3. A 41-year-old man came forward to donate a kidney to his brother. 000 mismatch, excellent kidney function, no DSA. His GP reported that he had a positive Heaf test.
Positive Heaf test results indicate previous TB infection or vaccination
Positive test results (grades 1 and 2) indicate prior BCG vaccination; grades 3 and 4 indicate latent or active tuberculosis.
Therefore, a correct evaluation of the donor:
Medical record. Investigate the history of untreated or inadequately treated tuberculosis.
Endemic exposures. Travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the previous 2 years, being destitute or a refugee, incarceration, and alcoholism may be associated with LTBI.
Radiographic manifestations include apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, and pleural thickening.
Donation is contraindicated if the donor has active TB, and the donor should be treated for 69 months with a four-drug regimen.
If the donor has latent tuberculosis, he or she should receive INH plus pyridoxine for six months, after which the recipient can be properly counseled and receive chemoprophylaxis under the supervision of the ID team.
Positive heaf test mean this patient could be exposed to mycobacterium TB previously so we need to investigate more if the TB is active or not by doing blood PCR and urine PCR for TB if it positive I will exclude him from donation
A 41-year-old man has expressed his willingness to donate a kidney to his brother. The compatibility between the two is excellent, with a 000 mismatch and no donor-specific antibodies (DSA). However, the man’s general practitioner (GP) has reported a positive Heaf test result.
The Heaf test is a skin test conducted to determine if an individual has been previously exposed to tuberculosis (TB) and has developed immunity. The Heaf gun, equipped with disposable single-use heads, is the recommended tool for administering the test. It injects purified protein derivative into the skin over the flexor surface of the left forearm. The test is then read between 3 and 10 days later. It is important to avoid injecting into areas containing superficial veins.
The results of the Heaf test are interpreted based on a scale. A negative result indicates no induration, possibly with six-minute puncture scars, which could be attributed to avian TB or BCG vaccination. Grade 1 is characterized by four to six papules, also considered negative and potentially resulting from previous BCG or avian TB exposure. Grade 2 indicates the formation of confluent papules that form an indurated ring, signifying a positive result. Grade 3 shows central filling to form a disc, also indicating a positive result. Grade 4 represents severe induration greater than 10 mm, possibly accompanied by blistering, which is strongly indicative of a positive result.
Grades 1 and 2 may be attributed to previous BCG vaccination or avian TB exposure. Grades 2 to 4 are considered positive and should be managed as latent TB. In such cases, the patients should undergo a chest X-ray.
The patient, who wishes to donate a kidney, should be treated for latent TB infection before proceeding with the donation. The recommended treatment options include rifampicin 10mg/kg (up to 600mg) once daily for 4 months, rifampicin 10mg/kg plus isoniazid 5mg/kg daily for 3 months, or isoniazid 5mg/kg daily for 6-9 months (or 15mg/kg twice weekly for 6-9 months) in combination with pyridoxine 25-50mg to prevent peripheral neuropathy.
If a donor is diagnosed with active TB infection, their organs should not be used for transplantation. In cases where the diagnosis is made post-transplantation, the recipient should immediately initiate therapy for active infection based on local guidelines.
However, if a donor has a history of successfully treated TB for at least 6 months, their organs can be considered for transplantation.
In this specific case, it is advisable to delay the donation process and provide the donor with a short and effective treatment regimen for latent TB, such as 3 months of isoniazid plus rifampicin, following further evaluation. Alternatively, a longer course of isoniazid monotherapy for 6 or 9 months, accompanied by pyridoxine supplementation as recommended by the US Centers for Disease Control and Prevention (CDC), can be considered.
Positive heaf test, also called Sterneedle test ,which is not done these days and has been replaced by newer tests i.e., quantiFERON-TB Gold test or T-spot tests indicates immunity of individual to T.B due to previous exposure or BCG vaccination.it has a scale of 4 and 2-4 indicates positive test.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.Active T.B is a contraindication to donation,however,latent T.B needs treatment.Various regimens availavle like Isoniazid monotherapy for 6 months, Rifampicin plus Isoniazid daily for 3 month,Rifapentine and Isoniazid weekly for 3 months.
REFERENCES:
BTS Guidelines for Living Donor Transplantation.4th Edition
TB in kidney Transplantation Lecture by Prof. Ahmed Skoker
· Heaf test is A skin test to determine whether an individual is immune to tuberculosis due to previous exposure, carried out prior to vaccination or latent TB infection (LTBI).
· The Heaf test is defined by scale from 1-4. Grades 1 and 2 may be the result of previous BCG or avian tuberculosis. Grades 2-4 are considered positive and should be managed as latent TB and need chest Xray.
· This donor has a positive tuberculin skin test. Therefore it is important to ensure that he does not have active TB infection that would discard him from donation.
We need to ask for symptoms including fever, cough, night sweats and weight loss and carry a thorough clinical examination and carry some investigations including:
· Sputum examination (if the patient is coughing and producing sputum) for microscopy, AAFBs and gen xpert test.
o CXR to assess for pleural effusion, consolidations and nodular opacities
o So, if the patient does not have any signs, symptoms, radiological or microbiological evidence of TB, then the patient has LTBI and being a donor, there is a risk of transmitting the dormant bacilli to the recipient who may develop active TB in view of the immunosuppression medication that will be received. This results in a significant morbidity and mortality.
· The donor requires treatment for the LTBI. regimens available are:
INH plus rifaputin once weekly for 3 months
INH daily for six months
Rifampicin daily for four months
INH/Rifampin daily for three months
· He will need to complete the treatment before proceeding for the transplant.
· Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
· If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines.
References:
1. Munoz P, Rodriguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clin Infect Dis 2005; 40: 581– 587.
2. OPTN; Guidance for Identifying Risk Factors for Mycobacterium tuberculosis (MTB) During Evaluation of Potential Living Kidney Donors.
● Positive Heaf test means that this donor had previous exposure to TB either by infection or by the vaccine.
● Donor-derived TB remains an important infectious complication of solid-organ transplantation .
● Increased awareness of donor risk factors may allow targeted testing for latent and unrecognized active TB in potential donors
● Donor must evaluated as :
☆ In case of history of latent TB-treated appropriately the risk for Transmission
is l ower but the recipient had to be monitored clinically
☆ History of latent TB-treated insufficiently or not treated or treatment details not clear or new diagnosis of latent TB-positive TST or Interferon gamma release assay found during pre-transplant evaluation and evaluation finds no evidence of active TB
the risk for Transmission is moderate and
donor has to take some/all of chemoprophylaxis and besides chemoprophylaxis of recipient with clinical monitoring.
☆ In case of unexplained pulmonary apical fibrosis in donor without cavitation and without additional testing the risk of transmission is variable and donation pending further evaluation .
☆ History of active MTB treated appropriately over 2 years ago the risk of transmission is lower to moderate and the recipient need clinical monitoring with cultures of previous TB sites if possible. And TB prophylaxis for recipient.
☆ History of active TB-site remote from transplant treated appropriately within 2 years. The risk of transmission is lower to moderate and recipient need clinical monitoring with cultures of previous TB sites if possible with chemoprophylaxis of recipient.
☆ History of active TB-site remote from transplant treated insufficiently and/or with other than standard regimen excluding disseminated or CNS TB the risk of transmission is higher and increased risk if less than 2 years since active TB diagnosis live donor had to be differed until adequately treated with infectious disease specialist consultation and cultures of previous TB sites prior to transplant if possible .
☆ History of active renal TB treated appropriately. (If not treated appropriately donation should be deferred until after appropriate treatment) , the risk of transmission is moderate treatment must verify with clinical monitoring and use chemoprophylaxis for recipient we need cultures of previous TB site(s) and infectious disease specialist consultation.
References:
Guidance for Identifying Risk Factors for Mycobacterium tuberculosis (MTB) During Evaluation of Potential Living Kidney Donors. Organ procurement and transplantation network.
The Heaf test, a Diangnostic skin test, was long performed to determine whether or not patient had been exposed to TB infection.
All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplan.Every effort must be made to diagnose and treat LTBI and active tuberculosis in both livedonor and recipient before transplantation.The tuberculin skin test (TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade.Negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI.Thus, in low-risk patients, IGRAs could be considered as the sole approach, because the use of a more specific test might reduce the rate of false-positive results and, consequently, the number of patients who will unnecessarily be exposed to LTBI therapy. On the other hand, in high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
The heaf test is a skin test for TB immunization. If it was positive, the patient had had exposure to TB. If negative, BCG vaccine was needed. The other tests for LTBI are: PPD or tuberculin skin test and interferon-gamma release assay (IGRA) like QuantiFERON-TB (QFT). IGRA is more sensitive and specific for LTBI in recipients. Comprehensive history and physical exam are essential for the diagnosis of LTBI. Potential recipients with a history of TB, high-dose corticosteroids, DM, or living in an endemic area should be screened by CXR and above mentioned tests for LTBI. Diagnosis and treatment of LTBI in both donor and recipient according to WHO 2018 guidelines are necessary.
Treatment of LTBI: 6 or 9
months of isoniazid monotherapy, rifampicin plus INH daily or rifampicin plus
INH weekly for 3 months.
Heaf test is a Skin testing for tuberculosis like a tuberculin skin test (TST). Then this patient would be managed as possible latent TB: – Would do chest CT for greater clarity of lung lesions. – If not, I would start treatment for latent TB – If positive, I would do bronchoscopy for BAL and perform BAAR and PCR for tuberculosis to try to exclude active TB and start latent treatment
REFERENCE: – Dacso CC. Skin Testing for Tuberculosis. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 47.
– Sorohan BM, Ismail G, Tacu D, Obrișcă B, Ciolan G, Gîngu C, Sinescu I, Baston C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens. 2022 Sep 13;11(9):1041. doi: 10.3390/pathogens11091041. PMID: 36145473; PMCID: PMC9505385.
‘Heaf test’ is a skin test previously being used to determine whether an individual is immune to TB either due to previous exposure or prior BCG vaccination.
How I can proceed?
– History regarding exposure to active TB patient.
– Prior history of TB
– Test for latent TB : TST, IGRA
– If TST and IGRA positive then treatment for latent TB infection ( INZ for 6 month or INZ and rifampicin for 3 month)
Donor brother, well-matched and immunologically excellent pair. Donor “Heaf test” is positive – a skin test previously being used to determine whether an individual is immune to tuberculosis due to previous exposure or prior BCG vaccination. Negative heaf test cases need BCG vaccination.
Now days, “Heaf test” is replaced by Tuberculin Skin Test (TST).
Positive TST should indicate more specific tests like quanti-FERON-TB Gold test or T-spot tests, detail clinical examination and imaging to differentiate between latent and active TB infection: – Sputum for AFB, Culture & Gene- Xpert – QuantiFERON-TB-Gold / T-spot test – ESR, CRP – Imaging – CXR /HRCT chest . Positive TST, negative TB Gold test suggests prior exposure or vaccination
Both TST and quantiFERON-TB Gold tests positive without clinical and radiological evidence of active TB, indicate latent TB –> that donor should be treated with Rifampicin + INH for 3 months. Radiological and / or clinical symptoms suggestive of TB with positive TST + positive quanti FERON-TB Gold test indicate active disease. Treatment of Latent TB infection in Donor: 1. INH + Rifampicin daily for 3 months 2. Rifampicin daily for 4 months 3. INH only daily for 6 months.
John GT et al; Dx and Mgt of TB in transplant donors; A donor derived infection consensus conference report.AM J Transplant.2012 sep ; 12(9)
4. Morris MI, Daly JS, Blumberg E, et al. Diagnosis and management of tuberculosis in transplant donors: a donor-derived infections consensus conference report. Am J Transplant 2012 Sep;12(9):2288-300. doi: 10.1111/j.1600-6143.2012.04205.x. Epub 2012 Aug 6. Erratum in: Am J Transplant. 2013 Feb;13(2):528. PMID: 22883346.
The Heaf test is a skin test, was previously performed to determine exposure to TB infection. Also known as the Sterneedle test, it was administered by a Heaf gun. The reading of the Heaf test was defined by a scale:
· Negative – No induration, maybe six minute puncture scars · Grade 1 – four to six papules (also considered negative) · Grade 2 – Confluent papules form indurated ring (positive) · Grade 3 – Central filling to form disc (positive) · Grade 4 – Disc >10 mm with or without blistering (strongly positive)
Grades 1 and 2 could result from previous BCG or avian tuberculosis, rather than human TB infection. Grade 3 and 4 were referred for chest X-ray. Positive Heaf test should be followed by detailed history regarding exposure to TB, travel to TB endemic areas, recent TB infection in contacts. Following examination, chest X-ray should be done along with: 1. Sputum AFB, Culture & Gene- Xpert. 2. QuantiFERON-TB-Gold In-Tube test (QFT). 3. ESR, CRP.
Treatment of Latent TB infection in Donor: 1. Rifampin daily for 4 months 2. INH + Rifampin daily for 3 months 3. INH only daily for 6 months. Active TB in donor is contraindication for transplant.
●The Heaf Test shows if people have antibodies against TB
● If they have not they may need a vaccination.
● Tuberculin liquid was placed on the skin, left to form a film and then six needles were plunged into the skin to a depth of 2 mm.
● If a red hard area appeared after three days, the test showed they had tuberculosis, were naturally immune or had acquired immunity in some way.
●now this test not recommended for LTBI screening
● diagnosis of latent TB we should perform TST or IGRA
● IGRA being better option because is not affected by previous BCG vaccination .
● we should evaluate the history of exposure
● physical examination
● CXR
●bronchial aspiration or sputum samples for staining and culture
●if TST and IGRAs are positive ==> donation should be delayed and receive a protocol treatment;
● screening the recipient for HIV
Management of LTBI in recipient (WHO )
Isoniazid alone ==>, daily for 6 or 9 months
Daily rifampicin alone ==> for 3–4 months
Daily isoniazid plus rifampicin==> for 3–4 months
Weekly rifapentine plus isoniazid ==> for 3 months (12 doses)
The case scenario is a prospective transplant recipient with a positive heaf test and how to manage for transplantation
Heaf test was historically used in the UK till it was replaced by the mantoux test….This was after the year 2005…. The current WHO guidelines recommend IGRA (interferon Gamma release Assay) and Tuberculin skin testing by Mantoux method for screening of latent TB infection…
A heaf gun was used to simultaneously inject various serum samples under the skin…. The skin was poked with needles that had been soaked in tuberculin purified protein derivative (PPD). A hefier gun with single disposable needle is used to inject the PPD on the flexor aspect of the left forearm….the strength of PPD was 1,00,000 units per ml in a six circular pattern….. The test is read after 5 to 7 days….
heaf score is graded as follow
negative – Absence of induration – negative
grade 1 – 4-6 papules – negative
grade 2 – confluent papules creating a ring – positive
grade 3 – filling the center to form a disc (positive)
grade 4 – disc more than 10mm with or without scar (positive)
In this patient we need to take a detailed history of contact with patient with active TB, history of prior ATT, history of previously untreated latent TB, and history of any active TB like cough, night sweats, fever or hemoptysis
Treatment for LTBI in the recipient is important to prevent life threatening TB after transplant and tuberculosis after renal transplantation will impair the graft function…
Treatment for LTBI should adhere to WHO guidelines in 2018 which is Six month of isoniazid monotherapy…. Other options are Rifampicin monotherapy for 4 months if transplant is not being planned in the near future… for children < 15 years old 3 months daily Rifampicin and Isoniazid monotherapy for 3 months is recommended
in this scenario i will start the latent TB trreatment for 6 months….and proceed for transplant. .I will avoid rifampicin based treatment as it has significant interaction with immunosuppressive
The Heaf test is a skin test, was previously performed to determine exposure to TB infection. Also known as the Sterneedle test, it was administered by a Heaf gun.
The reading of the Heaf test was defined by a scale:
· Negative – No induration, maybe six minute puncture scars
· Grade 1 – four to six papules (also considered negative)
· Grade 2 – Confluent papules form indurated ring (positive)
· Grade 3 – Central filling to form disc (positive)
· Grade 4 – Disc >10 mm with or without blistering (strongly positive)
Grades 1 and 2 could result from previous BCG or avian tuberculosis, rather than human TB infection.
Grade 3 and 4 were referred for chest X-ray.
Positive Heaf test should be followed by detailed history regarding exposure to TB, travel to TB endemic areas, recent TB infection in contacts. Following examination, chest X-ray should be done along with:
1. Sputum AFB, Culture & Gene- Xpert.
2. QuantiFERON-TB-Gold In-Tube test (QFT).
3. ESR, CRP. Treatment of Latent TB infection in Donor:
1. Rifampin daily for 4 months
2. INH + Rifampin daily for 3 months
3. INH only daily for 6 months.
Active TB in donor is contraindication for transplant.
· How would you proceed? Heaf test is a diagnostic skin test to determine whether the patient was exposed to tuberculosis infection. It was known as Sterneedle test, it was administered by Heaf gun, graded by a scale into four grades. It was discontinued in 2005. To determine if the BCG vaccine was needed, it was thought to be easier to interpret, if negative considered for vaccination. False negative Heaf test Nontuberculosis mycobacteria, and BCG vaccination. A patient with Heaf positive test needs further evaluation to confirm and exclude tuberculosis. Need good history for previous exposure, infection, vaccination, and treatment, thorough physical examination. Rule out; for diagnosis and location, Mantoux test, CXR PA view, CBC with ESR and CRP, if sputum for AFB, GeneXpert, If any latent infection first treat with INH for six month or rifampicin for six months, or in combination. References; 1. ttps://www.uptodate.com/contents/tuberculosis-in-solid-organ-transplant-candidates-and-recipients?topicRef=115049&source=related_link#:~:text=Back-,Tuberculosis%20in%20solid%20organ%20transplant%20candidates%20and%20recipients,-Topic. 2. https://en.wikipedia.org/wiki/Heaf_test. 3. https://thorax.bmj.com/content/55/11/887.
A 41 year old potential donor has a positive Heaf test.
A positive Heaf test is one in which there is vesiculation at the site of innoculation of the Tuberculin sample.
A history
Past history of BCG vaccine
Past history of tuberculosis, and treatment
Investigations
A Mantoux test
A chest X-ray
An abdominopelvic Ultrasound Scan
A full blood count
An ESR
A sputum sample for Gene X-pert. Or bronchial washings for Gene Xpert
The aim of these investigations is to locate the site of the tuberculosis infection.
Then treatment of the donor will start
He should get the 2 months of Rifampicin, Isoniazid, Pyrazinamide and Ethmabutol. Then 4 months of Rifampicin and Isoniazid.
When is this potential donor fit to donate?
Will the recipient need to be treated for Tb?
Positive Heaf test: The greater the risk of exposure, the higher the PPV. Causes of false-positive tests:
· Nontuberculous mycobacteria
· BCG vaccination
Management of individuals with positive test
· Any patient with a positive test for TB infection needs evaluation to exclude TB disease prior to initiation of treatment for TBI.
· The evaluation includes clinical history, physical examination, and chest radiograph.
· Patients with relevant clinical manifestations (cough >2 weeks’ duration, fevers, night sweats, weight loss) and/or abnormal CXR should submit three sputum samples for AFB smear, mycobacterial culture, and nucleic acid amplification testing
Treatment of latent tuberculosis
Transplant candidates and recipients should be treated for latent TB when there is no evidence of active TB and any of the following criteria are met:
1) Initial or boosted TST with induration ≥5 mm or a positive IGRA
2) History of untreated latent TB
3) Receipt of an organ from a donor known to have untreated latent TB Regimen selection
· If the transplant is unlikely to occur within the following 4 to 6 months, rifampin for 4 months is recommended.
· Other options pre-transplant are isoniazid plus rifapentine for 12 weeks, or isoniazid plus rifampin for 3 months
the decision of accepting or refusing of donor can not depend on heat test alone, so he need more history and work up…
IGRA test more sensitive and specific (our center depend on IGRA test)
CXR ,sputum for AFB ,…ETC
Multipuncture methods (including the Tine test and the Heaf test) should not be used; they may be easier to administer but are not accurate because it is not possible to precisely control the amount of tuberculin.
So, we use the Tuberculin skin test. The TST consists of intradermal injection of tuberculin material, which stimulates a delayed-type hypersensitivity response mediated by T lymphocytes and, in patients with prior mycobacterial exposure, causes induration at the injection site within 48 to 72 hours.
All individuals with a positive test for TB infection (positive tuberculin skin test or interferon-gamma release assay result) warrant evaluation to exclude TB disease prior to initiation of treatment for TBI.
