRI when indicated .
PET/CT scan when indicated
Treatment of LTBI in donor and recipient:
The WHO 2018 guidelines
_ Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence. _Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
_ Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
_ The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone
Treatment of active TB:
Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines (WHO, 2017, 2018c).
Conclusions:
Kidney transplantation is now widely practiced in countries with high and low prevalence of tuberculosis. High awareness of the likelihood of tuberculosis or ITL is needed prior to kidney transplantation to reduce kidney allograft-related injury, morbidity, and death
level 5
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.
Summarise this article
All transplant recipients and donors should undergo TB screening.
Latent tuberculosis Definition by the World Health Organisation A state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB disease
There is no standard test to diagnose Latent TB
Who Recommendations-
· TST
· IGRA ( Quantiferon TB Gold test and T Spot)
IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients
sIGRAs (both QFT and T-SPOT) have been shown to be more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
A diagnostic approach for detection of active and latent tuberculosis
History
Contact with TB patient
Previous Tb
Symptoms
Cough , Night sweats, anorexia, weight loss
Examinations
Investigations
Blood CP/ESR
CRP
Renal and liver functions
AFB microscopy and culture
Histology
Gene Xpert MTB
Tests for Latent TB
TST
IGRA
Imaging
Chest X Ray
Renal ultrasound
HRCT
PET/Ct
Risk Factors for TB- History of TB, previous rejection episodes, high-dose corticosteroids, diabetes mellitus and those living in endemic areas
In low TB endemic countries, LTBI screening is recommended for- a high prevalence of TB or those with a high likelihood of progression from LTBI to active disease-
(close contacts of patients with active tuberculosis, recently arrived foreign-born persons, drug users, incarcerated persons, and homeless individuals)
Treatment of LTBI in donor and recipient
Adults and children in countries with high and low TB incidence- Isoniazid monotherapy for 6 months
Children and adolescents aged in countries with high incidence of TB- Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment
LTBI in countries with a low TB incidence- 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
Treatment of active TB
It should be as per WHO guidelines
What is the level of evidence provided by this article?
Level of Evidence- V
I like your summary, level of evidence, and analysis
Summary
Introduction
This article concerns itself with latent TB in kidney transplant recipients, particularly the aspects related to prevention, diagnosis and treatment. This is an essential topic to consider because of the intense complications that can arise from active TB in renal transplant recipients, the worst of which involves death of the allograft or even the patient.
Discussion
TB in the recipient can come from increased susceptibility to infection due to immunosuppression, or from live donors born in endemic areas, or from latent TB foci which get reactivated post transplant. WHO recommends three tests for screening recipients for LTBI and active TB disease. These include
IGRAs are highly specific for M.TB antigens and thus lead to more accuracy in identifying LTBI in our immunocompromised patients.Both of the above mentioned types of IGRAs are also more sensitive than TST. However, if resources are low, TST can still be used.
Detailed hisory of both donor and recipient is to be taken to screen for LTBI and active TB prior to transplantation. This includes checking for prior contact with active pulmonary TB and previous TB treatment.
Investigations include
Good prevention strategies will include routine screening protocols of all donors and recipients for LTBI and active TB. Chest Xray and further investigations are warranted in cases with prior history of TB, previous rejection episodes, high dose corticosteroids, diabetes mellitus.
LTBI screening is recommended especially in populations with high prevalence of TB. Chest Xray, detailed history, and risk assessment is to be done for travel or migration.
Treatment of LTBI involves the following according to WHO guidelines :
Treatment of active TB involves :
Adherence to treatment of one standardized regime, completion of duration of the regime, and close monitoring and early identification of adverse effects of drugs all enhance the effectiveness of treatment.
Conclusion
TB in kidney recipient is a significant complication because it can lead to loss of allograft or even the patient. The way to deal with this would be intensive screening protocols. In the case of LTBI, patients need to strictly adhere to the regimen that has been created for them, and complete the drug program. This ensures a higher degree of success in eradicating the infection and protecting the allograft.