The evaluation includes clinical history, physical examination, and chest radiograph. TB disease may be asymptomatic in patients with HIV infection.
A 41-year-old man came forward to donate a kidney to his brother. 000 mismatch, excellent kidney function, no DSA. His GP reported that he had a positive Heaf test. How would you proceed?
· In the immunological point of view he is an excellent donor. · Here, Heaf test is positive. This is a skin test to determine whether an individual is immune to tuberculosis due to previous exposure or prior BCG vaccination. Negative cases should be vaccinated.
· Now-a-days Heaf test is replaced by TST and if positive the following approaches should be initiated. – Positive test should be interpreted with other more specific tests like quantiFERON-TB Gold test or T-spot tests combined with clinical presentation and imaging studies to differentiate between active and latent TB – Positive TST and negative quantiFERON-TB Gold test sugesst prior exposure or vaccination – Positive TST + positive quantiFERON-TB Gold test without clinical and radiological evidence of active TB, indicate latent TB and that donor should be treated accordingly with Rifampicin +INH for 3 months – If radiological or clinical evidence suggestive of TB with positive TST + positive quantiFERON-TB Gold test, active disease. Need to treat with full course of anti TB prior to donation.
Reference: (i) Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD (ii) UpToDate
The heaf test had been used in the past and is replaced recenly by TST .
Positive test should be interpreted with other more specific tests like quantiFERON or T-spot tests combined with clinical presentation and imaging studies to differentiate between active and latent TB status
positive TST + negative quantiFERON sugesst prior exposure or vaccination
positive TST + positive quantiFERON without clinical and radiological evidence of active TB , indicate latent TB and that donor should receive RFM +INH for 3 months
radiological or clinical evidence of TB with positive tests point out to active TB that abort donation.
Donor has good immunological profile and suits the recipient need
HEAF test ( read skin test for TB ) is not diagnostic of active TB in donor
In India , all are BCG vaccinated so skin test can be false positive
complete work up of donor is must
IGRA is better test to diagnose latent TB
CXR , ESR , symptoms , past history of TB are all valid points to consider
all attempts should be done to detect and treat latent TB in donor
single agent daily for 6 months or two agents twice a week for 6 months as per national TB policy
Get hx for risk factors; coming from an endemic area, close contacts wit a pt untreated for TB, resident in a homeless shelter, health care worker etc.
Get hx for risk factors for reactivation ; HIV, previous transplant or chemotherapy, DM, steroids use, cigarette smoking >1pack/day, underweight/malnutrition, lymphoma, leukemia, neck and head cancers etc.
Prior to treatment, do tests to R/O active TB e.g sputum for gene xpert or AAFBS staining, CXR etc to minimize undertreatment that increases the risk of resistance.
Assess other comorbidities that might affect treatment ; Alcohol use -heavy, hepatitis, injection of recreational drugs, those with hepatitis and use of hepatotoxic medications.
Treat the pt if no active TB.
In low incidence settings i.e TB incidence rate <100/100000;
RIF based regimen preferred due to higher completion rates, efficacious and low hepatotoxicity. This options include ;RIF OD X 4/12/INH +RIF OD X 3/12/INH + RPT Weekly x 3/12
For those with contraindications to RIF,INH monotherapy for 6-9/12 used.
2 .In high incidence settings i.e TB incidence rate > 100/100000,RIF based regimen preferred.
REF;
UPTO DATE – TX of LTBI in non pregnant adults without HIV.
John GT et al; Dx and Mgt of TB in transplant donors; A donor derived infection consensus conference report.AM J Transplant.2012 sep ; 12(9)
Case of Potential Donor with a positive HEAF test done by GP
I would start by taking a detailed history and examination of the potential donor to determine they are from an endemic area, if they had BCG vaccine in the past, Previous PTB, Exposure to TB case. I would also assess if they have symptoms of active TB such as cough, sputum, weight loss, pyrexia, chills, rigours, sweats.
Next I would repeat the Tuberculin skin test and do a blood Interferon Gamma Release Assay test, together with general Labs such as FBC, ESR and CRP. I would take a Chest Xray.
The aim of the evaluation is to determine if the donor has Latent TB Infection or Active TB. The TST may be positive because of BCG vaccination, while the IGRA test is less affected by BCG vaccination. Both test are not able to differentiate between latent and active infection, and cannot predict which latent infections are at high risk of developing active disease. Hence the importance of a good clinical evaluation assessing for signs and symptoms of active disease. Further tests such as a Chest Xray are useful in this regard.
If after the evaluation the donor is deemed to have LTBI, they will be offered prophylaxis as per local guidelines. In Botswana it would be daily INH for six months, with Bit B6. The transplant donation can go ahead after the donor has taken all or some of the treatment.
If the donor is deemed to have Active TB, They will need to complete TB treatment as per the local TB protocol. In Botswana it would be at least two Months of RHZE intensive phase followed by four months of RH continuation phase. They can donate after completing the treatment.
It is also important to carefully screen the donor since they are brothers and may be contacts
Reference
Morris MI, Daly JS, Blumberg E, Kumar D, Sester M, Schluger N, Kim SH, Schwartz BS, Ison MG, Humar A, Singh N, Michaels M, Orlowski JP, Delmonico F, Pruett T, John GT, Kotton CN. Diagnosis and management of tuberculosis in transplant donors: a donor-derived infections consensus conference report. Am J Transplant. 2012 Sep;12(9):2288-300. doi: 10.1111/j.1600-6143.2012.04205.x. Epub 2012 Aug 6. Erratum in: Am J Transplant. 2013 Feb;13(2):528. PMID: 22883346.
The Heaf test, a diagnostic skin test, was long performed to determine whether or not patient had been exposed to tuberculosis infection.
The reading of the Heaf test was defined by a scale:
Negative – No induration, maybe six minute puncture scars
Grade 1 – four to six papules (also considered negative)
Grade 2 – Confluent papules form indurated ring (positive)
Grade 3 – Central filling to form disc (positive)
Grade 4 – Disc >10 mm with or without blistering (strongly positive)
Grades 1 and 2 could result from previous BCG or avian tuberculosis, rather than human TB infection.
Patients who were found to have a grade 3 or 4 reaction were referred for X ray and follow-up.
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)
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 .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.
Clinical workup of donors and transplant recipients to screen for LTBI and active TB.
Every effort must be made to diagnose and treat LTBI and active tuberculosis in both live donor and recipient before transplantation .TreatmentofLTBI should follow WHO 2018 guidelines.
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.
The heaf test is an old test for diagnosis of mycobacterium infection and is now been replaced by the tuberculin skin test.
Positive heaf test may be related to BCG vaccine, LTBI or active TB infection
A whole workup is needed including
· History of traveling to an endemic area or close exposure
· History of symptoms or signs related to TB infection like night sweating, low-grade fever, and weight loss
· Clinical and radiological assessment of pulmonary and extrapulmonary TB infection sites
· Laboratory tests like IGRA, NAA, and AFB.
Based on the results donors can be classified into 3 main categories
1. Vaccinated (positive TST and negative IGRA): go-ahead with the donation
2. LTBI (positive for both TST and IGRA with the negative clinical and radiological findings of active TB infection): treatment for 4m with rifampicin or 3 m with rifampicin and INH for both donor and recipient.
3. Active TB (positive AFB or NAA): he should be excluded from donation. References Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Bogdan Marian Sorohan, Gener Ismail, Dorina Tacu, Bogdan Obris, Gina Ciolan, Costin Gîngu, Ioanel Sinescu and Cătălin Baston Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors Guilherme Santoro-Lopes, Aruna K. Subramanian, Israel Molina,José María Aguado, Ricardo Rabagliatti, and Oscar Len,
it is skin test called also Sterneedle test done by heaf gun and used to determine the person was exposed to TB or not, and was preferred in the UK, because it was thought to be easier to interpret, with less variability between observers, and less training was required to administer and read the test.
The reading of the Heaf test was defined by a scale:
Negative – No induration, maybe six minute puncture scars
Grade 1 – four to six papules (also considered negative)
Grade 2 – Confluent papules form indurated ring (positive)
Grade 3 – Central filling to form disc (positive)
Grade 4 – Disc >10 mm with or without blistering (strongly positive)
Grades 1 and 2 could result from previous BCG or avian tuberculosis, rather than human TB infection.
persons who were found to have a grade 3 or 4 reaction were referred for X-ray and follow-up.
so in this case, positive test means this donor needs full investigations to determine he is active TB or latent including CXR and CT chest , PCR for TB
if active infection found , this is an absolute contraindication for donation but if latent infection, needs prophylactic treatment by INH for 6 months
The Heaf test, a diagnostic skin test, was long performed to determine whether or not children had been exposed to tuberculosis infection. The test was named after F. R. G. Heaf. Also known as the Sterneedle test,it was administered by a Heaf gun (trademarked “Sterneedle”) a spring-loaded instrument with six needles arranged in a circular formation which was inserted in the wrist or shoulder. Until 2005, the test was used in the United Kingdom to determine if the BCG vaccine was needed; the Mantoux test is now used instead.
Since the test raises a question of previous exposure , detail history examination and work up is needed to rule out active infection. If no active infection then such patients can be offered INH prophylaxis for atleast six months.
HEAF TEST:
It was used to decide whether there is need to give BCG vaccine.
A spring-loaded gun mounted with very short needles produces a circle of six punctures in the forearm through which tuberculin is introduced. If the test is positive a reaction causes the skin to become red and raised, indicating that the individual is immune. If the test is negative a vaccine (BCG) should be given.
But now this test is no longer in use:
Since, BCG vaccine does not provide immunity against TB infection. It just prevents severe form of tuberculosis. So BCG is in national immunization program in endemic countries given at birth. It has no role in non-endemic zones.
Secondly, screening for tuberculosis is done through Mountoux test that too in symptomatic person and if positive further work up is done to confirm diagnosis.
In asymptomatic donors there is no protocol of diagnosing LTBI and treating the same before donation.
So as per our policy, i shall move ahead for transplant
Donor 000 mismatch no DSA but with positive heaf test
Heaf test was used to determine if one was exposed to TB or not.
Purified protein derivative was injected into the skin and the test was read 2-7 days later. The results were graded between 0-4 where zero was negative, grade 1-2 positive indicate prior BCG vaccination, grade 3-4 active/latent TB.
This test is no longer done and has largely been replaced with TST.
Workup
For this donor its paramount we differentiate whether it is latent TB or active TB.
A detailed history on symptoms of chronic cough, weight loss and night sweats that would suggest active TB is required.
Further history on travel to endemic area, recent contact of persons with active TB, their social status whether they are homeless or incarcerated is needed.
This should be followed by work up that should include a CXR, sputum for AAFB and Gene Xpert if they have a productive cough or if it’s inducible. This would identify active pulmonary TB.
For extra pulmonary TB the work up will be guided by the presentation.
For latent TB the two test that can be done is TST and IGRA. IGRA is superior to TST since there are no false positive with prior BCG confirmation.
Treatment
If the donor has active TB then this is an absolute contraindication to donation and treatment with 4 drug regimen (RHZE) should be started.
If the donor has latent TB then this is not a contraindication to transplantation.
Treatment should ideally be completed before transplant, but if transplant is required urgently then can be done and the recipient given LTBI treatment after transplantation.
Treatment for latent TB can be:
Isoniazid 5mg/kg/day for 6 months
Rifampicin plus isoniazid for 3 months
Isoniazid should be given with vitamin B6 supplementation
References
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Bogdan Marian Sorohan, Gener Ismail, Dorina Tacu, Bogdan Obris, Gina Ciolan, Costin Gîngu, Ioanel Sinescu and Cătălin Baston
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
Guilherme Santoro-Lopes, Aruna K. Subramanian, Israel Molina,José María Aguado, Ricardo Rabagliatti, and Oscar Len,
How would you proceed?
Heaf test was a diagnostic approach to determine whether or not a patient is exposed to TB infection and it is not been done routinely.
In this donor it should be differentiate whether he has active tuberculosis or tuberculosis infection(latent TB) based on;
History of patient like fever, cough, night sweat and weight
TST
IGRA, IGRA would have less false positive compared to TST.
if active TB than need to treat first.
If latent TB (tuberculosis infection)
Before transplantation it should be treated ideally, but can proceed with transplantation and treatment of donor should be completed for TBI and recipient should receive chemoprophylaxis
Rifampin 10mg/kg daily for 4 months (4R) OR
Rifa 10mg/kg plus INH 5mg/Kg daily for 3 month(3HR) OR
Rifa upto 900mg/body weight weekly plus INH 15mg/kg weekly for 3 months(3HP) has better compliance.
The Heaf test, a diagnostic skin test, was long performed to determine whether or not patient had been exposed to tuberculosis infection.
The Heaf test was discontinued in 2005.
Until 2005, the test was used to determine if the BCG vaccine was needed.
A Heaf gun was used to inject multiple samples of testing serum under the skin at once. The reading of the Heaf test was defined by a scale:[6]
Negative – No induration, maybe six minute puncture scars
Grade 1 – four to six papules (also considered negative)
Grade 2 – Confluent papules form indurated ring (positive)
Grade 3 – Central filling to form disc (positive)
Grade 4 – Disc >10 mm with or without blistering (strongly positive)
Heaf test in not accurate to assess this patient or immune status of TB.
We need to take history related to past history of TB,contact with tubeculous one,travelling to endamic area. to differentiate is it latent or active. Investigation
TST
IGRA
IGRA seems to present some advantages over TST in this patient,and also not affected by BCG vaccine. Treatment of latent TB infection:
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 . References
Positive Heaf test indicate previous TB exposure either vaccination or infection
Positive test (low grade 1,2) indicate previous BCG vaccin
high grade (3 and 4) indicate latent TB or active TB
So, proper evaluation of the donor:
Medical history. The history of untreated or insufficiently treated TB should be investigated
Endemic exposures. Travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the last 2 years, homeless or refugee status, incarceration and alcoholism may be associated with LTBI.
Radiographic findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening.
If the donor has active TB: donation is contraindicated and the donor should be treated for 69 months with 4 drug regimen
If the donor has latent TB: the donor should receive INH single drug plus pyridoxin for 6 months, then donation can be done with proper counselling of the recipient and receive chemoprophylaxis under guidance of ID team.
3. A 41-year-old man came forward to donate a kidney to his brother. 000 mismatch, excellent kidney function, no DSA. His GP reported that he had a positive Heaf test.
Issues/ concerns: –
– potential donor to the brother
– 000 mismatch, excellent kidney function, no DSA
– positive heaf test
Introduction
– Heaf test is a diagnostic skin test used to determine whether or not a person is immune to tuberculosis and it is usually done prior to vaccination
– a positive test is indicated by the skin becoming red and raised after introducing tuberculin into the skin and this suggests that the patient is immune to tuberculosis
– if the test is negative, the BCG vaccine should be given
– a heaf gun is used to inject samples of the testing serum under the skin at once – the needles are dipped in tuberculin purified protein derivative (PPD) and pricked into the skin
– the test is read 2-7 days later according to a scale graded from negative to grade 4 with grade 4 being strongly positive
– there is a potential risk of transmission of TB by solid organ transplantation
– based on detailed medical and epidemiological history, organ donors can be risk stratified into low, moderate and high-risk categories for risk of TB infection or LTBI
– immunologic tests (i.e., TST and IGRA) should be interpreted cautiously, a negative test does not rule out active TB
– molecular test for mycobacterial culture are preferred to the standard culture because of the shorter turn-around-time
– kidney donation should be deferred in suspected or confirmed cases of active TB except in dire circumstances
– potential living donors ought to be screened with TST, IGRA, chest radiographs and treated for LTBI where indicated
– it is preferable that treatment for LTBI or active TB be completed before donation unless there is an urgent indication for transplantation taking into account the severity of the infection
o INH + Rifapentine weekly for 12 weeks
o INH + Rifampin for 3 months
o INH for 6 months
o Rifampin 4 months
it is preferable to offer treatment prior to donation but this decision can be individualized depending on the situation
treat both the recipient post-transplant (and donor, as indicated) if the recipient received a graft from a donor known to have untreated LTBI
it is not necessary to treat the recipient if the donor is fully treated prior to transplantation
– Active TB treatment (CDC 2022): –
Intensive phase involves 2months of Rifampicin, Isoniazid, Pyrazinamide, Ethambutol (RHZE) plus pyridoxine
Continuation phase consists of 4months of Rifampicin and Isoniazid (RH) plus pyridoxine
References
1. Simkins J, Donato-Santana C, Morris MI, Abbo LM, Camargo JF, Anjan S, et al. Treatment of latent tuberculosis infection with short-course regimens in potential living kidney donors. Transplant infectious disease : an official journal of the Transplantation Society. 2020 Apr;22(2):e13244. PubMed PMID: 31923346. Epub 2020/01/11. eng.
2. Rose G. The risk of tuberculosis transmission in solid organ transplantation: Is it more than a theoretical concern? The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale. 2005 Sep;16(5):304-8. PubMed PMID: 18159565. Pubmed Central PMCID: PMC2095042. Epub 2007/12/27. eng.
3. Morris MI, Daly JS, Blumberg E, Kumar D, Sester M, Schluger N, et al. Diagnosis and management of tuberculosis in transplant donors: a donor-derived infections consensus conference report. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2012 Sep;12(9):2288-300. PubMed PMID: 22883346. Epub 2012/08/14. eng.
4. Subramanian AK, Theodoropoulos NM. Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious diseases community of practice of the American Society of Transplantation. Clinical transplantation. 2019 Sep;33(9):e13513. PubMed PMID: 30817030. Epub 2019/03/01. eng.
5. Sterling TR, Njie G, Zenner D, Cohn DL, Reves R, Ahmed A, et al. Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020. MMWR Recommendations and reports : Morbidity and mortality weekly report Recommendations and reports. 2020 Feb 14;69(1):1-11. PubMed PMID: 32053584. Pubmed Central PMCID: PMC7041302 completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed. Epub 2020/02/14. eng.
The index case involves a prospective renal donor for his brother with low immunological risk (000 mismatch and no DSA), with a history of a positive Heaf test.
Heaf test was a test which was used to assess exposure to mycobacterium bacilli in a person. The test was performed using 6 needles soaked in tuberculin PPD (pure protein derivative) injected in a circular fashion over flexor aspect of forearm. The test was assessed after 2-7 days, looking for induration at the injection site. This test is not done nowadays. Heaf test is similar to a tuberculin skin test (TST).
Grading of the test result was done as Negative (No induration), Grade 1 (4-6 papules: negative), Grade 2 (an indurated ring formed by confluent papules: positive), Grade 3 (filling the center to form a disc: positive), Grade 4 (Disc >10 mm with or without blistering: strongly positive) (1).
Interpretation:
Grade 1 & 2: due to prior BCG vaccination, or avian tuberculosis
Grade 3 & 4: To be assessed for tuberculosis by getting chest X ray and other investigations (Possibility of latent TB/ active TB).
The index donor should be evaluated for tuberculosis by getting a detailed history including symptoms like cough, low grade fever, weight loss, past history of tuberculosis diagnosis and treatment, or any history of exposure to someone with tuberculosis (2). Other factors to be assessed include history of stay or travel to an endemic zone of tuberculosis for more than 3 months, social risk factors like working in healthcare, homelessness, alcohol or other substance abuse, prison exposure, and medical risk factors including diabetes, and having an underweight BMI (2,3).
Further testing in form of Interferon Gamma Release Assay (IGRA) should be done (4). A chest X ray and sputum examination should be performed.
If the index donor shows any signs of active tuberculosis (symptoms, radiological lesions, a positive sputum test), then the donation is contraindicated and the prospective donor should be treated for tuberculosis. If there is a past history of tuberculosis treatment in the donor, then organ donation can be proceeded with after a detailed counselling of the recipient, with chemoprophylaxis post-transplant under the guidance of an infectious disease specialist (2).
If the index donor is diagnosed to have latent tuberculosis, then the donor should be treated for latent tuberculosis using isoniazid for 9 months (5). Other options include rifampicin for 4 months and weekly isoniazid and rifapentine for 3 months (5,6). The organ donation can take place with a detailed counselling of the recipient, with chemoprophylaxis post-transplant under the guidance of an infectious disease specialist (2). There are no recommendations regarding timing of donation after diagnosis of latent tuberculosis in donor, but it is preferable to donate after completion of treatment, although donation can be done earlier also (2).
References:
Galbraith NS, Hanson A, Shoulman R, Andrews DW, Lee DB. Interpretation of positive reactions to Heaf tuberculin test in London schoolchildren. Br Med J. 1972 Mar 11;1(5801):647-9. doi: 10.1136/bmj.1.5801.647. PMID: 4622617; PMCID: PMC1787811.
Lentine KL, Kasiske BL, Levey AS, Adams PL, Alberú J, Bakr MA, Gallon L, Garvey CA, Guleria S, Li PK, Segev DL, Taler SJ, Tanabe K, Wright L, Zeier MG, Cheung M, Garg AX. KDIGO Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors. Transplantation. 2017 Aug;101(8S Suppl 1):S1-S109. doi: 10.1097/TP.0000000000001769. PMID: 28742762; PMCID: PMC5540357.
Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL, Desmond E, Keane J, Lewinsohn DA, Loeffler AM, Mazurek GH, O’Brien RJ, Pai M, Richeldi L, Salfinger M, Shinnick TM, Sterling TR, Warshauer DM, Woods GL. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Infect Dis. 2017 Jan 15;64(2):111-115. doi: 10.1093/cid/ciw778. PMID: 28052967; PMCID: PMC5504475.
Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation. 2018 Feb;102(2S Suppl 2):S60-S65. doi: 10.1097/TP.0000000000002014. PMID: 29381579.
Subramanian AK, Theodoropoulos NM; Infectious Diseases Community of Practice of the American Society of Transplantation. Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious diseases community of practice of the American Society of Transplantation. Clin Transplant. 2019 Sep;33(9):e13513. doi: 10.1111/ctr.13513. Epub 2019 Mar 22. PMID: 30817030.
Krishnamoorthy S, Kumaresan N, Zumla A. Latent tuberculosis infection and renal transplantation – Diagnosis and management. Int J Infect Dis. 2019 Mar;80S:S73-S76. doi: 10.1016/j.ijid.2019.01.049. Epub 2019 Feb 6. PMID: 30738187.
Heaf test is an old PPD skin test used for children and young adults to check if they have been exposed to TB infection.
If Heaf test is negative, this indicates the need for BCG vaccine.
Heaf test discontinued on 2005 because the manufacturer stopped the production of tuberculin derivatives and Heaf gun because of financial unsustainability.
The reading of the Heaf test was defined by a scale:
· Negative – No induration, maybe six-minute puncture scars
· Grade 1 – four to six papules also considered negative)
· Grade 2 – Confluent papules form indurated ring (positive)
· Grade 3 – Central filling to form disc (positive)
· Grade 4 – Disc >10 mm with or without blistering (strongly positive)
Grades 1 and 2 could result from previous BCG or previous avian tuberculosis, rather than human TB infection.
Persons who are found to have a grade 3 or 4 reaction, they should be referred for chest X-ray and IGRAs to rule out latent TB.
Mantox test has replaced Heaf test. Equivalent Mantoux test:
· 0–4 mm induration (Heaf 0-1)
· 5–14 mm induration (Heaf 2)
· >15 mm induration (Heaf 3-4)
If confirmed latent TB:
Untreated Latent TB without active infection is not a contra-indication for donation.
The risk of TB transmission from donor with treated latent TB is low.
Age 65y or below: start treatment for Latent TB unless it is contr-indicated because of liver disease.
Latent TB is not always treated if thought to be drug resistant, in this case regular monitoring to check for active infection.
It is better to defer donation till treatment is completed.
Treatment involves:
1- Rifampicin +INH for 3 months. Or
2- INH for 6 months.
The recipient is the brother of the donor with good donation offer. The recipient should be tested for Latent TB as well. Treatment before transplantation is better.
most current guidelines recommend the use of TST for the screening of LTBI in solid organ candidates/recipients and living donors.
(IGRAs) is a new diagnostic tools that emerged in the last decade.
In comparison to TST, they have some benefits, including the avoidance of interpreting bias, a reduction in false-positive results associated with prior nontuberculous mycobacterial exposure or BCG vaccination, and they are likely more sensitive in candidates with advanced cirrhosis and chronic renal failure because they have a higher yield and better correlation with clinical risk factors for LTBI in these patients.
Patients who are deemed to be at a high risk for LTBI include those who were born in or formerly resided in endemic countries, household contacts of an active TB infection, and those who work or reside in high-risk environments, such as prisons and homeless shelters.
Because the predictive results of both tests are influenced by the expected prevalence of LTBI, some doctors advise adjusting the diagnostic strategy based on the estimated risk of infection. The adoption of a more precise test may lower the rate of false-positive results and, as a result, the number of patients who would be exposed to LTBI medication unnecessarily, making IGRAs the sole method in low-risk patients. To increase the sensitivity of screening, both tests may be carried out on high-risk patients, and any positive result should be interpreted as proof of LTBI.
Candidates should take the TST or IGRA for LTBI evaluation. An induration of 5 mm or more at 48 to 72 hours should be regarded as a positive reaction if TST is chosen as the screening test. In order to assess a boosted-related skin conversion, a second TST should be done 7 to 10 days following the first TST.
Both tests might be run, and any positive results would be taken as proof of LTBI. In order to prevent TST-mediated enhancement of later IGRA responses, IGRA should always be carried out before to or concurrently with TST implantation whenever this dual-test technique is used.
Before beginning LTBI treatment, all individuals with positive results from any of these tests must be ruled out for active TB infection. This assessment entails looking for symptoms and signs that could point to TB, performing a chest radiograph, and imaging additional body sites in cases when extrapulmonary manifestations are present. The necessary clinical specimens should be collected for microbiological confirmation of the diagnosis if any indication of an active infection is discovered during this workup. Transplantation should be delayed once active TB infection has been identified until the condition is adequately treated with appropriate care and smears are negative.
If the microbiologic diagnosis of tuberculosis in the donor is only discovered after organ transplantation, treatment for active infection in the recipient should begin right away in accordance with local regulations. All M. tuberculosis isolates from the donor should undergo drug susceptibility testing since identifying medication resistance may be crucial for determining the course of treatment for the recipients. reference :
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD8.
This expected excellent match donor is showing a positive head test
in such findings, he may have latent TB or previous vaccination or had a previous infection with TB.
In such a case, he may need treatment with 6 months of INH before transplantation. As a risk of having active TB post renal transplant as per the EBM.
This donor needs full evaluation and workup if he is symptomatic
Positive TST induration of more than 5 mm needs treatment of latent TB with isoniazid for around six months before transplantation. Further evaluation with chest x-ray, CBC , biochemistry and most importantly, history and physical examination.
after transplantation careful monitoring is needed
How do you proceed Skin testing for tuberculosis (TB) utilizes a form of the diagnostic reagent tuberculin. The multiple puncture technique is referred to as the Heaf, or tine test. Purified protein derivative injected by single or multiple injection methods. it can given as first strength” (1 TU) or “second strength” (250 TU) and is equivalent to a 1:100 concentration .
Grades of Heaf test negative – minute puncture scars, no induration grade 1 – at least 4 puncture points are indurated grade 2 – coalescence of puncture points forming a ring of induration grade 3 – extensive induration (5 – 10 mm) grade 4 – severe induration (>=10mm); may be central blistering
It can be used to determine if a person has previous exposure to Tuberculosis or has been vaccinated . PPD is given on flexor surface of forearm and reading is done after 3 days It is utmost important to rule out tuberculosis in kidney donors., A thorough history and detailed physical examination in must.
He will need investigation including- Blood CP/ESR, Renal and liver functions, CRP Chest X Ray and if any concern then HRCT AFB smear and culture IRGA- High specificity in detecting LTBI
Treatment Oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily Other options include- RIF 600 mg daily for 4 months INH and rifapentine weekly for 12 weeks
Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation. 2018 Feb;102(2S Suppl 2):S60-S65.
The donor has a positive tuberculin skin test
A positive TST would indicate latent TB infection (LTBI) or previous BCG vaccination
It is important to ensure that the donor does not have active TB infection.
The donor should be asked about symptoms of:
Cough
Fever
Night sweats
Unintentional weight loss
A thorough examination carried out:
Assess for lymph nodes
RS examination
Abdominal examination – to assess for hepatosplenomegally
Investigations:
CBC
ESR
Sputum (if the patient is coughing and producing sputum) – for microscopy, AAFBs , gen xpert
CXR – to assess for pleural effusion, consolidations, nodular opacities
If the patient does not have any signs, symptoms, radiological or microbiological evidence of TB, then the patient has LTBI
Since he is a donor, there is a risk of transmitting the dormant bacilli to the recipient who has a much higher risk of developing active TB which is associated with significant mortality and morbidity
The donor needs to be treated for the LTBI. There are several regimens available:
INH plus rifapentin once weekly for 3 months
INH daily for six months
Rifampicin daily for four months
INH/Rifampin daily for three months
He will need to complete the treatment before proceeding for the transplant
Heaf test positive may indicate past TB infection, BCG vaccination or atypical MBT infection.Tuberculin skin test (TST) and the interferon gamma release assay (IGRAs) are approved screening methods for LTBI. These tests do not differentiate active from latent TB, and may be negative during times of active infection. Latent TBI is a cause of active disease in the post-transplant period, if undetected, may rapidly progress to aggressive form with extrapulmonary manifestations(1).
How would you proceed?
1. History and Examination:
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).
I will consider the following points to make a decision regarding the transplant process with this donor(1,2):
1. If this potential kidney donor with history of latent TB-treated appropriately, the risk of transmission is lower and the transplant can be proceeded to with this donor provided careful clinical monitoring of the recipient not to have DD-TBI.
2. The risk of transmission is moderate if there is a history of latent TB-treated insufficiently or not treated or treatment details not clear OR new diagnosis of latent TB-positive TST or Interferon gamma release assay found during pre-transplant evaluation; evaluation finds no evidence of active TB. In this setting, with moderate risk of transmission, I will consider deferring transplant if possible until donor has taken some/all of chemoprophylaxis and consider chemoprophylaxis of recipient beside clinical monitoring.
3. Unexplained pulmonary apical fibrosis in donor without cavitation and without additional testingcarries variable risk of transmission. I will defer donation and consider further evaluation.
4. History of active MTB treated appropriately over 2 years ago: there is lower to moderate risk of transmission. I will monitor recipient clinically, consider cultures of previous TB sites if possible and suggest chemoprophylaxis of recipient.
5. History of active TB-site remote from transplant, treated appropriately within 2 years: associated with higher increased risk if less than 2 years since active TB diagnosis. In such setting, I will defer live donors until adequately treated; consider consult with infectious disease specialist; recommend cultures of previous TB sites prior to transplant if possible.
6. History of active renal TB treated appropriately. (If not treated appropriately donation should be deferred until after appropriate treatment). This situation is associated with moderate risk of transmission. I will verify treatment; monitor clinically; recommend chemoprophylaxis for recipient; recommend cultures of previous TB site(s); consider consult with infectious disease specialist.
Therapeutic Regimens(3):
1. Timing of Treatment: treatment for LTBI should be started before transplant.
2. For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
3. Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
4. Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
References
1. OPTN;Guidance for Identifying Risk Factors for Mycobacterium tuberculosis (MTB) During Evaluation of Potential Living Kidney Donors.
2. Diagnosis and Management of Tuberculosis in Transplant Donors: A Donor-Derived Infections Consensus Conference Report”. Morris MI, Daly JS, Blumberg E, Kumar D, Sester M, Schluger N, Kim SH, Schwartz BS, Ison MG, Humar A, Singh N, Michaels M, Orlowski JP, Delmonico F, Pruett T, John GT, Kotton CN. Am J Transplant. 2012 Aug 6.
3. Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation. 2018 Feb;102(2S Suppl 2):S60-S65. doi: 10.1097/TP.0000000000002014. PMID: 29381579.
A 41-year-old man came forward to donate a kidney to his brother. 000 mismatch, excellent kidney function, no DSA. His GP reported that he had a positive Heaf test.
How would you proceed? Heaf test is A skin test to determine whether an individual is immune to tuberculosis due to previous exposure, carried out prior to vaccination ,if negative,=> the individual should be vaccinated.
A Heaf gun with disposable single use heads is recommended. The gun injects purified protein derivative equivalent to 100,000 units per ml to the skin over the flexor surface of the left forearm. The test is read between 3 and 10 days later. The injection must not be into sites containing superficial veins.
The reading of the Heaf test was defined by a scale:
Grade 1 – four to six papules (also considered negative)- avian TB/BCG
Grade 2 – Confluent papules form indurated ring (positive)
·Grade 3 – Central filling to form disc (positive)
Grade 4 – severe induration >10 mm with or without blistering (strongly positive) Grades 1 and 2 may be the result of previous BCG or avian tuberculosis. Grades 2-4 considered positive and should be managed as latent TB, should send the patients for chest Xray.
The patient should be treated for LTBI by one of the followings: He should be treated before donation. Rifampicin 10mg/kg (max 600mg) once daily for 4 months. Rifampicin 10mg/kg+ Isoniazid 5 mg/kg daily for 3 months. Isoniazid 5mg/kg daily for 6-9 months or 15mg/kg twice weekly for 6-9 months, to be given with pyridoxine 25-50mg to prevent peripheral neuropathy.
Organs from donors with known active TB infection should be discarded. If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines.
Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
Delay donation and give the donor short and effective treatment with 3 months of INH + Rifampicin for latent tb after evaluation
or
Long course: Isoniazid monotherapy for 6 or 9 month with pyridoxine tabs 10-50mg according to The US CDC recommendations .
References: *American Journal of Transplantation 2012; 12: 2288–2300.doi: 10.1111/j.1600-6143.2012. 04205. *Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD *Munoz P, Rodriguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clin Infect Dis 2005; 40: 581– 587.
*Sterling TR, Njie G, Zenner D, et al. Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020. MMWR Recomm Rep 2020;69(No. RR-1):1–11. *CDC Treatment Regimens for Latent TB Infection
Although the multiple puncture technique(heaf ,tine test ) has found favor as a screening
tool, a positive result should be confirmed by Mantoux testing unless vesiculation has taken place.
Thus, Mantoux testing is the procedure of choice. Mantoux testing has the advantage of
using a standard amount of a standard potency reagent and thus is quantifiable and
reproducible.(1).
Donors with positive test:
Evaluation for TB disease:
History,symptoms,sign and contacts.
CXR.
Patient with symptoms summits 3 sputum samples for TB test.
Search for comorbidities : — liver disease, neuropathy, and concomitant medications.
Regimens for treatment of TBI are associated with hepatotoxicity; the risk of hepatotoxicity is greatest with isoniazid and less so for the rifamycin-based regimens. Baseline liver enzyme testing is appropriate for the following nonpregnant adult;
●Patients with heavy alcohol use, liver disease, or chronic hepatitis ●Patients currently injecting drugs ●Patients on potentially hepatotoxic medications ●Patients with history of elevated serum transaminase concentrations
Selecting a regimen : none of the available treatment regimens has been shown to be superior to any of the others. Therefore, the choice of regimen is based largely on the likelihood of adherence, the potential for adverse effects, and preference (of the patient, provider, and/or public health program).
Low-incidence settings low-incidence settings (TB incidence rate <100 per 100,000 population), CDC) and National Tuberculosis Controllers Association (NTCA) in 2020, which favor a rifamycin-based regimen over isoniazid monotherapy.
Given detection of increased levels of nitrosamine impurities in samples of rifampin (RIF) and rifapentine (RPT) announced by the US Food and Drug Administration (FDA) in August 2020 . isoniazid (INH) monotherapy may be considered as an alternative regimen for adults with newly diagnosed TBI. INH for 6 months. High-incidence settings : TB incidence rate ≥100 per 100,000 population who may warrant TBI treatment consist of close contacts of TB cases.
For these individuals, a rifamycin-based regimen (4R, 3HR, or 3HP) .
the World Health Organization, which favors the regimen of INH daily for six months or
2_ Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020. AUSterling TR, Njie G, Zenner D, Cohn DL, Reves R, Ahmed A, Menzies D, Horsburgh CR Jr, Crane CM, Burgos M, LoBue P, Winston CA, Belknap R .MMWR Recomm Rep. 2020;69(1):1. Epub 2020 Feb 14.
Is an old test used before to check that the person exposed to TB before or not , usually was done before vaccination , if it is negative , indicates the need for BCG vaccine.
The reading is performed as a scale from negative to 4 .
Grade 1-2 may be due to previous vaccination , grade 3-4 should proceed for chest X-ray , IGRA to rule out latent or active infection
If confirmed latent TB , should be treated and to postpone donation until treatment
Treatment :
INH daily for 6 months or
Rifampicin alone for 4 months or
INH plus Rifampicin daily for 3 months or
INH and Rifampicin weekly for 3 months
References
Simkins J, Donato-Santana C, Morris MI, Abbo LM, Camargo JF, Anjan S, et al. Treatment of latent tuberculosis infection with short-course regimens in potential living kidney donors. Transplant infectious disease : an official journal of the Transplantation Society. 2020 Apr;22(2):e13244. PubMed PMID: 31923346. Epub 2020/01/11. eng.
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD
The Heaf test is a skin test was used to determine exposure to TB infection, it was discontinued and currently replaced by Mantoux test (PPD).
-Positive results might indicate BCG vaccination or avian tuberculosis.
*Both donor and potential recipient should be evaluated and screened for LTBI and active TB ( especially they are brother) for the following;
– TB remains a relevant public health problem.
– 10% of people with LTBI will progress to developing active TB disease.
– The risk of TB reactivation is higher in immunocompromised individuals.
– TB resulted in significant morbidity and mortality.
Screening for LTBI : Identify risk factors:
– BCG vaccination ( as it may influence the screening test)
– Previous TST results.
– Exposure to individuals with active TB in the household or workplace
– Prior residence or travel to areas highly endemic for TB.
– Any history of previous TB or TB treatment. Screening tests;
-There is no gold standard test. WHO recommended the following: TST, IGRA
* Tuberculin skin test (TST) :
– Unreliable advanced CKD and immunosuppressed individuals.
– The result might be falsely positive in previous BCG vaccination
* IGRAs; (QuantiFERON-TB and T-SPOT ):
– High specificity in detecting LTBI in immunocompromised.
– More sensitive than the TST for the diagnosis of LTBI in KTRs.
– Result will not be affected by BCG vaccine.
*The result of these test should be interrupted with caution;
– Both cannot distinguish latent TB infection from active disease.
– Both might be falsely negative or indeterminate results in immunocompromised individual, as they assess the immune response of the body to MTB. – Neither TST nor IGRAs are recommended for diagnosing active infection.
*Since the sensitivities of TST and IGRA do not overlap fully both modalities preferred to be used in screening in those with high pre‐test probability of LTBI in whom a single positive test result might change clinical management. ( LTBI, previous vaccination, active TB)
*CXR.
*Patients with a prior history of positive TST or IGRA testing to be screened for active TB.
– Signs and symptoms of active TB.
– Sputum for smear, culture, PCR.
*The result of the screening test will further guide the management:
*Active TB in :
– Donor is a contraindication to organ donation. Transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
-Recipient needs to be treated prior to transplant.
LTBI: Donor: -Untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered. -The risk of transmission is low if therapy for LTBI was completed before donation.
Recipient:
-When possible, should be started before transplant, and can often be completed while the patient is on the waitlist.
-If urgent transplant is indicated, the treatment can be held peri-operatively and resumed when medically possible until completion of the originally planned course.
– Caution with rifamycins after transplant.
Regimen AST; INH 300 mg/d for 9 months, with oral pyridoxine 25 to 50 mg daily or twice weekly by (DOT) 9 months of therapy is preferred over 6months because of better protection. Monitoring for side effect; hepatotoxicity, neurotoxicity, drug-drug interaction ( IS level)
Alternative regimens
Rifampin for 4 months or INH with rifapentine for 12 weeks.
Can be used in the pre‐transplant setting.
Should be avoided if possible or used with caution post‐transplant due to interactions with IS.
References: Subramanian, AK, Theodoropoulos, NM; on behalf of the Infectious Diseases Community of Practice of the American Society of Transplantation. Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious diseases community of practice of the American Society of Transplantation. Clin Transplant. 2019; 33:e13513. Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation. 2018 Feb;102(2S Suppl 2):S60-S65. doi: 10.1097/TP.0000000000002014. PMID: 29381579. Sundaram M, Adhikary SD, John GT, Kekre NS. Tuberculosis in renal transplant recipients. Indian J Urol. 2008 Jul;24(3):396-400. doi: 10.4103/0970-1591.42625. PMID: 19468476; PMCID: PMC2684355. Krishnamoorthy S, Kumaresan N, Zumla A. Latent tuberculosis infection and renal transplantation – Diagnosis and management. Int J Infect Dis. 2019 Mar;80S:S73-S76. doi: 10.1016/j.ijid.2019.01.049. Epub 2019 Feb 6. PMID: 30738187.