Level of evidence
Level of evidence is 5.
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.
Screening and diagnosis of LTBI
A diagnostic approach for detection of active and latent TB:
Treatment of LTBI in donor and recipient
Treatment of active TB
Level of evidence: V (narrative review)
I like your summary, level of evidence, analysis and take home messages.
Typing whole sentence in bold amounts to shouting.
Introduction
Organisation (WHO) as ‘a state of persistent immune response to stimulation by mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’ (WHO, 2018b). Up to 10% of people with LTBI will progress to developing active TB
Screening and diagnosis of LTBI
Kidney transplantation is universally performed in high and low TB endemic countries.
All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplant.
Kowada recommends an active TB screening with IGRA for all renal allograft recipients with individualized risk assessment of each of the patients during LTBI treatment.
Those patients are recommended to initiate anti-TB treatment while they were on the waiting list, aiming at a complete treatment schedule prior to transplantation.
If there is a need to undergo transplantation, it’s worthwhile to temporarily stop the drug intake and recommence the treatment schedule to completion once patients were clinically stable
Treatment of LTBI in donor and recipient
As tuberculosis could directly affect the allograft function, it is extremely important to make the utmost effort to prevent transmission of TB infection in such a select subgroup of patients.
Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month.
There is a need for well-designed prospective controlled cohort trials of short course LTBI treatment regimens in transplant recipients, which should assess their efficacy, safety, hepatotoxicity and adherence to treatment
Treatment of active TB
Treatment of drug-sensitive and drug resistant active TB disease in renal transplant recipients should follow WHO treatment guidelines (WHO, 2017, 2018c).
Treatment of patients with active tuberculosis detected after renal allograft transplantation remains a challenging task.
Rifampicin interferes with the efficacy of many drugs by interfering with their metabolism
It may not be an ideal choice for patients taking oral contraceptives or HIV-infected individuals on protease inhibitors or non-nucleoside reversetranscriptase inhibitors.
Rifampicin and can be used in combination with Isoniazid for the treatment of latent tuberculosis infection (Matteelli et al, 1999).
Proactive TB screening with IGRA with individualized risk assessment of each of the patients and monitoring the drug toxicity during LTBI treatment is to be recommended for all renal allograft recipients
Findings
Up to 10% of people with LTBI will progress to developing active TB
Conclusion
TB is a serious complication in renal transplant recipients and causes much morbidity and mortality.
Transplant recipients are at a higher risk of re-activating LTBI from within themselves or from the transplanted donor kidney.
Several guidelines are available and are consistent in recommending that all donors and recipients are routinely screened for LTBI and active TB disease prior to transplant whenever possible.
A high degree of awareness of the possibility of TB is required in all renal transplant patients so that it can be diagnosed and treated early, reducing the risk of loss of allograft.
I like your summary.
LTBI
Summary of the Article
Introduction
TB is the most common infection that causes death worldwide.
1.7 billion people were estimated to have latent TB in 2017.
LTBI is defined by WHO as a state of persistent immune response to stimulation by M.TB antigen with no evidence of clinically manifested active TB.
Up to 10% of people with LTBI are at risk to develop active TB, this risk will be higher with higher morbidity and mortality in patients with other risk factors;
1/3 of kidney trans[lant recipients will lost their allograft due to TB, and most cases of TB infection are due to reactivation of latent infection.
Screening and diagnosis
History;
Symptoms
Full clinical examination
Lab
Tests for LTBI
Imaging
Treatment of LTBI in donor and recipient (WHO 2018)
Treatment of active TB (WHO 2018)
Conclusion
Level of evidence
Level ((V))
Review Article
Do you think IGRA has a better specificity than tuberculin test, and therefore higher LR ratio?
What is your comment on this statement of mine. You may or may not agree with me.