Great Dr Hadeel. Can expand you on your statement ‘When possible, should be started before transplant, and can often be completed while the patient is on the waitlist.‘
Generally for SOT candidate treatment of LTBI preferred to be started and completed before transplantation to decrease the risk of reactivation post-transplantation.
KT candidates on dialysis they can wait, However, this might not be applicable for other SOT if it was indicated urgently as a life saving like in liver transplant.
Heaf test is not accurate to assess immune status for TB.
Assessment of risk for TB:
. History of previous infection with TB , treatment of active TB, or close contact with active TB patient.
.Diagnosis of latent TB IGRA being better TST as it is not affected by previous BCG vaccination .
. In case of donor with latent TB, according to CDC and National Tuberculosis Controller Association, we proceed for 3 month rifampicin regimen such as oral rifampin ,INH and pyridoxine.
Heaf test was historically used in the UK until 2005 and then replaced by Mantaux test. A heaf gun was used to simultaneously inject various serum samples under the skin. The skin was poked with needles that had been soaked in tuberculin pure protein derivative (PPD). A heifer gun with single-use disposable heads was suggested. On the flexor surface of the left forearm, the gun administered PPD equivalent to 100,000 units per ml in a six-part circular pattern. The exam was graded two to seven days later. Injections were not permitted in places with superficial veins. The Heaf test score was determined on a scale: Negative – Absence of induration, maybe six-minute puncture scars Grade 1 – four to six papules (also considered negative) 2nd grade: confluent papules create an indurated ring (positive) Grade 3 – Filling the center to form a disc (positive) Grade 4 – Disc more than 10 millimeters with or without scorching (strongly positive) Grades 1 and 2 may be caused by BCG or avian tuberculosis instead of a human TB infection.
Approach to clinical scenario
According to WHO guidelines on latent Tb screening, includes 2 tests: Mantoux test and Interferon gamma release assays (IGRAs). In this case, diagnostic strategy for detecting active and/or latent tuberculosis would be as follows: Request detailed history of contact with a patient with active TB. History of prior anti-tuberculosis therapy. constitutional symptoms such as cough, fever, anorexia, night sweats, and weight loss or other symptoms like hemoptysis.
Therapy of LTBI in the recipient and donor
It is crucial to take all possible precautions to stop the spread of TB infection in such people since TB could directly impair how well an allograft functions. Efforts must be made to detect and treat LTBI and active TB in both the live donor and recipient prior to transplantation. Therapy for LTBI should adhere to WHO 2018 recommendations. LTBI treatment options
– Six months of isoniazid monotherapy (recommended in countries with high & low TB incidence). – 3 months of daily Rifampicin and Isoniazid therapy (for children and adolescents under 15 years old). – Weekly Isoniazid and Rifapentine for three months.
How would you proceed? Heaf test is a skin test to diagnose latent TB, was used in UK, it is a spring-loaded instrument with six needles arranged in a circular formation which was inserted in the wristor shoulder, the needles were dipped with purified protein derivative and pricked in to the skin. The reading of the Heaf test was defined by a scale: · Negative – No induration, maybe six minute puncture scars- avian TB /BCG · Grade 1 – four to six papules (also considered negative)- avian TB/BCG · Grade 2 – Confluent papules form indurated ring (positive) · Grade 3 – Central filling to form disc (positive) · Grade 4 – Disc >10 mm with or without blistering (strongly positive)
Grades 2-4 considered positive and should be managed as latent TB, should send the patients for chest Xray. The patient should be treated for LTBI by one of the followings: Rifampicin 10mg/kg (max 600mg) once daily for 4 months. Rifampicin 10mg/kg+ Isoniazid 5 mg/kg daily for 3 months. Isoniazid 5mg/kg daily for 6-9 months or 15mg/kg twice weekly for 6-9 months, to be given with pyridoxine 25-50mg to prevent peripheral neuropathy. He should be treated before donation. References: Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD
How would you proceed? According to the guidelines both donor and recipients should be screened for LTBI or possible active TB as part of the transplant workupactive MTB is a contraindication for donation and should follow local protocol for treatment as the general populationMedical history including epidemiological history is he from an endemic area with a higher rate of TB including previous history of TB or treatment history for active TB, any BCG scar, any history of exposure or contact with an active case of TB at the workplace, or social history if he is homeless, refugee, alcoholic abuse, malnutrition or working in humanitarians, travel history in the last 2 years to an endemic area, previous TST or IGRA testing positive or treated for LTBIPhysical examination focus on LAP and chest examination, CXR for any fiberoptic apical lesion, calcified lymph node, or pleural thickeningHeaf test for TB
heaf test, it’s six needle guns sterilized by flaming. puncture skin test after cleaning the skin of the forearm cleaned isopropyl alcohol and p.p.d was applied by dropper and spread with the end-plate of the gun before firing usually wait for 7 days to interpret the test results and grades from 0-4
The positive Heaf test appears to be too sensitive. Both a negative and grade 1 positive should be negative and not significant and these children are given the B.C.G. vaccine. 4 or more palpable skin papules of at least 1 mm grade 2, grade 3 papules forming a ring in the middle, and grade 4 vehicular ulceration should be regarded as significant and the children investigated for M. tuberculosis infection.
he will be considered high risk for LTBI if confirmed he is from the endemic area then in addition to TST will do IGRA test as it will increase the sensitivity of the screening if positive will be treated on the line of LTBI provide he is asymptomatic with negative cxr with INH 300mg /day and pyridoxin 25 – 50mg for total 6 months and the transplantation will be postponed till he completed the course. some preferred 9 months of treatment with a lower rate of recurrence especially in the endemic area.
Alternative treatment
Rifampin in a dose of 600 mg for 4 months.
INH+ weekly rifapentine for 3 months.
References
1. Galbraith NS, Hanson A, Shoulman R, Andrews DW, Lee DB. Interpretation of positive reactions to Heaf tuberculin test in London schoolchildren. Br Med J. 1972 Mar 11;1(5801):647-9. doi: 10.1136/bmj.1.5801.647. PMID: 4622617; PMCID: PMC1787811.
2. Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis recommendations for solid organ transplant recipients and donors. Transplantation. 2018;102(2) Suppl 2:S60–SS5.
3.Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD
The Heaf test is a diagnostic skin test performed in order to determine whether or not a child has been exposed to tuberculosis.
Patients who exhibit a negative reaction to the test may be offered BCG vaccination.
The test is named after F. R. G. Heaf.
A Heaf gun with disposable single use heads is recommended.
The gun injects purified protein derivative equivalent to 100,000 units per ml to the skin over the flexor surface of the left forearm.
The test is read between 3 and 10 days later.
The injection must not be into sites containing superficial veins.
The reading of the Heaf test is defined by a scale:
negative – minute puncture scars, no induration
grade 1 – at least 4 puncture points are indurated
grade 2 – coalescence of puncture points forming a ring of induration
grade 3 – extensive induration (5 – 10 mm)
grade 4 – severe induration (>=10mm); may be central blistering
Grades 1 and 2 may be the result of previous BCG or avian tuberculosis.
Children who have a grade 3 or 4 reaction
I would proceed in following manner:
Medical history. The history of untreated or insufficiently treated TB should be investigated, as well as previous reactive IGRA or TST.
Endemic exposures within last 2 years
Radiographic findings, such as apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, or pleural thickening.
Active TB infection should be ruled out in donors at increased risk by obtaining samples, for example, sputum or bronchoalveolar lavage, to test for the presence of M. tuberculosis
Organs from donors with known active TB infection should be discarded.
If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines.
Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation. 2018 Feb;102(2S Suppl 2):S60-S65. doi: 10.1097/TP.0000000000002014. PMID: 29381579.
Check for risk factors for TB(1)
Country of origin
· Immigrants from TB endemic countries (incidence>100/100000)
Social risk factors
· Close contacts of individuals with TB disease,
· homelessness,
· injection drug use,
· work or residence in facilities (e.g. homeless shelters, correctional facilities)
Medical risk factors
· History of untreated TB
· Radiographic evidence prior TB
· If previously treated for either TB disease or LTBI, anti-TB drug(s), treatment duration, and adherence should be verified.
Look for active disease (pulmonary and extrapulmonary) (2)
· Symptoms like chronic cough, night sweats, weight-loss, fever, anorexia
· CXR
· Induced Sputum for ZN stain, (NAAT) Xpert MTN/RIF
· USG Whole abdomen
· CT/ MRI (when indicated)
Consider treatment as LTBI if no active disease (1)
Defer donation till completion of treatment (1) Treatment of LTBI should follow WHO 2018 guidelines (3)
· INH monotherapy- 6 months
· Rifampicin + INH daily- 3 months
· Rifapentine and Isoniazid weekly for 3 months
My preference would be Rifampicin plus INH daily for 3 months, pyridoxine 25-50mg and close monitoring for hepatotoxicity. References:
Morris MI, Daly JS, Blumberg E, Kumar D, Sester M, Schluger N, et al. Diagnosis and management of tuberculosis in transplant donors: a donor-derived infections consensus conference report. Am J Transplant. 2012;12(9):2288-300.
Malinis M, Koff A. Mycobacterium tuberculosis in solid organ transplant donors and recipients. Curr Opin Organ Transplant. 2021;26(4):432-9.
Krishnamoorthy S, Kumaresan N, Zumla A. Latent tuberculosis infection and renal transplantation – Diagnosis and management. Int J Infect Dis. 2019;80S:S73-S6.
👉 Heaf test represents an immunological reaction to TB antigen, which can give false positive result in case of prior BCG vaccine or living in high endemic area for TB.
👉 Heaf test or now what is called manteau test is used to diagnose latent TB infection, so we must proceed to IGRA test which is more sensitive and not give false positive results to exclude latent TB.
👉 In addition, epidemiological data regrading the residence or travel to endemic areas, contact with open TB cases or exposure to infection or past history of treatment from TB are essential steps in evaluation.
👉 In addition, CXR and HRCT are needed to exclude any pulmonary affection.
👉 Exclusion of active TB by sputum analysis for AFB, culture on BACTEC system, geneXpert study are essential to exclude active TB
👌 Active TB is absolute contraindication to donation, and therapy should be started immediately and must be isolated till clearance of sputum from his brother.
👌 Latent TB should be treated prior to consideration as donor by 4 months oral rifampin, or 6 months of INH or 3 months of combined INH and rifampin.
The Heaf test: is a skin test, to see the exposure to tuberculosis infection in the past.
Defined by a scale:
Negative – No induration
Grade 1 – four to six papules (also considered negative)
Grade 2 – Confluent papules form indurated ring (positive)
Grade 3 – Central filling to form disc (positive).
Grade 4 – Disc >10 mm with or without blistering (strongly positive).
I would proceed with detail History of past TB disease, or close contact with TB infected person or working in highly prevalent area and living with high-risk groups (prison inmates, homeless, drug abuser)
Important Investigations in pretransplant period of both Donor and Recipient: –
-Chest x-ray/ Chest CT scan.
-Sputum AFB, Culture & Gene- Xpert.
-QuantiFERON-TB-Gold In-Tube test (QFT).
–ESR, CRP.
Treatment of Latent TB infection in Donor
-Rifampin daily for 4 months
-INH + Rifampin daily for 3 months
-INH only daily for 6 – months.
Check investigation after treatment and before donation.
If diagnosed active TB, donation should be cancelled and start treatment of the donor.
References:
1-Galbraith NS, Hanson A, Shoulman R, Andrews DW, Lee DB. Interpretation of positive reactions to Heaf tuberculin test in London schoolchildren. Br Med J. 1972;1(5801):647-649. doi:10.1136/bmj.1.5801.647.
2-Singh, N., & Paterson, D. L. (1998). Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clinical infectious diseases, 27(5), 1266-1277.
Heaf test is a diagnostic skin test to determine whether or not person had been exposed to tuberculin infection.
grate 1 and 2 results from previous BCG or avian tuberculous rather than human T.B infection.
grade 3 or 4 need CXR and follow .
if the donor confirms active T.B the transplant is canceled and the pateint should receive the treatment of T.B..
pretransplant screening for latent T.B infection for the donor and recipient by obtaining a history of prior exposure or LTBitreatment, TST and CXR , also IGRAs are increasingly used.
in this living donor with positive TST and confirm diagnosis of LTBI should offer treatment for latent T.B. prior to donation as per local or national guidelines and the treatment should be completed before transplantation. there is no data on the optimal duration of LTB therapy
options of therapy include INH for 6 or 9 months with pyridoxine
INH plus rifampcin or rifapentine for 3 month and this regimen as guidlines of WHO 2018
References
Queipo JA, Broseta E, Santos M, Sanchez-Plumed J, Budia A, Jimenez-Cruz F. Mycobacterial infection in a series of 1261 renal transplant recipients. Clin Microbiol Infect 2003; 9: 518– 525.Google Scholar
3 Munoz P, Rodriguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clin Infect Dis 2005; 40: 581– 587.View
Introduction; –Current guidelines provide recommendations for latent TB screening in all KT candidates and donors before transplantation. –There are no gold standard tests for diagnosing latent TB accurately in KT candidates, but IGRA seems to present some advantages over TST in patients with ESRD. –The incidence and prevalence of latent TB in KT recipients is higher than in KT candidates and therefore KT recipients should be more frequently screened.
-The importance of diagnosis is supported by the fact that undiagnosed and untreated latent TB after KT significantly increases the risk of active TB. –Treatment of latent TB should be considered only after active TB has been excluded. –Treatment of KT recipients with latent TB is important for preventing the risk of reactivation.
-Treatment in KT patients is indicated in one of the following conditions:
*A positive TST or IGRA test,
*History of untreated TB,
*History of recent contact with an active TB patient,
*When the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB. How would you proceed? The following history will be obtained from the donor: –History of staying in country with high TB incidence > 3 months, –History of close contact with open TB infection, –History of working with high-risk groups (prison inmates, homeless, drug abuse) –Past history of infection or treatment for LTBI or active TB, -Past history of anti TB medications & duration of treatment, -Past history of BCG vaccination, -Family history for active or LTBI. Work Up; –Heaf test was used to assess individual immune status for TB ,but it is not accurate test and should not depend on it in this case. -Positive Heaf test indicates presence of immune response to TB protein either BCG vaccine or latent infection. -Sputum sample for AFB stain -IGRA (Quantiferon test) -CXR -LFTs (before starting anti TB medications) Treatment; -Donor should be referred to Pulmonology for clearance before proceeding for KT. –In the KT setting, the preferred treatment of latent TB is;
(Isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6.
-A regimen based on rifampicin is not recommended.
-Evaluation of liver enzymes during treatment, initially bi-weekly for 6 weeks and monthly thereafter, is recommended. References; –Bumbacea, D.; Arend, S.M.; Eyuboglu, F.; Fishman, J.A.; Goletti, D.; Ison, M.G.; Jones, C.E.; Kampmann, B.; Kotton, C.N.; Lange, C.; et al. The Risk of Tuberculosis in Transplant Candidates and Recipients: A TBNET Consensus Statement. Eur. Respir. J. 2012, 40, 990–1013. –Subramanian, A.K.; Theodoropoulos, N.M. Mycobacterium Tuberculosis Infections in Solid Organ Transplantation: Guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation. Clin. Transplant. 2019, 33, e13513. –Meije, Y.; Piersimoni, C.; Torre-Cisneros, J.; Dilektasli, A.G.; Aguado, J.M. Mycobacterial Infections in Solid Organ Transplant Recipients. Clin. Microbiol. Infect. 2014, 20 (Suppl. 7), 89–101. –Shu, C.-C.; Tsai, M.-K.; Lin, S.-W.; Wang, J.-Y.; Yu, C.-J.; Lee, C.-Y. Latent Tuberculosis Infection Increases in Kidney Transplantation Recipients Compared With Transplantation Candidates: A Neglected Perspective in Tuberculosis Control. Clin. Infect. Dis. 2020, 71, 914–923.
Thank you Dr Mohamed Abou Elenein
Well done for the detailed answer.
Can you clarify the exact role of BCG vaccine in the donor if he fulfils the above criteria such as staying in a country with high TB incidence > 3 months OR –History of close contact with open TB infection, –History of working with high-risk groups (prison inmates, homeless, drug abuse).
This potential kidney donor seems to be excellent, with zero mismatch, young with no DSA. However, he has positive Heaf test. This could mean previous vaccination, latent or active TB. To differentiate between them we need to take detailed history of vaccination, current or previous symptoms of TB, treatment of TB or contact with TB patients. Also we need to know how strong was the positivity. If all are negative, then we need to do a chest ray, CRP to make sure no active disease, especially if Heaf was grade 3-4 positive. If no active disease, then to diagnose latent TB, we need to do Mantoux test or IGRA. 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).
If confirmed to have latent TB (LTBI), WHO 2018 guidelines outline the following treatment options for LTBI (WHO, 2018b):
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 of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
In our center we use INH with pyridoxine for 9 months.
References:
1-S. Krishnamoorthy et al. / International Journal of Infectious Diseases 80 (2019) S73–S76
Thank you Dr Muntasir Mohammed. Whilst your answer was very detailed I feel I’m lost. You referred to: 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.
Then you mentioned 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
So you referred to 6 month and 9 month of INH monotherapy in low incidence countries. I do not know even what is the difference numerically between high and low incidence countries.
Would you be able to simplify your recommendation for this case please?
Will delayed the donation and give the donor short and effective treatment with 3 months of INH + Rifampicin for latent tb after evaluation.
History of exposure to active tb, previous tb, treatment for tb
chest x ray, sputum for afb1,2,biopsy or fnac of any lymph node, lft, crp, rft, uric acid
If diagnosed active TB, donation should be cancelled and start treatment of the donor. References
Sterling TR, Njie G, Zenner D, et al. Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020. MMWR Recomm Rep 2020;69(No. RR-1):1–11. DOI: http://dx.doi.org/10.15585/mmwr.rr6901a1
Simkins J, Donato-Santana C, Morris MI, Abbo LM, Camargo JF, Anjan S, Natori Y, Guerra G. Treatment of Latent Tuberculosis Infection with Short-Course Regimens in Potential Living Kidney Donors [abstract]. Am J Transplant. 2019; 19 (suppl 3).
Galbraith NS, Hanson A, Shoulman R, Andrews DW, Lee DB. Interpretation of positive reactions to Heaf tuberculin test in London schoolchildren. Br Med J. 1972 Mar 11;1(5801):647-9. doi: 10.1136/bmj.1.5801.647. PMID: 4622617; PMCID: PMC1787811.
A skin test to determine whether or not an individual is immune to tuberculosis due to previous exposure ,carried out prior to vaccination if negative, the individual should be vaccinated. Heave test is classified into 4 grades.
Grades 1 and 2 may be the result of previous BCG or avian tuberculosis. Children who have a grade 3 or 4 reaction require X-ray and follow-up.
MY approach to this case :
-History (prior TB exposures, history of active TB, travel or residence in en-demic regions and past TST results), physical examination(pneumonia, unexplained cachexia or lymphadenopathy),IGRAs test , sputum cultures and nucleic acid amplification tests , thoracic imaging (old granulomatous disease,apical scarring, new infiltrates).
– IGRAs have been shown to be of increased specificity antigens derived from M. tuberculosis compared with TST .
-Since he is a living donor the transplant can be delayed until a full evaluation of possible latent or active TB is performed.
Pretransplant recipient screening protocols often include obtaining a history of potential prior exposure or LTBI treatment, tuberculin skin testing(TST) or interferon-gamma release assays (IGRAs) and chest radiography (CXR) .
Recommendations for the management of LTB :
Short course regimens include:
-Three months of once-weekly isoniazid plus rifapentine. -Four months of daily rifampin. -Three months of daily isoniazid plus rifampin .
Long course : Isoniazid monotherapy for 6 or 9 month with pyredoxine tabs 10-50mg according to The US CDC recommendations . -In our center we used INH monotherapy for 6month. Reference :
1.American Journal of Transplantation 2012; 12: 2288–2300.doi: 10.1111/j.1600-6143.2012.04205.x
Heaf test was used to assess individual immune status for TB ,but it is not accurate test and should not dedpend on it in this case.
Assess patient riskfor TB
1- History of orevoius TB infection , treatment or close contact with patient with active TB.
2- For diagnosis of latent TB either TST or IGRA is recommended with IGRA being better option asit is not affected by previous BCG vaccination .
3- If the donor was latent TB , CDC and national tuberculosis controller association prefers 3 month rifampicine based regimen such as oral rifampin + INH and pyridoxine 25 mg .
The Heaf test:is a diagnostic skin test, was long performed to determine whether or not children had been exposed to tuberculosis infection which is not used since 2005.
The reading of the Heaf test was defined by a scale:
Negative – No induration, maybe six minute puncture scars
Grade 1 – four to six papules (also considered negative)
Grade 2 – Confluent papules form indurated ring (positive)
Grade 3 – Central filling to form disc (positive).
Grade 4 – Disc >10 mm with or without blistering (strongly positive).
Our case came positive Heaf test:
We should cover all points:
-History of staying in a tuberculous endemic area > 3 months and history of close contact with TB infected person.
-Working with high-risk groups (prison inmates, homeless, drug abuse)
-Past history of infection or treatment for TB, drugs used, and duration. Investigations:-
-Chest x-ray/ Chest CT scan.
-Sputum AFB, Culture & Gene- Xpert.
-QuantiFERON-TB-Gold In-Tube test (QFT).
-BAL if possible for a higher yield of sputum analysis.
-ESR, CRP. Might be active or latent TB: Treatment of Latent TB infection
This clinical state needs to be treated even if he is not donating kidney as 80-90% of LTBI will reactivate if not treated.
Treatment plan will be one of the following:
-Rifampin daily for 4 months
-INH + Rifampin daily for 3 months
-INH only daily for 6 – months.
Check investigation after treatment and before donation.
If diagnosed active TB, donation should be cancelled and start treatment of the donor. References:
1-Galbraith NS, Hanson A, Shoulman R, Andrews DW, Lee DB. Interpretation of positive reactions to Heaf tuberculin test in London schoolchildren. Br Med J. 1972;1(5801):647-649. doi:10.1136/bmj.1.5801.647.
2-Singh, N., & Paterson, D. L. (1998). Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clinical infectious diseases, 27(5), 1266-1277.
Multipuncture methods (including the Tine test and the Heaf test) should not be used; they may be easier to administer but are not accurate because it is not possible to precisely control the amount of tuberculin
Exclude TB disease prior to treatment of TB infection
Prior to starting treatment for TB infection, we ensure that there are no signs or symptoms of TB disease (previously termed active TB) based on history (eg, fever, cough, weight loss, night sweats), physical examination, and chest radiography. This evaluation is important to avoid inadvertent undertreatment of TB disease, which can lead to emergence of drug resistance.
Testing for TB infection (previously termed latent TB infection) is reserved for individuals who are at increased risk of developing TB disease and would thus benefit from treatment
●Individuals at increased risk of recent infection (eg, close contacts of persons with untreated TB disease ●Individuals at high risk of reactivation if infected (eg, immunocompromised individuals) ●Individuals at moderate or slightly increased risk of reactivation who reside in an area where TB is prevalent
In general, either IGRA or TST may be used; , particularly for patients who are unlikely to return to have the TST read and for patients with a history of Bacille Calmette-Guerin (BCG) vaccination administered after 12 months of age.
.
Only those who would benefit from treatment of LTBI should undergo testing, so a decision to test presupposes a decision to treat if the test is positive.
If the first test is negative, close contacts of patients with active pulmonary TB should undergo a second test eight weeks later. Many TB programs test casual contacts only once at eight weeks after exposure.
FOR OUR CASE POST PONE UNTIL TB SCREEN FOR BOTH DONOR -Recipient IGRA is preferable if available NOT DEPEND ON RESULT OF HEAF TEST
TREATMENT LATENT TB
-Heaf test is a skin test used to detect if an individual is immune to tuberculosis, it is used to be done before vaccination. If positive it indicates that the case is immune needs no vaccine and if negative means that the case needs to receive BCG vaccine
Current international guidelines recommend using TST and/or IGRAs for LTBI screening for donors and recipients , infact IGRAs are more specific with higher r positive and negative predictive values but are more expensive
A history of untreated LTBI without active infection in the donor is not a contraindication for donation. The risk of transmission is low if LTBI therapy course was completed before organ donation and transplant recipients from such donors can be clinically monitored without receiving LTBI therapy.
Therefore both donor and recipeint have to undergo screening for LTBI
So this donor can be accepted but treated first and after confirmation of full clearance of TB donation can proceed .
LTBI therapy includes oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
9 months of therapy provides better protection compared to 6 months .
INH should be monitored for hepatotoxicity by checking liver function tests every
2 weeks for 6 weeks, then monthly afterwards .
Other regimens containing rifamycins can be used including Rifampicin 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
Fluoroquinolones (± ethambutol) have been proposed for LTBI therapy but less efficient Reference
-Meinerz G, Silva CKD, Dorsdt DMB, et al. Latent tuberculosis screening before kidney transplantation in the South of Brazil. J Bras Nefrol. 2021;43(4):520-529. doi:10.1590/2175-8239-JBN-2020-0189
-Santoro-Lopes G et al . Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation 2018 , Volume 102 , Number 2S-2
Heaf test Was the test used till 2005 and then discontinued and substituted by the Mantoux test Used for determining the previous exposure to M.TB How proceed First, the donor and recipient should be screened against latent TB (the recipient will be immunocompromised so he has a high risk for reactivation post-transplantation);
Exclude the active disease especially, if there is a clinical manifestation.
Hence LTB should be screened for, by TST and IGRAs, if there is positive results donation should be delayed and receive a protocol treatment;
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 daily for 3 months as an alternative to INH monotherapy as a preventive treatment for children and adolescents aged <15 years in countries with high Tb incidence.
RIF and INH weekly for 3 months is offered as an alternative to INH monotherapy as a preventive treatment for adults and children in countries with high Tb incidence.
In low TB incidence countries; INH monotherapy for 9 months or 3 months of weekly RIf and INH or 3-4 months of RIF alone.
Donations can be conducted after cure of the disease
References;
Aguado JM, Herrero JA, Gavaldá J, et al. Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain, Transplantation, 1997, vol. 63 (pg. 1278-86)
2Muñoz P, Rodriguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants, Clin Infect Dis, 2005, vol. 40 (pg. 581-7)
3Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management, Clin Infect Dis, 1998, vol. 27 (pg. 1266-77)
4s l. Guidelines for the prevention and management of infectious complications of solid organ transplantation, Am J Transplant, 2004, vol. 4 (Suppl 10)(pg. 37-41)
I like your summary, and analysis. You mention 3 possible options for prophylaxis against latent TB in recipients. Which one would you choose for your patients?
A 41-year-old man came forward to donate a kidney to his brother. 000 mismatch, excellent kidney function, no DSA. His GP reported that he had a positive Heaf test.
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The Heaf test is a diagnostic skin test used to determine if a child has been exposed to tuberculosis.
The BCG test is named after F. R. G. Heaf.
The Heaf test was used in the UK to determine if the BCG vaccine was needed, but was withdrawn due to lack of manufacturers.
The Heaf test gives six individual injections.
The test is read between 2 and 7 days later.
The Heaf test is a scale of negative to positive, with grades 1-4 requiring X-ray and follow up due to previous BCG or avian tuberculosis.
Other Tests
Mantoux test positive levels range from 0-4 mm to >15 mm.
Mantoux test is preferred for tuberculosis diagnosis.
How would you proceed?
1- Medical history
I will should ask about the patient’s history of TB exposure, infection, or disease.
It is also important to consider demographic factors (e.g., country of origin, age, ethnic or racial group, occupation) that may increase the patient’s risk for exposure to TB or to drug-resistant TB.
medical conditions, such as HIV infection or diabetes, that increase the risk of latent TB infection progressing to TB disease.
2- Physical examination
Can provide valuable information about the patient’s overall condition and other factors that may affect how TB is treated, such as HIV infection or other illnesses.
3- Chest x-ray/CT.
A posterior-anterior chest radiograph is used to detect chest abnormalities, but cannot diagnose TB.
May be used to rule out the possibility of pulmonary TB in a person who has had a positive reaction to a TST or TB blood test and no symptoms of disease.
3- And other laboratory tests
Microbiology
Acid-fast-bacilli (AFB) on a sputum
A positive culture for M. tuberculosis confirms the diagnosis of TB disease, and laboratories should report positive results within 24 hours to the primary health care provider and TB control program.
4- Full blood count
CBC /ESR is usually raised/ KFT/LFT/CRP/.Urinanalysis and AFB urine cultures)
TST and IGR are current screening methods based on adaptive host immune response.
5- Tuberculin Skin Test (TST)
The Tuberculin Skin Test (TST) measures the immune response to purified protein derivative (PPD) in Mycobacterium tuberculosis complex antigens.
Tuberculin units are applied intradermally to form a 6-10mm wheal, followed by a follow-up visit.
6- Interferon Gamma Release Assay (IGRA)
IGRA and T-SPOT.TB are two assays approved by the US Food and Drug Administration for LTBI screening.
They are preferred for individuals who may not return for a TST reading and may be more persuasive in patients with prior BCG immunization due to lack of cross-reactivity
Indications
Screening should be done to identify those at risk for new infection, such as close contacts of patients with active TB, immigrants from TB-endemic regions, immunocompromising conditions, chronic steroid use, diabetes mellitus, and young age.
Test Selection
The CDC, IDSA, and WHO guidelines recommend the use of either IGRA or TST for the screening of tuberculosis, with the TST being preferred for children younger than 5-years-old and those who need repeat testing annually.
TST is preferred over IGRA in individuals 5 years or older with a high risk of progression to disease, but if necessary by law or credential bodies, IGRA is recommended.
Simultaneous or sequential testing is not recommended, but repeat testing with TST or IGRA can be done.
6-month isoniazid, or 9-month isoniazid, or 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months isoniazid plus rifampicin, or 3–4 months rifampicin alone.
However, the Panel could not reach a consensus and voted on the equivalence of
3–4 months isoniazid plus rifampicin and 3–4 months rifampicin alone as alternative options to 6-month isoniazid.
Sixty per cent of the Panel members voted for 4-month rifampicin alone as an equivalent option to 6-month isoniazid while 53% voted for 3–4 months isoniazid plus rifampicin as an equivalent option to 6-month isoniazid.
WHO Library Cataloguing-in-Publication Data Guidelines on the management of latent tuberculosis infection.1.Latent Tuberculosis. 2.Immunologic Tests. 3.Mycobacterium Tuberculosis – immunology. 4.Antitubercular Agents.5.Guideline. I.World Health Organization.ISBN 978 92 4 154890 8 (NLM classification: WF 200)
Rajput R, Singh P, Sarin R, Sethi P, Sharma S. Diagnostic accuracy of loop-mediated isothermal amplification assay for extra-pulmonary tuberculosis in Indian population. J Microbiol Methods. 2019
Brown M, Varia H, Bassett P, Davidson RN, Wall R, Pasvol G (2007). “Prospective study of sputum induction, gastric washing, and bronchoalveolar lavage for the diagnosis of pulmonary tuberculosis in patients who are unable to expectorate”. Clin Infect Dis 44 (11): 1415-20. doi:10.1086/516782. PMID 17479935.
I like your clinical approach that is well-referenced. I appreciate a judicious use of investigations. Typing whole sentence in bold or typing in capitals amounts to shouting.
Positive Heaf test indicates presence of immune response to TB protein either BCG vaccine or latent infection. It is improtant to confirm the diameter of induration and use IGRA assay depends on the local protocol.
Both D and R to be assessed thouroughly and treated for any active or latent TB before proceed to transplant.
A potential kidney donor with positive Heef test (TST)
All renal transplant donors should undergo screening for LTBI and active TB disease prior to transplantation
First rule out active TB
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, and homeless)
Test for LTBI with either Tuberculin skin test (TST) or IGRA assays
TST test:
o Is carried out by injecting intradermal purified protein derivate (PPD) in the forearm of an individual. An induration reaction of 15mm or larger, read after 48 or 72h, is considered indicative of past or current mycobacterial infection. TST is based on delayed-type hypersensitivity (DTH) skin reactivation to tuberculin PPD
o Affected by a complex array of factors such as age, nutritional and immunological status, the time interval between antigen exposure and the test performance, BCG vaccination (positive in the BCG-vaccinated individual), immunosuppression, genetic background, and cross-reactivity with environmental nontuberculosis mycobacteria and perhaps other pathogens
Advantages of IGRAs:
1. Avoid interpreting bias
2. Reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination
3. More sensitive in candidates with CRF and advanced cirrhosis
Limitations of IGRAs:
1. The NPV of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI
2. Higher cost
3. Frequent occurrence of conversions and reversions of test results when serial screening is performed (may complicate the interpretation of their results among SOT candidates)
o In low-risk patients: do only IGRAs, because the use of a more specific test might reduce the rate of false-positive results and, consequently, the number of patients who will unnecessarily be exposed to LTBI therapy
o In high-risk patients: do both tests (IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses), and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening
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)
Treatment of LTBI in donor (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
Monitor for hepatotoxicity with at least serum ALT checked every 2 weeks for 6 weeks, then monthly thereafter
So, for the index case, I will do the following:
o I will ask for high risk of TB (contact with active TB, recently arrived from travel abroad, drug users, incarcerated persons, and homeless) and history of vaccination
o Exclude active pulmonary and extra pulmonary TB (history, symptoms, investigations, clinical examination, and imaging)
o As TST is susceptible to false-positive results (BCG vaccine), I will do IGRA test (TSPOT.TB or QuantiFeron). It is more sensitive and specific for diagnosing LTBI (generally do only IGRAs in areas of high incidence of TB, and both tests in areas of low incidence)
o If confirmed to be LTBI, I will treat with Isoniazid monotherapy for 6 months with close monitor for hepatotoxicity with at least serum ALT checked every 2 weeks for 6 weeks, then monthly thereafter (there are other options)
o Treat living donor with LTBI before transplantation
References
1. Carranza C, Pedraza-Sanchez S, de Oyarzabal-Mendez E and Torres M (2020) Diagnosis for Latent Tuberculosis Infection: New Alternatives. Front. Immunol. 11:2006. doi: 10.3389/fimmu.2020.02006
2. Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020
3. Krishnamoorthy S, Kumaresan N, Zumla A. Latent tuberculosis infection and renal transplantation – Diagnosis and management. Int J Infect Dis. 2019 Mar;80S:S73-S76. doi: 10.1016/j.ijid.2019.01.049. Epub 2019 Feb 6. PMID: 30738187.
4. Santoro-Lopes, Guilherme, Subramanian, Aruna, Molina, Israel, Aguado, José María, Rabagliatti, Ricardo, Len, Osca. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation 102(2S):p S60-S65, February 2018.
Heaf test – It’s a form of tuberculin skin test to ascertain whether or not an individual is immune to tuberculosis before vaccination. A spring-loaded gun mounted with very short needles produces a circle of six punctures in the forearm through which tuberculin is introduced. A positive reaction causes the skin to become red and raised, indicating that the individual is immune. If the test is negative a vaccine (BCG) should be given.
Another form of tuberculin skin test in mantoux test. Both Heaf and Mantoux test are useful in testing exposure to tubercule bacilli.
Blood test to also ascertain previous exposure includes the Interferon gamma release assay.
Recent contacts to a patient with active TB disease,
Persons with fibrotic changes on chest radiograph consistent with old TB,
Organ transplant recipients,
Persons who are immunosuppressed for other reasons (e.g., taking the equivalent of ≥15 mg/day of prednisone for 1 month or longer, taking TNF-α antagonists), needs to be treated for latent infection.
People with a TST reaction of 10 or more millimeters who are:
From countries where TB is common, including Mexico, the Philippines, Vietnam, India, China, Haiti, and Guatemala, or other countries with high rates of TB. (Of note, people born in Canada, Australia, New Zealand, or Western and Northern European countries are not considered at high risk for TB infection, unless they spent time in a country with a high rate of TB.)
Injection drug users,
Residents and employees of high-risk congregate settings (e.g., correctional facilities, nursing homes, homeless shelters, hospitals, and other health care facilities),
Mycobacteriology laboratory personnel,
Children under 4 years of age, or children and adolescents exposed to adults in high-risk categories; needs to be treated for latent infection.
Persons with no known risk factors for TB may be considered for treatment of LTBI if they have either a positive IGRA result or if their reaction to the TST is 15 mm or larger.
In this scenario, a positive heaf test is suggestive of a latent infection and should be treated before transplantation. Thorough history and investigation of donor should also be done to rule out active tuberculosis.
In some TB endemic countries, routine donor screening for latent tuberculosis is not usually done since it is likely to be positive. Therefore, all post-transplant patient are placed on INH prophylaxis for 6 months.
The Heaf test is a diagnostic skin test was used in the past to determine whether or not children had been exposed to tuberculosis infection and need for BCG vaccination. The Mantoux test or tuberculin sensitivity test, or (PPD test for purified protein derivative) is a tool for screening for tuberculosis (TB) and for tuberculosis diagnosis.
According to the guidelines published by Centers for Disease Control and Prevention in 2005, interpretation of Mantoux test as the following: Baseline test: ≥10 mm is positive .0 to 9 mm is negative Serial testing without known exposure: Increase of ≥10 mm is positive Known exposure: ≥5 mm is positive in patients with baseline of 0 mm ≥10 mm is positive in patients with negative baseline or previous screening result of >0 Recently interferon gamma release assays (IGRAs) have become common in clinical use in the 2010s.
In current practice in renal transplant units The QuantiFERON-TB Gold blood test is routinely used ,it measures the patient’s immune reactivity to the TB bacterium, and is useful for initial and serial testing of persons with an increased risk of latent or active tuberculosis infection. Guidelines for its use were released by the CDC in December 2005.
The target now to screen for latent TB infection (LTBI) in the potential living donor: Since the latent infection can be transmitted to recipient,screening is very important to avoid a deadly infection after kidney transplantation: Screening includes previous TB history, chest radiograph findings, and tuberculin test (TST) ,interferon-gamma release assays (IGRAs) results and /Or QuantiFERON gold test results (There is no gold standard test to diagnose LTBI).
-In the current scenario ,if screening for latent TB came positive ,So LTBI treatment is recommended after transplantationfor recipients with a donor’s positive screening. -The recommended drug for LTBI treatment is INH 5-10mg/kg/day (maximum 300mg), to be initiated within 30 days of transplantation and maintained for 6 to 12 months (preferably 9 months).
-Monitoring for liver toxicity is mandatory which defined as an increase in aminotransferases above 3 times the normal value with symptoms (nausea, abdominal pain, jaundice) or above 5 times the normal reference values.
References: Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis recommendations for solid organ transplant recipients and donors. Transplantation. 2018;102(2) Suppl 2:S60–SS5.
Positive Heaf test denotes probable latent infection with TB.
Additional serologic test with Quantiferon TB gold to support the diagnosis .
Post transplant TB is drastic infection with risk of dissemination and miliary tuberculosis consequent development. General incidence of post transplant recipient tuberculosis is 6% , 4% out of 6% is attributed to donor transmission via the donated allograft.
In these circumstances its better to clear the donor by treating his latent TB with protocol short course of anti-TB :
1] INH and Rifapentine for 3 months of weekly dosing.
2] Daily Rifampin for 4 months.
3] INH and Rifampin daily dosing for 3 months.
If the patient is non compliant and there is no other donor for this patient, then the option would be to proceed with transplant and commence on prophylactic anti TB as per the protocols mentioned, with close observation of CNi trough level and monitoring for any toxicity.
References:
1] M.I.Moris et al .Diagnosis and Management of Tuberculosis in Transplant Donors: A Donor-Derived Infections Consensus Conference Report.American journal of transplantation:06 August 20122] Treatment Regimens for Latent TB Infection | TB | CDC https://www.cdc.gov › tb › topic › treatment › ltbi
Thankyou but you have to be more strict :
rule out a LTBI in the recipient as well, as it’s activation is the commonest cause of TB disease in the R.
You are using low incidence country protocols.
If R is negative and you agreed not to wait then what is your policy.
The heaf test was long used in the UK to test if children have been exposed to tuberculosis and its use was stopped in 2005. It is now replaced by the Mantoux test
A positive result could be grade 1 to grade 4
Grade 1 and 2 means previous BCG vaccine or avian tuberculosis
Grades 3 and 4, must be referred for further workup
The following history will be obtained from the donor
Country of birth or history of staying in a tuberculous endemic area > 3 months
History of close contact with TB infected person
History of working with high-risk groups (prison inmates, homeless, drug abuse)
Past history of infection or treatment for TB, drugs used, and duration
Investigations
Chest x-ray/ Chest CT scan
sputum AFB, Cuture & Gene- Xpert
BAL if possible for a higher yield of sputum analysis
ESR, CRP
WBC + differentials
The outcome of the investigation could be:
Latent TB infection – most likely as there is not clinical symptoms suggestive of TB in the history given
Active TB infection
previous BCG vaccination
Treatment of Latent TB infection
This clinical state needs to be treated even if he is not donating kidney as 80-90% of LTBI will reactivate if not treated.