Hi Prof
The TST is not sensitive in advance CKD and as well as in immunocompromised patient, while IGRA is more sensitive and specific exactly in detecting latent TB
Summarise this article
Introduction
o Tuberculosis (TB) is the commonest infectious disease worldwide
o Definition of latent tuberculosis infection (WHO): a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically active TB disease
o 10% will develop active TB
o Risk factors for re-activation LTBI include diabetes, malnutrition, HIV, and immunosppressions
o Active TB in renal transplant recipients is higher than general population and causes morbidity and death with allograft loss
o Causes of TB in recipients mostly due to re-activation of LTBI or from donor kidney (also acquiring new infection)
o Clinical presentation of TB in renal transplant is differ from that in the general population and needs high degree of awareness of suspicion
Screening and diagnosis of LTBI and active TB
History
o Previous TB infection
o Contact with active TB patient
Symptoms:
o Chronic cough, weight loss, night sweats, and anorexia
Clinical examination:
o Examine for active pulmonary tuberculosis
o Exclude extra pulmonary TB
Investigations
o CBC, CRP, RFT, LFT, microscopy for AFB and culture, biopsy or aspirate histology (AFB or granuloma), and genXpert MTB/Ris Assay (on sputum, urine or biopsy)
Tests for LTBI
1. Tuberculin skin test (TST): unreliable in advanced CKD/immunosuppressive patients
2. IGRA test (TSPOT.TB or QuantiFeron): more sensitive and specific for diagnosing LTBI
Imaging
o Chest x ray, renal ultrasound, MRI or CT scan (where indicated), and PET/CT scan (where indicated)
Pathogenesis of LTBI in post transplant recipients:
1. No donor or recipient TB: allograft free of TB
2. Donor TB/recipient free: donor derived TB
3. Recipient TB/donor free: endogenous recipient re-activation
4. No donor or recipient TB: denovo recipient infection
BTS screening for LTBI:
1. Areas of high incidence of TB
2. High risk of TB in low incidence areas (contact with active TB, recently arrived from travel abroad, drug users, incarcerated persons, alcohol abuse or injection drug use, and homeless)
Treatment of LTBI in donor and recipient (WHO 2018 guidelines)
1. Isoniazid monotherapy for 6 months (both adults and children) in countries with high and low TB incidence
2. Rifampicin and Isoniazid daily for 3 months (children and adolescents aged <15 ) in countries with a high TB incidence
3. Rifapentine and Isoniazid weekly for 3 months (both adults and children) ) in countries with a high TB incidence
4. In countries of low TB incidence: 9 months of Isoniazid, Rifapentine and Isoniazid weekly for 3 months, Rifampicin and Isoniazid for 3-4 months, and rifampicin alone for 3 months
Treatment of active TB
After transplant is challenging:
1. Hepatotoxicity (rifampicin and isoniazid)
2. Peripheral neuropathy (isoniazid)
3. Rifampicin (interactions with oral contraceptives, antiretrovirals)
Enhance effectiveness of treatment:
1. Adherence to one specific regimen
2. Completion of the recommended duration
3. Close monitoring and early identification of adverse effects
Conclusions
o Transplant recipients are at high risk of re-activating LTBI due to immunosuppression causing mortality and morbidity, in addition to allograft loss
o Routine screening of all donors and recipients for LTBI is required and active TB prior transplant
o A high degree of awareness of the possibility of TB is required
What is the level of evidence provided by this article?
Level V (narrative review)
I like your summary, level of evidence, and analysis.
Introduction:
-TB is the commonest infectious disease cause of death worldwide.
-WHO defined LTBI as a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease.
-10% of people with LTBI will progress to active TB disease.
– In KTRs, TB is highly prevalent, and it is associated with significant morbidity and mortality.
– The diagnosis and treatment of TB donors and transplant recipients is challenging.
Screening and diagnosis of LTBI
-There is no gold standard test. WHO recommended the following:
* Tuberculin skin test (TST) :
– Unreliable advanced CKD and immunosuppressed individuals.
– still used in low resource setting.
* IGRAs; (QuantiFERON-TB and T-SPOT ):
– High specificity in detecting LTBI in immunocompromised.
– IGRAs more sensitive than the TST for the diagnosis of LTBI in KTRs.
– British Thoracic Society guidelines suggest screening for LTBI where TB is endemic or having risk factor for TB while living in low incidence area.
– CXR is part of the screening.
– Detailed background history of previous exposure to patients with TB and risk factor assessment
Treatment of LTBI:
WHO 2018 guidelines for LTBI treatment;
– Treatment of choice; Isoniazid INH monotherapy for 6 months ( both adult and children).
– Alternative to 6 months monotherapy:
– Rifampicin + INH daily for 3 months (for children in high TB incidence ).
– Rifapentine + INH weekly for 3 months (for both adults and children in high TB incidence).
– In low TB incidence; INH for 9 months of isoniazid, or regimen of weekly rifapentine +INH for 3 months, or INH + rifampicin for 3–4 months, or 3–4 months of rifampicin alone
Treatment of active TB:
– It is challenging task and should follow WHO treatment guidelines.
– Hepatotoxicity is a serious side effects of TB medications.
– Rifampicin interact with many immunosuppressive drugs reducing its level and antiretroviral treatment.
– Rifabutin has fewer pharmacologic interactions with antiretroviral agents
– treatment effectiveness enhanced by close monitoring and early identification of the adverse effects
Level of evidence : 5 narrative review.
Summary
Introduction
TB is the commonest infectious cause of death worldwide.
WHO defines LTBI as a state of persistent immune response to stimulation by MTB antigens with no clinical symptoms.
Persons with LTBI, 10% of them in their lifetime will develop active TB disease.
Incidence of TB in kidney transplant recipients is higher than general population, and it’s associated with allograft loss in a third of the patients.
TB in the kidney transplant recipient could be due to reactivation of the LTBI or due to new infection that rapidly progresses to milliary TB.
Clinical presentation of TB in kidney transplant recipients differs from that of the general population.
Screening and diagnosis
All kidney transplant recipients and their donors should be screened for TB prior to transplantation.
No gold standard test.
WHO approves three test: tuberculin skin test and IGRA (Quantiferon and T spot).
Tuberculin skin test not reliable in CKD and in patients on immunosuppressants.
IGRA more sensitive and specific than tuberculin skin test, however limited studies on specificity and sensitivity of IGRA and TST in organ recipients.
CXR and a detailed history is essential in screening.
Treatment of LTBI
Recommended LTBI treatment as per WHO 2018 guidelines
Treatment of active disease
Treatment in renal transplant recipient should follow WHO guidelines.
Caution:
Level of evidence
This was a review of articles making it level V.
I like your summary, level of evidence, and analysis.
Rifampicin is mistyped as Rifampiccin
Thank you prof.
Sorry for the typos.
Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime.
The authors wrote nice work up for LTBI from clinical assessment to radiograph, cultures and look for LTBI with TST and or IGRA.
IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients
The article explores treatment of both latent and active TB infections and pointed to drug side effects like liver, neuro toxicity.
Rifampicin alter metabolism of CNI and it is important to monitor the levels closely
Level of evidence: review article
SHort and sweet
Summary:
Introduction:
TB is the leading infectious disease killer globally (WHO, 2018a). 2017 had 1.3 million TB deaths. The latest modeling recalculations show that 1.7 billion persons globally have latent Mycobacterium tuberculosis infection (LTBI). The WHO defines latent tuberculosis infection as a condition of sustained immunological response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no indication of clinically apparent active TB illness’ (WHO, 2018b). 10% of LTBI patients will acquire active TB.