Any of the following regimens could be used for treatment
INH + Rifapentine – weekly for 3 months
Rifampin daily for 4 months
INH + Rifampin daily for 3 months
INH only daily for 6 – months
References
TB in kidney Transplantation Lecture by Prof. Ahmed Skoker
Jose´ Marı´a Aguado, Julia´ n Torre-Cisneros, Jesu´s Fortu´n, et al. Tuberculosis in Solid Organ Tranplant Recipient: Consensus Statement of the group for the Study of Infection in Transplant Recipient (GESITRA)of the Spanish Society of Infectious Disease and Clinical Microbiology. Clinical Infectious Disease. 2009; 48:1276-84.
BTS Guidelines for Living Donor Transplantation.4th Edition
In general, all donors should be evaluated for the presence of latent TB
2 test are used to detect latent TB, tuberculin skin test (TST) and IGRA, any one of them can be used for donor assessment, but patients who have received BCG vaccination in early life (especially if the vaccine is received in the primary school) can have false positive TST, so they should be evaluated by IGRA
So in the current case if there is no history of previous vaccination, I will treat the donor as a case of latent TB before transplantation provided that the CXR is normal, sputum is negative for AFP and the patient is asymptomatic. I will use rifampicin for 3 months. If the patient cannot wait, I will transplant the patient and start treatment for latent TB using Rifampicin free regimens
On the other hand, if there is history of previous vaccination, I will order IGRA
If IGRA is negative, I will proceed with donation
If IGRA is positive I will treat the donor as a case of latent TB before transplantation provided that the CXR is normal, sputum is negative for AFP and the patient is asymptomatic. I will use rifampicin for 3 months. If the patient cannot wait, I will transplant the patient and start treatment for latent TB using Rifampicin free regimens
If IGRA gives an indeterminate result it should be repeated, if still indeterminate, the decision to treat is case by case after evaluating the risk (drug toxicity) and benefit (current of previous exposure risk )
If sputum for AFP was positive, donor should be excluded
If radiology is suspicious for TB (apical fibronodular lesions, calcified solitary nodule, calcified lymph nodes, or pleural thickening) thorough evaluation is indicated to exclude TB as a cause and if present donor should be excluded
Treatment of donor latent TB is impotent since If the donor has latent TB and did not receive treatment it carry a risk of transmission to the recipient and if that happen the recipient should be treated for latent TB before possible progression to active disease
Protocols for treatment of latent TB
Rifampin for 4 months
INH+ rifapentine for 3 months
INH + rifampin for 3 months
INH in a dose of 5 mg/kg (maximum dose 300 mg) daily for adults and 10 to 15 mg/kg (maximum dose 300 mg) daily for children together with oral pyridoxine 25 to 50 mg daily for 6-9 months.
Patient should be monitored for liver enzymes and bilirubin at baseline then monthly
So … In the current patient I will do IGRA (if the patient is not vaccinated), CXR, sputum for AFP (if IGRA is positive)
Thankyou remember to start the donor is the brother so the option to wait is there.
you are right TST can be also due to BCG vaccine but IGRA is due to interferon gamma release assay, and Quantiferon are not.
THe criteria to treat the brother depends on many factors among which is ,is the country in question of high incidence or low incidence which can dictate the treatment protocols.
So councelling the couple is needed.
This donor is heaf positive indicating patient previously vaccinated and has immunity against tuberculosis but recipient post kidney transplant may develop latent TB so the QuantiFERON-TB-Gold In-Tube test (QFT) is widely used for assessing latent TB; however, it is currently unclear whether the pre-KT QFT of the recipient and donor can predict post-KT TB.
interferon-gamma release assays (IGRA) is superior to tuberculin test; If positive indicates recipient with high risk of reactive TB ( 1-15% in incidence), and should be counselling regarding activation of tuberculosis.
So better to cancel this donor
However there is currently no gold standard for LTBI diagnosis.
TST may be unreliable in patients with advanced chronic kidney disease & in those on immuno-suppressive agents.
IGRAs have a high specificity for LTBI detection in immuno-suppressed patients & are more specific to M.tb antigens.
IGRAs are more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
My diagnostic approach to for detection of active & latent tuberculosis in this scenario would be as follows: History:
Ask for H/O previous contact with a patient with active TB.
H/O previous TB treatment.
Symptoms of chronic cough, fever, anorexia, night sweats, & weight loss.
Clinical examination:
Examine for signs of active pulmonary TB.
Exclude extra-pulmonary TB.
Investigations:
CBC & differential
CRP
Renal & liver function test
IGRAS test
Microscopy & culture for AFB
Gene XpertMTB test
CXR
Screen the potential recipient for LBTI:
Chest radiography & other screening tests prior to transplant.
BTS guidelines suggest screening for LTBI where tuberculosis incidence rates are high or in patients with risk factors for developing TB in low incidence areas.
Other indications for screening include:
History of TB
Previous rejection episodes
High-dose corticosteroids
Diabetes mellitus
Those living in endemic areas.
Treatment of LTBI in donor & recipient:
TB could directly affect the allograft function, therefore, it is important to make all efforts to prevent transmission of TB infection in such patients.
Before transplantation, every effort must be taken to identify & treat LTBI & active TB in both the live donor & recipient.
Treatment of LTBI should follow WHO 2018 guidelines (WHO, 2018).
Treatment options for LTBI (WHO 2018 guidelines):
Isoniazid monotherapy for 6 months (recommended in countries with high & low TB incidence).
Rifampicin plus Isoniazid daily for 3 months as an alternative to 6 months of isoniazid monotherapy (for children & adolescents < 15 years.
Rifapentine & Isoniazid weekly for 3 months (an alternative to 6 months of Isoniazid monotherapy in countries with a high TB incidence).
For LTBI treatment in countries with low TB incidence, the following alternatives to 6 months of isoniazid monotherapy are advised:
9 months of isoniazid
3-month regimen of weekly rifapentine plus isoniazid
3–4 months of isoniazid plus rifampicin
3–4 months of rifampicin alone.
References
Sriram Krishnamoorthya, Natarajan Kumaresana , Alimuddin Zumlab,Latent tuberculosis infection and renal transplantation – Diagnosis and management, International Journal of Infectious Diseases 80 (2019) S73–S76
– Some people may react to the TST even though they are not infected with M. tuberculosis. The causes of these false-positive reactions may include, but are not limited to, the following: Previous TB vaccination with the Bacillus Calmette-Guérin (BCG) vaccine.
Living donors should be evaluated like transplant recipients.
According to CDC general population standards, live donors’ TSTs should be positive or negative.
The first step is to look into QFT as an alternative. can differentiate between positive secondary to BCG vaccine or ( latent or active infection).
-Starting with a symptom evaluation and chest x-ray, MTB infection should be ruled out
Before organ donation,
Recent TST or IGRA converts with a latent TB infection should be treated before donation(oral INH 300 mg daily for 9 months).
Donors with active TB should not donate organs.
In transplant candidates who have had BCG immunization, IGRA testing may be preferable to TST since BCG does not affect IGRA findings.
References:
Singh, N., & Paterson, D. L. (1998). Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clinical infectious diseases, 27(5), 1266-1277.
Thankyou well done .so your options are depending on
LTBI in donor only
LTBI in D,R (remember they are brothers with possible proximity)
After councelling if the D only has LTBI ,they don’t want to wait how will you manage that.
Donors with distant MTB infection are at risk for transmission, but at lower risk for active disease due to decreased reactivation rate. Donors with a history of LTBI or active tuberculosis should be excluded from donation until further treatment can be performed. Latent TB-positive TST or Interferon gamma release assay found during pre-transplant evaluation.
consider deferring transplant if possible until donor has taken some/all of chemoprophylaxis and consider chemoprophylaxis of recipient; monitor clinically.
Bennett DE, Courval, JM. Prevalence of tuberculosis infection in the Unites States population: the national health and nutrition examination survey, 1999-2000. American Journal of Respiratory and Critical Care Med 2008; 177 (3):348-355 2008
WHO (2010). Global tuberculosis control 2010. Geneva, World Health Organisation: 1-218.
Diagnosis and Management of Tuberculosis in Transplant Donors: A Donor-Derived Infections Consensus Conference Report”. Morris MI, Daly JS, Blumberg E, Kumar D, Sester M, Schluger N, Kim SH, Schwartz BS, Ison MG, Humar A, Singh N, Michaels M, Orlowski JP, Delmonico F, Pruett T, John GT, Kotton CN. Am J Transplant. 2012 Aug 6.
History of TB, clinical or radiological, treatment given
History of BCG-vaccination
IGRA for low risk group
Both IGRA & TST for high risk e.g., endemic areas, TB contact, those who live or work in correctional facilities or homeless shelter
Ideally when considering duat testing, IGRA should be done first or at the same time with TST to avoid TST -mediated boosting of subsequent IGRA responses
Rule out active TB e.g symptoms & signs, CXR
Any evidence of active infection must be confirm by microbiology & transplant is postponed
Drug susceptibility test in any specimen positive for M.tuberculosis
A history of untreated LTBI without evidence of active infection is not a contraindication to donation provided that, the recipient will preventive TB therapy
Once active infection is excluded, this is considered a LTBI and should be best treated before donation with oral INH 300 mg daily for 9 months with pyridoxne 25 to 50 mg daily.
Monitor closely for hepatotoxicity
Alternative therapy are; rifampycin for 4 months or INH + rifapentine weekly for 12 weeks or fluroquinolone +/- ethambutol
Source; TB recommendation for SOT recipient & donors (Guilherme Santoro-Lopes et al.)
Thankyou options for treatment depends upon wether they are in a low or high incidence country.ie, if you are in Canada or Yemen where TB is very prevailant.
The currently FDA-approved screening methods for LTBI in the United States include the Tuberculin skin tests (TST) and the IGRAs: QuantiFERON-TB Gold in Tube assay (QFT) and T-SPOT TB. None of these tests differentiates active from latent TB, and it is not uncommon for any of these tests to be negative during times of active infection.
However, recent U.S. guidelines recommend using IGRA instead of the TST for diagnosing LTBI. IGRA is especially recommended as the preferred test for persons who have received BCG. Although IGRA is more expensive than the TST, health economics analyses have found that the tests are cost-effective as they reduce the number of individuals needing unnecessary chemoprophylaxis and monitoring while on drug therapy. Therefore, IGRA has been increasingly replacing the TST for screening LTBI.
So, since this donor has positive Tuberculin skin tests (TST) and he is asymptomatic, he should be investigated further for latent TB.
Ref. Moon SM, Park IA, Kim SM, Park SJ, Lee SO, Choi SH, Kim YS, Woo JH, Kim SH, Jung JH, Kim YH. Living donor and recipient screening for latent tuberculosis infection by tuberculin skin test and interferon-gamma releasing assay in a country with an intermediate burden of tuberculosis. Journal of Infection and Chemotherapy. 2013 Jan 1;19(5):1009-13.
Since he is a donor, yes, I will do IGRAs. Accordingly, if positive, then active TB infection must be excluded. If no active disease is evident, he might have LTB.
A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but the administration of preventive therapy to all recipients should be considered.
The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, therefore, transplant recipients from such donors can be clinically monitored without receiving LTBI therapy.
Ref. Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis recommendations for solid organ transplant recipients and donors. Transplantation. 2018 Feb 1;102(2S):S60-5.
Heaf test is not used in Brazil and was formerly used to define whether there was previous exposure to the vaccine and the need for an extra dose of vaccine against Tuberculosis.
This model later fell into disuse with methods that were easier to interpret, such as the PPD, but it is no longer used to define whether there is a need for an extra dose of the vaccine.
The positivity of this test only suggests that the patient has been previously vaccinated and has an immune response against tuberculosis.
Brazil is an endemic country for Tuberculosis.
Here, the Ministry of Health suggests chemoprophylaxis for latent tuberculosis if the skin test (PPD) is greater than 10 and the patient is in the context of immunosuppression (anti-TNF alpha, HIV, transplantation).
Chest X-ray is sufficient to rule out disease activity and proceed with LTBI instead of classical treatment.
Both a negative and grade 1 positive should be regarded as not significant . Heaf grades 2, 3, and 4 should be regarded as significant and investigated for M. tuberculosis infection.
Diagnosis of LTBI includes either an interferon-gamma release assay (IGRA) or a TST.
To check for active TB before starting LTBI treatment using-
History
physical examination
chest radiography
bacteriologic investigations like sputum for AFB,HYNES or TB GOLD test
sos HRCT chest
Positive Heaf test results indicate previous TB infection or vaccination
Positive test results (grades 1 and 2) indicate prior BCG vaccination; grades 3 and 4 indicate latent or active tuberculosis.
Therefore, a correct evaluation of the donor:
Medical record. Investigate the history of untreated or inadequately treated tuberculosis.
Endemic exposures. Travel to or residence in endemic areas, exposure to active TB infection in the household or workplace within the previous 2 years, being destitute or a refugee, incarceration, and alcoholism may be associated with LTBI.
Radiographic manifestations include apical fibronodular lesions, calcified solitary nodules, calcified lymph nodes, and pleural thickening.
Donation is contraindicated if the donor has active TB, and the donor should be treated for 69 months with a four-drug regimen.
If the donor has latent tuberculosis, he or she should receive INH plus pyridoxine for six months, after which the recipient can be properly counseled and receive chemoprophylaxis under the supervision of the ID team.
Positive heaf test mean this patient could be exposed to mycobacterium TB previously so we need to investigate more if the TB is active or not by doing blood PCR and urine PCR for TB if it positive I will exclude him from donation
A 41-year-old man has expressed his willingness to donate a kidney to his brother. The compatibility between the two is excellent, with a 000 mismatch and no donor-specific antibodies (DSA). However, the man’s general practitioner (GP) has reported a positive Heaf test result.
The Heaf test is a skin test conducted to determine if an individual has been previously exposed to tuberculosis (TB) and has developed immunity. The Heaf gun, equipped with disposable single-use heads, is the recommended tool for administering the test. It injects purified protein derivative into the skin over the flexor surface of the left forearm. The test is then read between 3 and 10 days later. It is important to avoid injecting into areas containing superficial veins.
The results of the Heaf test are interpreted based on a scale. A negative result indicates no induration, possibly with six-minute puncture scars, which could be attributed to avian TB or BCG vaccination. Grade 1 is characterized by four to six papules, also considered negative and potentially resulting from previous BCG or avian TB exposure. Grade 2 indicates the formation of confluent papules that form an indurated ring, signifying a positive result. Grade 3 shows central filling to form a disc, also indicating a positive result. Grade 4 represents severe induration greater than 10 mm, possibly accompanied by blistering, which is strongly indicative of a positive result.
Grades 1 and 2 may be attributed to previous BCG vaccination or avian TB exposure. Grades 2 to 4 are considered positive and should be managed as latent TB. In such cases, the patients should undergo a chest X-ray.
The patient, who wishes to donate a kidney, should be treated for latent TB infection before proceeding with the donation. The recommended treatment options include rifampicin 10mg/kg (up to 600mg) once daily for 4 months, rifampicin 10mg/kg plus isoniazid 5mg/kg daily for 3 months, or isoniazid 5mg/kg daily for 6-9 months (or 15mg/kg twice weekly for 6-9 months) in combination with pyridoxine 25-50mg to prevent peripheral neuropathy.
If a donor is diagnosed with active TB infection, their organs should not be used for transplantation. In cases where the diagnosis is made post-transplantation, the recipient should immediately initiate therapy for active infection based on local guidelines.
However, if a donor has a history of successfully treated TB for at least 6 months, their organs can be considered for transplantation.
In this specific case, it is advisable to delay the donation process and provide the donor with a short and effective treatment regimen for latent TB, such as 3 months of isoniazid plus rifampicin, following further evaluation. Alternatively, a longer course of isoniazid monotherapy for 6 or 9 months, accompanied by pyridoxine supplementation as recommended by the US Centers for Disease Control and Prevention (CDC), can be considered.
Positive heaf test, also called Sterneedle test ,which is not done these days and has been replaced by newer tests i.e., quantiFERON-TB Gold test or T-spot tests indicates immunity of individual to T.B due to previous exposure or BCG vaccination.it has a scale of 4 and 2-4 indicates positive test.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.Active T.B is a contraindication to donation,however,latent T.B needs treatment.Various regimens availavle like Isoniazid monotherapy for 6 months, Rifampicin plus Isoniazid daily for 3 month,Rifapentine and Isoniazid weekly for 3 months.
REFERENCES:
BTS Guidelines for Living Donor Transplantation.4th Edition
TB in kidney Transplantation Lecture by Prof. Ahmed Skoker
How would you proceed?
· Heaf test is A skin test to determine whether an individual is immune to tuberculosis due to previous exposure, carried out prior to vaccination or latent TB infection (LTBI).
· The Heaf test is defined by scale from 1-4. Grades 1 and 2 may be the result of previous BCG or avian tuberculosis. Grades 2-4 are considered positive and should be managed as latent TB and need chest Xray.
· This donor has a positive tuberculin skin test. Therefore it is important to ensure that he does not have active TB infection that would discard him from donation.
We need to ask for symptoms including fever, cough, night sweats and weight loss and carry a thorough clinical examination and carry some investigations including:
· Sputum examination (if the patient is coughing and producing sputum) for microscopy, AAFBs and gen xpert test.
o CXR to assess for pleural effusion, consolidations and nodular opacities
o So, if the patient does not have any signs, symptoms, radiological or microbiological evidence of TB, then the patient has LTBI and being a donor, there is a risk of transmitting the dormant bacilli to the recipient who may develop active TB in view of the immunosuppression medication that will be received. This results in a significant morbidity and mortality.
· The donor requires treatment for the LTBI. regimens available are:
· He will need to complete the treatment before proceeding for the transplant.
· Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
· If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines.
References:
1. Munoz P, Rodriguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clin Infect Dis 2005; 40: 581– 587.
2. OPTN; Guidance for Identifying Risk Factors for Mycobacterium tuberculosis (MTB) During Evaluation of Potential Living Kidney Donors.
● Positive Heaf test means that this donor had previous exposure to TB either by infection or by the vaccine.
● Donor-derived TB remains an important infectious complication of solid-organ transplantation .
● Increased awareness of donor risk factors may allow targeted testing for latent and unrecognized active TB in potential donors
● Donor must evaluated as :
☆ In case of history of latent TB-treated appropriately the risk for Transmission
is l ower but the recipient had to be monitored clinically
☆ History of latent TB-treated insufficiently or not treated or treatment details not clear or new diagnosis of latent TB-positive TST or Interferon gamma release assay found during pre-transplant evaluation and evaluation finds no evidence of active TB
the risk for Transmission is moderate and
donor has to take some/all of chemoprophylaxis and besides chemoprophylaxis of recipient with clinical monitoring.
☆ In case of unexplained pulmonary apical fibrosis in donor without cavitation and without additional testing the risk of transmission is variable and donation pending further evaluation .
☆ History of active MTB treated appropriately over 2 years ago the risk of transmission is lower to moderate and the recipient need clinical monitoring with cultures of previous TB sites if possible. And TB prophylaxis for recipient.
☆ History of active TB-site remote from transplant treated appropriately within 2 years. The risk of transmission is lower to moderate and recipient need clinical monitoring with cultures of previous TB sites if possible with chemoprophylaxis of recipient.
☆ History of active TB-site remote from transplant treated insufficiently and/or with other than standard regimen excluding disseminated or CNS TB the risk of transmission is higher and increased risk if less than 2 years since active TB diagnosis live donor had to be differed until adequately treated with infectious disease specialist consultation and cultures of previous TB sites prior to transplant if possible .
☆ History of active renal TB treated appropriately. (If not treated appropriately donation should be deferred until after appropriate treatment) , the risk of transmission is moderate treatment must verify with clinical monitoring and use chemoprophylaxis for recipient we need cultures of previous TB site(s) and infectious disease specialist consultation.
References:
Guidance for Identifying Risk Factors for Mycobacterium tuberculosis (MTB) During Evaluation of Potential Living Kidney Donors. Organ procurement and transplantation network.
The Heaf test, a Diangnostic skin test, was long performed to determine whether or not patient had been exposed to TB infection.