Methods:
A search was conducted in the PubMed database to locate papers and recommendations pertaining to the diagnosis and treatment of LTBI in renal transplantation. Articles on renal transplant patients who were diagnosed with LTBI and TB during the postoperative period were also examined. Guidelines provided by specialized societies were also taken into consideration.
Testing for LTBI:
All TB-endemic nations do kidney transplants. Renal transplant patients and donors should be screened for LTBI and active TB before transplant. No LTBI test is definitive. WHO recommends three tests for LTBI screening: TST, QuantiFERON-1-TB (QFT) Gold In-Tube, and T-SPOT1. Advanced chronic renal disease and immunosuppression may render the TST unreliable. IGRAs are highly specific to M. TB antigens and may identify LTBI in immunosuppressed individuals. IGRAs and TST screening for LBI in renal transplant patients have little evidence of their sensitivities and specificities.
Treatment of LTBI in donor and recipient:
LTBI treatment for adults and children in high- and low-TB countries is 6-month isoniazid monotherapy.
In high-TB nations, children and adolescents under 15 should be treated with rifampicin and isoniazid daily for 3 months instead of 6 months of isoniazid monotherapy.
Rifapentine and isoniazid given weekly for 3 months may be used as a preventative treatment for adults and children in high-TB nations instead of 6 months of monotherapy.
Alternatives to 6-month isoniazid monotherapy for LTBI treatment in low-TB countries include 9 months of isoniazid.
Treatment of active TB:
In active cases of tuberculosis, treatment in accordance with WHO standards
INH and rifampicin both have a number of potential adverse effects, but one of the most serious is hepatotoxicity.
As compared to rifampicin, the antiviral drug rifabutin showed a much lower potential for adverse drug interactions.
Pyridoxine, when given in conjunction with INH, has the ability to ward against peripheral neuropathy.
Level 5 of evidence
I like your summary, level of evidence, and analysis.
You mentioned TB antigen test.
Do you think GeneXpert in comparison to IGRA has a better specificity and therefore higher LR ratio?
Name of the study: Latent tuberculosis infection and renal transplantation Diagnosis and management
Year of the study: (2019)
Journal: International Journal of Infectious Diseases 2021 Impact Factor 9.022
Summery
Definition: Latent tuberculosis infection is defined by the World Health Organisation (WHO) as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens( in the form of positive skin test in non-vaccinated population or positive IGRA test with no evidence of clinically manifest active TB disease(in the form of negative symptoms and normal radiology)
Screening and diagnosis of LTBI
There is no gold standard test for diagnosing LTBI accurately.
WHO recommendations are
1-Diagnosis of persistent immunological response by Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs) which include (QuantiFERON1-TB (QFT)
Gold In-Tube and T-SPOT1).
2-Then exclude active TB disease by :History of exposure and symptoms then confirmed by radiology and laboratory investigations like acid fast bacilli.
Treatment of LTBI in donor and recipient
Its narrative review with evidence V.
Latent TB in kidney transplantation
Summary
· Reactivation of latent TB to active disease is common among KT.
· It has greater burden to increase morbidity and mortality.
· Risk factors as strong induction and immunosuppressive therapy, plus comorbidities as DM, HIV, CMV.
· Screening by TST and IGRA tests. IGRA has better sensitivity in immunocompromised patients and can differentiate between MTB and other MOTT (mycobacteria other than TB).
· While in active disease; search for AFB in either sputum or morning urine sample, GeneXpert is rapid and sensitive method in diagnosis, in sputum, urine or biopsy samples.
· Treatment of latent TB in recipients:
o INH + pyridoxine for 6-9 months.
o Oral rifampin for 4 months
· Treatment of active TB in recipients:
· Start immediately after diagnosis.
· 2 Regimens:
· 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.
· 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.
· Monitoring of adverse effects as hepatotoxicity as 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).
I like your summary, level of evidence, and analysis.
Do you think GeneXpert in comparison to IGRA has a better specificity and therefore higher LR ratio?
Thanks dear professor. I think IGRA has accepted sensitivity and specificity in case of latent TB as it represents sustained immune response to MTB. While geneXpert is highly sensitive in case of active TB disease.
Introduction:
Screening & diagnosis of LTBI:
LTBI treatment in donor & recipient:
Treatment of active TB:
Level of evidence is 5
I like your summary, level of evidence, and analysis.
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.
Yes Prof I agree with you about better specificity of IGRA
I like your summary, level of evidence, and analysis.
Do you think IGRA has a better specificity and therefore higher LR ratio?
I like your summary, level of evidence, and analysis.
Do you think IGRA has a better specificity and therefore higher LR ratio?
1-Summarise this article;
Introduction;
-There are 1.7 billion people worldwide with latent Mycobacterium tuberculosis infection (LTBI).
-World Health Organisation (WHO) defined Latent tuberculosis infection (LTBI); as a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease.
-Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime.
Risk factors for re-activation LTBI;
-Occur when conditions of immunosuppression are present such as diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients.
Screening and diagnosis of LTBI;
-There is no gold standard test for diagnosing LTBI accurately.
-WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs); (QFT & T-SPOT).
-The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agents.
-IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients & more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
-British Thoracic Society guidelines suggest screening for LTBI where tuberculosis incidence rates are high or in patients with risk factors for developing tuberculosis in low incidence areas: need to be evaluated with chest radiography and other screening tests as part of the screening for latent tuberculosis.
Treatment of LTBI in donor and recipient;
-The WHO 2018 guidelines for treatment options for LTBI;
-Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
-Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy.
-Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy.
Treatment of active TB;
-Treatment of patients with active tuberculosis detected after renal allograft transplantation remains a challenging task.
-Hepatotoxicity is a serious dose limiting side effects of both Isoniazid and Rifampicin and this risk is further accentuated in patients with pre-existing liver disease and alcoholics.
-Peripheral neuropathy caused by Isoniazid can be prevented by co-administration of pyridoxine.
-Rifampicin interferes with the efficacy of many drugs by interfering with their metabolism.
-Rifabutin has fewer pharmacologic interactions than Rifampicin and can be used in combination with Isoniazid for the treatment of latent tuberculosis infection.
Limitation;
-There is a need for well-designed prospective controlled cohort trials of short course LTBI treatment regimens in transplant recipients, which should also assess their efficacy, safety, hepatotoxicity and adherence to treatment.
-Patients may find completing the long course of LTBI treatment difficult due to adverse effects and the interactions with immunosuppressive drugs, hence shorter courses of treatment are recommended.
Conclusions;
-Due to immunosuppression, transplant recipients are at a higher risk of re-activating LTBI from within themselves or from the transplanted donor kidney.
-Kidney transplantation is now universally performed in high and low Tuberculosis endemic countries.
– A high degree of awareness of the possibility of TB is required in all renal transplant patients so that it can be diagnosed and treated early, reducing the risk of loss of allograft.
-WHO Management recommendations for LTBI screening and treatment should be followed.
2-What is the level of evidence provided by this article?
This systematic review and meta-analysis (LOE V).
I like your summary, level of evidence, and analysis.
You mention 3 possible options for prophylaxis against latent TB in recipients. Which one would you choose for your patients?
Thanks so much; our Prof;
our protocol:mono therapy (INH 300 mg OD + Pyridoxine 40 my OD) / for 6 months.
Noted
Q1.
Introduction
Screening & diagnosis of active & LTBI:
1.History:
2.Symptoms:
3.Full Clinical Examination
4.Work up
5.Test for LTBI
6.Imaging
Treatment of LTBI
Treatment of active tuberculosis
Conclusion
Q2. This was narrative review , level 5
I like your summary, level of evidence, and analysis.
How do you explain increased risk of rejection in these patients?
Thnxs prof;
This can be due to the following factors;
I agree, dear Ben
Thxs prof