All renal transplant recipients and their donors should undergo screening for LTBI and active TB disease prior to transplan.Every effort must be made to diagnose and treat LTBI and active tuberculosis in both livedonor and recipient before transplantation.The tuberculin skin test (TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors.IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade.Negative predictive value of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI.Thus, in low-risk patients, IGRAs could be considered as the sole approach, because the use of a more specific test might reduce the rate of false-positive results and, consequently, the number of patients who will unnecessarily be exposed to LTBI therapy. On the other hand, in high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
The heaf test is a skin test for TB immunization. If it was positive, the patient had had exposure to TB. If negative, BCG vaccine was needed.
The other tests for LTBI are:
PPD or tuberculin skin test and interferon-gamma release
assay (IGRA) like QuantiFERON-TB (QFT).
IGRA is more sensitive and specific for LTBI in recipients.
Comprehensive history and physical exam are essential for
the diagnosis of LTBI. Potential recipients with a history of TB, high-dose
corticosteroids, DM, or living in an endemic area should be screened by CXR and
above mentioned tests for LTBI. Diagnosis and treatment of LTBI in both donor
and recipient according to WHO 2018 guidelines are necessary.
Treatment of LTBI: 6 or 9
months of isoniazid monotherapy, rifampicin plus INH daily or rifampicin plus
INH weekly for 3 months.
Heaf test is a Skin testing for tuberculosis like a tuberculin skin test (TST).
Then this patient would be managed as possible latent TB:
– Would do chest CT for greater clarity of lung lesions.
– If not, I would start treatment for latent TB
– If positive, I would do bronchoscopy for BAL and perform BAAR and PCR for tuberculosis to try to exclude active TB and start latent treatment
REFERENCE:
– Dacso CC. Skin Testing for Tuberculosis. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 47.
– Sorohan BM, Ismail G, Tacu D, Obrișcă B, Ciolan G, Gîngu C, Sinescu I, Baston C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens. 2022 Sep 13;11(9):1041. doi: 10.3390/pathogens11091041. PMID: 36145473; PMCID: PMC9505385.
Heaf test’ is a skin test previously being used to determine whether an individual is
immune to TB either due to previous exposure or prior BCG vaccination .
Positive TST should indicate more specific tests like quanti-FERON-TB Gold test or T-spot tests.
History regarding exposure to active TB patient.
clinical examination and imaging to differentiate between latent and active TB infection
Prior history of TB ESR, CRP
Test for latent TB : TST, IGRA Sputum for AFB, Culture & Gene- Xpert
Imaging – CXR /HRCT chest
If TST and IGRA positive then treatment for latent TB infection ( INZ for 6 month or INZ and rifampicin for 3 month)
‘Heaf test’ is a skin test previously being used to determine whether an individual is immune to TB either due to previous exposure or prior BCG vaccination.
How I can proceed?
– History regarding exposure to active TB patient.
– Prior history of TB
– Test for latent TB : TST, IGRA
– If TST and IGRA positive then treatment for latent TB infection ( INZ for 6 month or INZ and rifampicin for 3 month)
Donor brother, well-matched and immunologically excellent pair.
Donor “Heaf test” is positive – a skin test previously being used to determine whether an individual is immune to tuberculosis due to previous exposure or prior BCG vaccination. Negative heaf test cases need BCG vaccination.
Now days, “Heaf test” is replaced by Tuberculin Skin Test (TST).
Positive TST should indicate more specific tests like quanti-FERON-TB Gold test or T-spot tests, detail clinical examination and imaging to differentiate between latent and active TB infection:
– Sputum for AFB, Culture & Gene- Xpert
– QuantiFERON-TB-Gold / T-spot test
– ESR, CRP
– Imaging – CXR /HRCT chest
.
Positive TST, negative TB Gold test suggests prior exposure or vaccination
Both TST and quantiFERON-TB Gold tests positive without clinical and radiological evidence of active TB, indicate latent TB –> that donor should be treated with Rifampicin + INH for 3 months.
Radiological and / or clinical symptoms suggestive of TB with positive TST + positive quanti FERON-TB Gold test indicate active disease.
Treatment of Latent TB infection in Donor:
1. INH + Rifampicin daily for 3 months
2. Rifampicin daily for 4 months
3. INH only daily for 6 months.
Active TBI in is contraindication for organ donation or transplant.
The donor needs to be treated with full course of ATT prior to donation.
Reference:
1. https://en.wikipedia.org/wiki/Heaf_test.
2. Lopes GS, Subramanian AK, Molina I, et al. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Uptodate https://www.uptodate.com/contents/tuberculosis-in-solid-organ-transplant-candidates-and-recipients?
4. Morris MI, Daly JS, Blumberg E, et al. Diagnosis and management of tuberculosis in transplant donors: a donor-derived infections consensus conference report. Am J Transplant 2012 Sep;12(9):2288-300. doi: 10.1111/j.1600-6143.2012.04205.x. Epub 2012 Aug 6. Erratum in: Am J Transplant. 2013 Feb;13(2):528. PMID: 22883346.
The Heaf test is a skin test, was previously performed to determine exposure to TB infection. Also known as the Sterneedle test, it was administered by a Heaf gun.
The reading of the Heaf test was defined by a scale:
· Negative – No induration, maybe six minute puncture scars
· Grade 1 – four to six papules (also considered negative)
· Grade 2 – Confluent papules form indurated ring (positive)
· Grade 3 – Central filling to form disc (positive)
· Grade 4 – Disc >10 mm with or without blistering (strongly positive)
Grades 1 and 2 could result from previous BCG or avian tuberculosis, rather than human TB infection.
Grade 3 and 4 were referred for chest X-ray.
Positive Heaf test should be followed by detailed history regarding exposure to TB, travel to TB endemic areas, recent TB infection in contacts. Following examination, chest X-ray should be done along with:
1. Sputum AFB, Culture & Gene- Xpert.
2. QuantiFERON-TB-Gold In-Tube test (QFT).
3. ESR, CRP.
Treatment of Latent TB infection in Donor:
1. Rifampin daily for 4 months
2. INH + Rifampin daily for 3 months
3. INH only daily for 6 months.
Active TB in donor is contraindication for transplant.
●The Heaf Test shows if people have antibodies against TB
● If they have not they may need a vaccination.
● Tuberculin liquid was placed on the skin, left to form a film and then six needles were plunged into the skin to a depth of 2 mm.
● If a red hard area appeared after three days, the test showed they had tuberculosis, were naturally immune or had acquired immunity in some way.
●now this test not recommended for LTBI screening
● diagnosis of latent TB we should perform TST or IGRA
● IGRA being better option because is not affected by previous BCG vaccination .
● we should evaluate the history of exposure
● physical examination
● CXR
●bronchial aspiration or sputum samples for staining and culture
●if TST and IGRAs are positive ==> donation should be delayed and receive a protocol treatment;
● screening the recipient for HIV
Management of LTBI in recipient (WHO )
Isoniazid alone ==>, daily for 6 or 9 months
Daily rifampicin alone ==> for 3–4 months
Daily isoniazid plus rifampicin==> for 3–4 months
Weekly rifapentine plus isoniazid ==> for 3 months (12 doses)
The case scenario is a prospective transplant recipient with a positive heaf test and how to manage for transplantation
Heaf test was historically used in the UK till it was replaced by the mantoux test….This was after the year 2005…. The current WHO guidelines recommend IGRA (interferon Gamma release Assay) and Tuberculin skin testing by Mantoux method for screening of latent TB infection…
A heaf gun was used to simultaneously inject various serum samples under the skin…. The skin was poked with needles that had been soaked in tuberculin purified protein derivative (PPD). A hefier gun with single disposable needle is used to inject the PPD on the flexor aspect of the left forearm….the strength of PPD was 1,00,000 units per ml in a six circular pattern….. The test is read after 5 to 7 days….
heaf score is graded as follow
negative – Absence of induration – negative
grade 1 – 4-6 papules – negative
grade 2 – confluent papules creating a ring – positive
grade 3 – filling the center to form a disc (positive)
grade 4 – disc more than 10mm with or without scar (positive)
In this patient we need to take a detailed history of contact with patient with active TB, history of prior ATT, history of previously untreated latent TB, and history of any active TB like cough, night sweats, fever or hemoptysis
Treatment for LTBI in the recipient is important to prevent life threatening TB after transplant and tuberculosis after renal transplantation will impair the graft function…
Treatment for LTBI should adhere to WHO guidelines in 2018 which is Six month of isoniazid monotherapy…. Other options are Rifampicin monotherapy for 4 months if transplant is not being planned in the near future… for children < 15 years old 3 months daily Rifampicin and Isoniazid monotherapy for 3 months is recommended
in this scenario i will start the latent TB trreatment for 6 months….and proceed for transplant. .I will avoid rifampicin based treatment as it has significant interaction with immunosuppressive
The Heaf test is a skin test, was previously performed to determine exposure to TB infection. Also known as the Sterneedle test, it was administered by a Heaf gun.
The reading of the Heaf test was defined by a scale:
· Negative – No induration, maybe six minute puncture scars
· Grade 1 – four to six papules (also considered negative)
· Grade 2 – Confluent papules form indurated ring (positive)
· Grade 3 – Central filling to form disc (positive)
· Grade 4 – Disc >10 mm with or without blistering (strongly positive)
Grades 1 and 2 could result from previous BCG or avian tuberculosis, rather than human TB infection.
Grade 3 and 4 were referred for chest X-ray.
Positive Heaf test should be followed by detailed history regarding exposure to TB, travel to TB endemic areas, recent TB infection in contacts. Following examination, chest X-ray should be done along with:
1. Sputum AFB, Culture & Gene- Xpert.
2. QuantiFERON-TB-Gold In-Tube test (QFT).
3. ESR, CRP.
Treatment of Latent TB infection in Donor:
1. Rifampin daily for 4 months
2. INH + Rifampin daily for 3 months
3. INH only daily for 6 months.
Active TB in donor is contraindication for transplant.
· How would you proceed?
Heaf test is a diagnostic skin test to determine whether the patient was exposed to tuberculosis infection. It was known as Sterneedle test, it was administered by Heaf gun, graded by a scale into four grades.
It was discontinued in 2005.
To determine if the BCG vaccine was needed, it was thought to be easier to interpret, if negative considered for vaccination.
False negative Heaf test Nontuberculosis mycobacteria, and BCG vaccination.
A patient with Heaf positive test needs further evaluation to confirm and exclude tuberculosis.
Need good history for previous exposure, infection, vaccination, and treatment, thorough physical examination.
Rule out; for diagnosis and location,
Mantoux test, CXR PA view, CBC with ESR and CRP, if sputum for AFB, GeneXpert,
If any latent infection first treat with INH for six month or rifampicin for six months, or in combination.
References;
1. ttps://www.uptodate.com/contents/tuberculosis-in-solid-organ-transplant-candidates-and-recipients?topicRef=115049&source=related_link#:~:text=Back-,Tuberculosis%20in%20solid%20organ%20transplant%20candidates%20and%20recipients,-Topic.
2. https://en.wikipedia.org/wiki/Heaf_test.
3. https://thorax.bmj.com/content/55/11/887.
A 41 year old potential donor has a positive Heaf test.
A positive Heaf test is one in which there is vesiculation at the site of innoculation of the Tuberculin sample.
A history
Investigations
The aim of these investigations is to locate the site of the tuberculosis infection.
Then treatment of the donor will start
He should get the 2 months of Rifampicin, Isoniazid, Pyrazinamide and Ethmabutol. Then 4 months of Rifampicin and Isoniazid.
When is this potential donor fit to donate?
Will the recipient need to be treated for Tb?
Positive Heaf test: The greater the risk of exposure , the higher the PPV.
Causes of false-positive tests:
· Nontuberculous mycobacteria
· BCG vaccination
Management of individuals with positive test
· Any patient with a positive test for TB infection needs evaluation to exclude TB disease prior to initiation of treatment for TBI.
· The evaluation includes clinical history, physical examination, and chest radiograph.
· Patients with relevant clinical manifestations (cough >2 weeks’ duration, fevers, night sweats, weight loss) and/or abnormal CXR should submit three sputum samples for AFB smear, mycobacterial culture, and nucleic acid amplification testing
Treatment of latent tuberculosis
Transplant candidates and recipients should be treated for latent TB when there is no evidence of active TB and any of the following criteria are met:
1) Initial or boosted TST with induration ≥5 mm or a positive IGRA
2) History of untreated latent TB
3) Receipt of an organ from a donor known to have untreated latent TB
Regimen selection
· If the transplant is unlikely to occur within the following 4 to 6 months, rifampin for 4 months is recommended.
· Other options pre-transplant are isoniazid plus rifapentine for 12 weeks, or isoniazid plus rifampin for 3 months
https://www.uptodate.com/contents/tuberculosis-in-solid-organ-transplant-candidates-and-recipients?topicRef=115049&source=related_link#:~:text=Back-,Tuberculosis%20in%20solid%20organ%20transplant%20candidates%20and%20recipients,-Topic
the decision of accepting or refusing of donor can not depend on heat test alone, so he need more history and work up…
IGRA test more sensitive and specific (our center depend on IGRA test)
CXR ,sputum for AFB ,…ETC
Multipuncture methods (including the Tine test and the Heaf test) should not be used; they may be easier to administer but are not accurate because it is not possible to precisely control the amount of tuberculin.
So, we use the Tuberculin skin test. The TST consists of intradermal injection of tuberculin material, which stimulates a delayed-type hypersensitivity response mediated by T lymphocytes and, in patients with prior mycobacterial exposure, causes induration at the injection site within 48 to 72 hours.
All individuals with a positive test for TB infection (positive tuberculin skin test or interferon-gamma release assay result) warrant evaluation to exclude TB disease prior to initiation of treatment for TBI.
The evaluation includes clinical history, physical examination, and chest radiograph. TB disease may be asymptomatic in patients with HIV infection.
A 41-year-old man came forward to donate a kidney to his brother. 000 mismatch, excellent kidney function, no DSA. His GP reported that he had a positive Heaf test.
How would you proceed?
· In the immunological point of view he is an excellent donor.
· Here, Heaf test is positive. This is a skin test to determine whether an individual is immune to tuberculosis due to previous exposure or prior BCG vaccination. Negative cases should be vaccinated.
· Now-a-days Heaf test is replaced by TST and if positive the following approaches should be initiated.
– Positive test should be interpreted with other more specific tests like quantiFERON-TB Gold test or T-spot tests combined with clinical presentation and imaging studies to differentiate between active and latent TB
– Positive TST and negative quantiFERON-TB Gold test sugesst prior exposure or vaccination
– Positive TST + positive quantiFERON-TB Gold test without clinical and radiological evidence of active TB, indicate latent TB and that donor should be treated accordingly with Rifampicin +INH for 3 months
– If radiological or clinical evidence suggestive of TB with positive TST + positive quantiFERON-TB Gold test, active disease. Need to treat with full course of anti TB prior to donation.
Reference:
(i) Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD
(ii) UpToDate
The heaf test had been used in the past and is replaced recenly by TST .
Positive test should be interpreted with other more specific tests like quantiFERON or T-spot tests combined with clinical presentation and imaging studies to differentiate between active and latent TB status
positive TST + negative quantiFERON sugesst prior exposure or vaccination
positive TST + positive quantiFERON without clinical and radiological evidence of active TB , indicate latent TB and that donor should receive RFM +INH for 3 months
radiological or clinical evidence of TB with positive tests point out to active TB that abort donation.
Donor has good immunological profile and suits the recipient need
HEAF test ( read skin test for TB ) is not diagnostic of active TB in donor
In India , all are BCG vaccinated so skin test can be false positive
complete work up of donor is must
IGRA is better test to diagnose latent TB
CXR , ESR , symptoms , past history of TB are all valid points to consider
all attempts should be done to detect and treat latent TB in donor
single agent daily for 6 months or two agents twice a week for 6 months as per national TB policy
Donor can be accepted
HOW TO PROCEED WITH A POSITIVE HEAF TEST.
2 .In high incidence settings i.e TB incidence rate > 100/100000,RIF based regimen preferred.
REF;
Case of Potential Donor with a positive HEAF test done by GP
I would start by taking a detailed history and examination of the potential donor to determine they are from an endemic area, if they had BCG vaccine in the past, Previous PTB, Exposure to TB case. I would also assess if they have symptoms of active TB such as cough, sputum, weight loss, pyrexia, chills, rigours, sweats.
Next I would repeat the Tuberculin skin test and do a blood Interferon Gamma Release Assay test, together with general Labs such as FBC, ESR and CRP. I would take a Chest Xray.
The aim of the evaluation is to determine if the donor has Latent TB Infection or Active TB. The TST may be positive because of BCG vaccination, while the IGRA test is less affected by BCG vaccination. Both test are not able to differentiate between latent and active infection, and cannot predict which latent infections are at high risk of developing active disease. Hence the importance of a good clinical evaluation assessing for signs and symptoms of active disease. Further tests such as a Chest Xray are useful in this regard.
If after the evaluation the donor is deemed to have LTBI, they will be offered prophylaxis as per local guidelines. In Botswana it would be daily INH for six months, with Bit B6. The transplant donation can go ahead after the donor has taken all or some of the treatment.
If the donor is deemed to have Active TB, They will need to complete TB treatment as per the local TB protocol. In Botswana it would be at least two Months of RHZE intensive phase followed by four months of RH continuation phase. They can donate after completing the treatment.
It is also important to carefully screen the donor since they are brothers and may be contacts
Reference
Morris MI, Daly JS, Blumberg E, Kumar D, Sester M, Schluger N, Kim SH, Schwartz BS, Ison MG, Humar A, Singh N, Michaels M, Orlowski JP, Delmonico F, Pruett T, John GT, Kotton CN. Diagnosis and management of tuberculosis in transplant donors: a donor-derived infections consensus conference report. Am J Transplant. 2012 Sep;12(9):2288-300. doi: 10.1111/j.1600-6143.2012.04205.x. Epub 2012 Aug 6. Erratum in: Am J Transplant. 2013 Feb;13(2):528. PMID: 22883346.
https://www.frontiersin.org/articles/10.3389/fimmu.2020.02006/full
Scenario 3
The Heaf test, a diagnostic skin test, was long performed to determine whether or not patient had been exposed to tuberculosis infection.
The reading of the Heaf test was defined by a scale:
Grades 1 and 2 could result from previous BCG or avian tuberculosis, rather than human TB infection.
Patients who were found to have a grade 3 or 4 reaction were referred for X ray and follow-up.
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)
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 .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.
Clinical workup of donors and transplant recipients to screen for LTBI and active TB.
Every effort must be made to diagnose and treat LTBI and active tuberculosis in both live donor and recipient before transplantation .TreatmentofLTBI should follow WHO 2018 guidelines.
The WHO 2018 guidelines outline the following treatment options for LTBI .
The heaf test is an old test for diagnosis of mycobacterium infection and is now been replaced by the tuberculin skin test.
Positive heaf test may be related to BCG vaccine, LTBI or active TB infection
A whole workup is needed including
· History of traveling to an endemic area or close exposure
· History of symptoms or signs related to TB infection like night sweating, low-grade fever, and weight loss
· Clinical and radiological assessment of pulmonary and extrapulmonary TB infection sites
· Laboratory tests like IGRA, NAA, and AFB.
Based on the results donors can be classified into 3 main categories
1. Vaccinated (positive TST and negative IGRA): go-ahead with the donation
2. LTBI (positive for both TST and IGRA with the negative clinical and radiological findings of active TB infection): treatment for 4m with rifampicin or 3 m with rifampicin and INH for both donor and recipient.
3. Active TB (positive AFB or NAA): he should be excluded from donation.
References
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Bogdan Marian Sorohan, Gener Ismail, Dorina Tacu, Bogdan Obris, Gina Ciolan, Costin Gîngu, Ioanel Sinescu and Cătălin Baston
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
Guilherme Santoro-Lopes, Aruna K. Subramanian, Israel Molina,José María Aguado, Ricardo Rabagliatti, and Oscar Len,
it is skin test called also Sterneedle test done by heaf gun and used to determine the person was exposed to TB or not, and was preferred in the UK, because it was thought to be easier to interpret, with less variability between observers, and less training was required to administer and read the test.
The reading of the Heaf test was defined by a scale:
Grades 1 and 2 could result from previous BCG or avian tuberculosis, rather than human TB infection.
persons who were found to have a grade 3 or 4 reaction were referred for X-ray and follow-up.
so in this case, positive test means this donor needs full investigations to determine he is active TB or latent including CXR and CT chest , PCR for TB
if active infection found , this is an absolute contraindication for donation but if latent infection, needs prophylactic treatment by INH for 6 months
The Heaf test, a diagnostic skin test, was long performed to determine whether or not children had been exposed to tuberculosis infection. The test was named after F. R. G. Heaf. Also known as the Sterneedle test,it was administered by a Heaf gun (trademarked “Sterneedle”) a spring-loaded instrument with six needles arranged in a circular formation which was inserted in the wrist or shoulder.
Until 2005, the test was used in the United Kingdom to determine if the BCG vaccine was needed; the Mantoux test is now used instead.
Since the test raises a question of previous exposure , detail history examination and work up is needed to rule out active infection. If no active infection then such patients can be offered INH prophylaxis for atleast six months.
HEAF TEST:
It was used to decide whether there is need to give BCG vaccine.
A spring-loaded gun mounted with very short needles produces a circle of six punctures in the forearm through which tuberculin is introduced. If the test is positive a reaction causes the skin to become red and raised, indicating that the individual is immune. If the test is negative a vaccine (BCG) should be given.
But now this test is no longer in use:
Since, BCG vaccine does not provide immunity against TB infection. It just prevents severe form of tuberculosis. So BCG is in national immunization program in endemic countries given at birth. It has no role in non-endemic zones.
Secondly, screening for tuberculosis is done through Mountoux test that too in symptomatic person and if positive further work up is done to confirm diagnosis.
In asymptomatic donors there is no protocol of diagnosing LTBI and treating the same before donation.
So as per our policy, i shall move ahead for transplant
Donor 000 mismatch no DSA but with positive heaf test
Heaf test was used to determine if one was exposed to TB or not.
Purified protein derivative was injected into the skin and the test was read 2-7 days later. The results were graded between 0-4 where zero was negative, grade 1-2 positive indicate prior BCG vaccination, grade 3-4 active/latent TB.
This test is no longer done and has largely been replaced with TST.
Workup
For this donor its paramount we differentiate whether it is latent TB or active TB.
A detailed history on symptoms of chronic cough, weight loss and night sweats that would suggest active TB is required.
Further history on travel to endemic area, recent contact of persons with active TB, their social status whether they are homeless or incarcerated is needed.
This should be followed by work up that should include a CXR, sputum for AAFB and Gene Xpert if they have a productive cough or if it’s inducible. This would identify active pulmonary TB.
For extra pulmonary TB the work up will be guided by the presentation.
For latent TB the two test that can be done is TST and IGRA. IGRA is superior to TST since there are no false positive with prior BCG confirmation.
Treatment
If the donor has active TB then this is an absolute contraindication to donation and treatment with 4 drug regimen (RHZE) should be started.
If the donor has latent TB then this is not a contraindication to transplantation.
Treatment should ideally be completed before transplant, but if transplant is required urgently then can be done and the recipient given LTBI treatment after transplantation.
Treatment for latent TB can be:
References
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Bogdan Marian Sorohan, Gener Ismail, Dorina Tacu, Bogdan Obris, Gina Ciolan, Costin Gîngu, Ioanel Sinescu and Cătălin Baston
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
Guilherme Santoro-Lopes, Aruna K. Subramanian, Israel Molina,José María Aguado, Ricardo Rabagliatti, and Oscar Len,
How would you proceed?
Heaf test was a diagnostic approach to determine whether or not a patient is exposed to TB infection and it is not been done routinely.
In this donor it should be differentiate whether he has active tuberculosis or tuberculosis infection(latent TB) based on;
if active TB than need to treat first.
If latent TB (tuberculosis infection)
Before transplantation it should be treated ideally, but can proceed with transplantation and treatment of donor should be completed for TBI and recipient should receive chemoprophylaxis
Reference UpToDate
How would you proceed?
The Heaf test, a diagnostic skin test, was long performed to determine whether or not patient had been exposed to tuberculosis infection.
The Heaf test was discontinued in 2005.
Until 2005, the test was used to determine if the BCG vaccine was needed.
A Heaf gun was used to inject multiple samples of testing serum under the skin at once. The reading of the Heaf test was defined by a scale:[6]
Negative – No induration, maybe six minute puncture scars
Grade 1 – four to six papules (also considered negative)
Grade 2 – Confluent papules form indurated ring (positive)
Grade 3 – Central filling to form disc (positive)
Grade 4 – Disc >10 mm with or without blistering (strongly positive)
Heaf test in not accurate to assess this patient or immune status of TB.
We need to take history related to past history of TB,contact with tubeculous one,travelling to endamic area. to differentiate is it latent or active.
Investigation
TST
IGRA
IGRA seems to present some advantages over TST in this patient,and also not affected by BCG vaccine.
Treatment of latent TB infection:
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 .
References
Antony, S.J.; Ynares, C.; Dummer, J.S. Isoniazid Hepatotoxicity in Renal Transplant Recipients. Clin. Transplant. 1997, 11, 34–37.
Meije, Y.; Piersimoni, C.; Torre-Cisneros, J.; Dilektasli, A.G.; Aguado, J.M. Mycobacterial Infections in Solid Organ Transplant Recipients. Clin. Microbiol. Infect. 2014, 20 (Suppl. 7), 89–101. [CrossRef]
Thank you.
Thank you.
3. A 41-year-old man came forward to donate a kidney to his brother. 000 mismatch, excellent kidney function, no DSA. His GP reported that he had a positive Heaf test.
Issues/ concerns: –
– potential donor to the brother
– 000 mismatch, excellent kidney function, no DSA
– positive heaf test
Introduction
– Heaf test is a diagnostic skin test used to determine whether or not a person is immune to tuberculosis and it is usually done prior to vaccination
– a positive test is indicated by the skin becoming red and raised after introducing tuberculin into the skin and this suggests that the patient is immune to tuberculosis
– if the test is negative, the BCG vaccine should be given
– a heaf gun is used to inject samples of the testing serum under the skin at once – the needles are dipped in tuberculin purified protein derivative (PPD) and pricked into the skin
– the test is read 2-7 days later according to a scale graded from negative to grade 4 with grade 4 being strongly positive
– there is a potential risk of transmission of TB by solid organ transplantation
– based on detailed medical and epidemiological history, organ donors can be risk stratified into low, moderate and high-risk categories for risk of TB infection or LTBI
– immunologic tests (i.e., TST and IGRA) should be interpreted cautiously, a negative test does not rule out active TB
– molecular test for mycobacterial culture are preferred to the standard culture because of the shorter turn-around-time
– kidney donation should be deferred in suspected or confirmed cases of active TB except in dire circumstances
– potential living donors ought to be screened with TST, IGRA, chest radiographs and treated for LTBI where indicated
– it is preferable that treatment for LTBI or active TB be completed before donation unless there is an urgent indication for transplantation taking into account the severity of the infection
How would you proceed? (1-3)
– detailed history: – drenching night sweats, TB contact, fevers, weight loss, cough, previous TB infection, history of LTBI
– thorough physical examination: – lymphadenopathy
– baseline investigations: – CBC, ESR, CRP, UECs, LFTs, HIV Ab, HBsAg, HCV Ab
– TST, IGRA to screen for LTBI
– if there is evidence for LTBI (positive TST/ IGRA) perform a thorough evaluation for active TB i.e., sputum smear, gene xpert, sputum m/c/s
– imaging: – chest radiograph, abdominopelvic ultrasound
– LBTI treatment: – (3-5)
o INH + Rifapentine weekly for 12 weeks
o INH + Rifampin for 3 months
o INH for 6 months
o Rifampin 4 months
– Active TB treatment (CDC 2022): –
References
1. Simkins J, Donato-Santana C, Morris MI, Abbo LM, Camargo JF, Anjan S, et al. Treatment of latent tuberculosis infection with short-course regimens in potential living kidney donors. Transplant infectious disease : an official journal of the Transplantation Society. 2020 Apr;22(2):e13244. PubMed PMID: 31923346. Epub 2020/01/11. eng.
2. Rose G. The risk of tuberculosis transmission in solid organ transplantation: Is it more than a theoretical concern? The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale. 2005 Sep;16(5):304-8. PubMed PMID: 18159565. Pubmed Central PMCID: PMC2095042. Epub 2007/12/27. eng.
3. Morris MI, Daly JS, Blumberg E, Kumar D, Sester M, Schluger N, et al. Diagnosis and management of tuberculosis in transplant donors: a donor-derived infections consensus conference report. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2012 Sep;12(9):2288-300. PubMed PMID: 22883346. Epub 2012/08/14. eng.
4. Subramanian AK, Theodoropoulos NM. Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious diseases community of practice of the American Society of Transplantation. Clinical transplantation. 2019 Sep;33(9):e13513. PubMed PMID: 30817030. Epub 2019/03/01. eng.
5. Sterling TR, Njie G, Zenner D, Cohn DL, Reves R, Ahmed A, et al. Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020. MMWR Recommendations and reports : Morbidity and mortality weekly report Recommendations and reports. 2020 Feb 14;69(1):1-11. PubMed PMID: 32053584. Pubmed Central PMCID: PMC7041302 completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed. Epub 2020/02/14. eng.
Thank you.
· How would you proceed?
The index case involves a prospective renal donor for his brother with low immunological risk (000 mismatch and no DSA), with a history of a positive Heaf test.
Heaf test was a test which was used to assess exposure to mycobacterium bacilli in a person. The test was performed using 6 needles soaked in tuberculin PPD (pure protein derivative) injected in a circular fashion over flexor aspect of forearm. The test was assessed after 2-7 days, looking for induration at the injection site. This test is not done nowadays. Heaf test is similar to a tuberculin skin test (TST).
Grading of the test result was done as Negative (No induration), Grade 1 (4-6 papules: negative), Grade 2 (an indurated ring formed by confluent papules: positive), Grade 3 (filling the center to form a disc: positive), Grade 4 (Disc >10 mm with or without blistering: strongly positive) (1).
Interpretation:
Grade 1 & 2: due to prior BCG vaccination, or avian tuberculosis
Grade 3 & 4: To be assessed for tuberculosis by getting chest X ray and other investigations (Possibility of latent TB/ active TB).
The index donor should be evaluated for tuberculosis by getting a detailed history including symptoms like cough, low grade fever, weight loss, past history of tuberculosis diagnosis and treatment, or any history of exposure to someone with tuberculosis (2). Other factors to be assessed include history of stay or travel to an endemic zone of tuberculosis for more than 3 months, social risk factors like working in healthcare, homelessness, alcohol or other substance abuse, prison exposure, and medical risk factors including diabetes, and having an underweight BMI (2,3).
Further testing in form of Interferon Gamma Release Assay (IGRA) should be done (4). A chest X ray and sputum examination should be performed.
If the index donor shows any signs of active tuberculosis (symptoms, radiological lesions, a positive sputum test), then the donation is contraindicated and the prospective donor should be treated for tuberculosis. If there is a past history of tuberculosis treatment in the donor, then organ donation can be proceeded with after a detailed counselling of the recipient, with chemoprophylaxis post-transplant under the guidance of an infectious disease specialist (2).
If the index donor is diagnosed to have latent tuberculosis, then the donor should be treated for latent tuberculosis using isoniazid for 9 months (5). Other options include rifampicin for 4 months and weekly isoniazid and rifapentine for 3 months (5,6). The organ donation can take place with a detailed counselling of the recipient, with chemoprophylaxis post-transplant under the guidance of an infectious disease specialist (2). There are no recommendations regarding timing of donation after diagnosis of latent tuberculosis in donor, but it is preferable to donate after completion of treatment, although donation can be done earlier also (2).
References:
Thank you, Amit
How would you proceed?
Heaf test is an old PPD skin test used for children and young adults to check if they have been exposed to TB infection.
If Heaf test is negative, this indicates the need for BCG vaccine.
Heaf test discontinued on 2005 because the manufacturer stopped the production of tuberculin derivatives and Heaf gun because of financial unsustainability.
The reading of the Heaf test was defined by a scale:
· Negative – No induration, maybe six-minute puncture scars
· Grade 1 – four to six papules also considered negative)
· Grade 2 – Confluent papules form indurated ring (positive)
· Grade 3 – Central filling to form disc (positive)
· Grade 4 – Disc >10 mm with or without blistering (strongly positive)
Grades 1 and 2 could result from previous BCG or previous avian tuberculosis, rather than human TB infection.
Persons who are found to have a grade 3 or 4 reaction, they should be referred for chest X-ray and IGRAs to rule out latent TB.
Mantox test has replaced Heaf test. Equivalent Mantoux test:
· 0–4 mm induration (Heaf 0-1)
· 5–14 mm induration (Heaf 2)
· >15 mm induration (Heaf 3-4)
If confirmed latent TB:
Untreated Latent TB without active infection is not a contra-indication for donation.
The risk of TB transmission from donor with treated latent TB is low.
Age 65y or below: start treatment for Latent TB unless it is contr-indicated because of liver disease.
Latent TB is not always treated if thought to be drug resistant, in this case regular monitoring to check for active infection.
It is better to defer donation till treatment is completed.
Treatment involves:
1- Rifampicin +INH for 3 months. Or
2- INH for 6 months.
The recipient is the brother of the donor with good donation offer. The recipient should be tested for Latent TB as well. Treatment before transplantation is better.
Thank you, Hamdy
most current guidelines recommend the use of TST for the screening of LTBI in solid organ candidates/recipients and living donors.
(IGRAs) is a new diagnostic tools that emerged in the last decade.
In comparison to TST, they have some benefits, including the avoidance of interpreting bias, a reduction in false-positive results associated with prior nontuberculous mycobacterial exposure or BCG vaccination, and they are likely more sensitive in candidates with advanced cirrhosis and chronic renal failure because they have a higher yield and better correlation with clinical risk factors for LTBI in these patients.
Patients who are deemed to be at a high risk for LTBI include those who were born in or formerly resided in endemic countries, household contacts of an active TB infection, and those who work or reside in high-risk environments, such as prisons and homeless shelters.
Because the predictive results of both tests are influenced by the expected prevalence of LTBI, some doctors advise adjusting the diagnostic strategy based on the estimated risk of infection. The adoption of a more precise test may lower the rate of false-positive results and, as a result, the number of patients who would be exposed to LTBI medication unnecessarily, making IGRAs the sole method in low-risk patients. To increase the sensitivity of screening, both tests may be carried out on high-risk patients, and any positive result should be interpreted as proof of LTBI.
Candidates should take the TST or IGRA for LTBI evaluation. An induration of 5 mm or more at 48 to 72 hours should be regarded as a positive reaction if TST is chosen as the screening test. In order to assess a boosted-related skin conversion, a second TST should be done 7 to 10 days following the first TST.
Both tests might be run, and any positive results would be taken as proof of LTBI. In order to prevent TST-mediated enhancement of later IGRA responses, IGRA should always be carried out before to or concurrently with TST implantation whenever this dual-test technique is used.
Before beginning LTBI treatment, all individuals with positive results from any of these tests must be ruled out for active TB infection. This assessment entails looking for symptoms and signs that could point to TB, performing a chest radiograph, and imaging additional body sites in cases when extrapulmonary manifestations are present. The necessary clinical specimens should be collected for microbiological confirmation of the diagnosis if any indication of an active infection is discovered during this workup. Transplantation should be delayed once active TB infection has been identified until the condition is adequately treated with appropriate care and smears are negative.
If the microbiologic diagnosis of tuberculosis in the donor is only discovered after organ transplantation, treatment for active infection in the recipient should begin right away in accordance with local regulations. All M. tuberculosis isolates from the donor should undergo drug susceptibility testing since identifying medication resistance may be crucial for determining the course of treatment for the recipients.
reference :
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD8.
Thank you, Asmaa
This expected excellent match donor is showing a positive head test
in such findings, he may have latent TB or previous vaccination or had a previous infection with TB.
In such a case, he may need treatment with 6 months of INH before transplantation. As a risk of having active TB post renal transplant as per the EBM.
This donor needs full evaluation and workup if he is symptomatic
Thank you, short answer, please expand.
Positive TST induration of more than 5 mm needs treatment of latent TB with isoniazid for around six months before transplantation. Further evaluation with chest x-ray, CBC , biochemistry and most importantly, history and physical examination.
after transplantation careful monitoring is needed
Thank you, short answer, please expand.
How do you proceed
Skin testing for tuberculosis (TB) utilizes a form of the diagnostic reagent tuberculin. The multiple puncture technique is referred to as the Heaf, or tine test. Purified protein derivative injected by single or multiple injection methods. it can given as first strength” (1 TU) or “second strength” (250 TU) and is equivalent to a 1:100 concentration .
Grades of Heaf test
negative – minute puncture scars, no induration
grade 1 – at least 4 puncture points are indurated
grade 2 – coalescence of puncture points forming a ring of induration
grade 3 – extensive induration (5 – 10 mm)
grade 4 – severe induration (>=10mm); may be central blistering
It can be used to determine if a person has previous exposure to Tuberculosis or has been vaccinated .
PPD is given on flexor surface of forearm and reading is done after 3 days
It is utmost important to rule out tuberculosis in kidney donors., A thorough history and detailed physical examination in must.
He will need investigation including-
Blood CP/ESR, Renal and liver functions, CRP
Chest X Ray and if any concern then HRCT
AFB smear and culture
IRGA- High specificity in detecting LTBI
Treatment
Oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily
Other options include-
RIF 600 mg daily for 4 months
INH and rifapentine weekly for 12 weeks
Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation. 2018 Feb;102(2S Suppl 2):S60-S65.
Thank you.
The donor has a positive tuberculin skin test
A positive TST would indicate latent TB infection (LTBI) or previous BCG vaccination
It is important to ensure that the donor does not have active TB infection.
The donor should be asked about symptoms of:
A thorough examination carried out:
Investigations:
CBC
ESR
Sputum (if the patient is coughing and producing sputum) – for microscopy, AAFBs , gen xpert
CXR – to assess for pleural effusion, consolidations, nodular opacities
If the patient does not have any signs, symptoms, radiological or microbiological evidence of TB, then the patient has LTBI
Since he is a donor, there is a risk of transmitting the dormant bacilli to the recipient who has a much higher risk of developing active TB which is associated with significant mortality and morbidity
The donor needs to be treated for the LTBI. There are several regimens available:
He will need to complete the treatment before proceeding for the transplant
Thank you, Hussein.
Thank you Professor Halawa
Heaf test positive may indicate past TB infection, BCG vaccination or atypical MBT infection.Tuberculin skin test (TST) and the interferon gamma release assay (IGRAs) are approved screening methods for LTBI. These tests do not differentiate active from latent TB, and may be negative during times of active infection. Latent TBI is a cause of active disease in the post-transplant period, if undetected, may rapidly progress to aggressive form with extrapulmonary manifestations(1).
How would you proceed?
1. History and Examination:
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).
I will consider the following points to make a decision regarding the transplant process with this donor(1,2):
1. If this potential kidney donor with history of latent TB-treated appropriately, the risk of transmission is lower and the transplant can be proceeded to with this donor provided careful clinical monitoring of the recipient not to have DD-TBI.
2. The risk of transmission is moderate if there is a history of latent TB-treated insufficiently or not treated or treatment details not clear OR new diagnosis of latent TB-positive TST or Interferon gamma release assay found during pre-transplant evaluation; evaluation finds no evidence of active TB. In this setting, with moderate risk of transmission, I will consider deferring transplant if possible until donor has taken some/all of chemoprophylaxis and consider chemoprophylaxis of recipient beside clinical monitoring.
3. Unexplained pulmonary apical fibrosis in donor without cavitation and without additional testingcarries variable risk of transmission. I will defer donation and consider further evaluation.
4. History of active MTB treated appropriately over 2 years ago: there is lower to moderate risk of transmission. I will monitor recipient clinically, consider cultures of previous TB sites if possible and suggest chemoprophylaxis of recipient.
5. History of active TB-site remote from transplant, treated appropriately within 2 years: associated with higher increased risk if less than 2 years since active TB diagnosis. In such setting, I will defer live donors until adequately treated; consider consult with infectious disease specialist; recommend cultures of previous TB sites prior to transplant if possible.
6. History of active renal TB treated appropriately. (If not treated appropriately donation should be deferred until after appropriate treatment). This situation is associated with moderate risk of transmission. I will verify treatment; monitor clinically; recommend chemoprophylaxis for recipient; recommend cultures of previous TB site(s); consider consult with infectious disease specialist.
Therapeutic Regimens(3):
1. Timing of Treatment: treatment for LTBI should be started before transplant.
2. For treatment of LTBI, the preferred regimen is oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
3. Alternative regimens containing rifamycins can be considered pretransplant, but should be avoided posttransplant because of immunosuppressive drug interactions. These regimens include RIF 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
4. Fluoroquinolones (± ethambutol) have been suggested for LTBI therapy.
References
1. OPTN;Guidance for Identifying Risk Factors for Mycobacterium tuberculosis (MTB) During Evaluation of Potential Living Kidney Donors.
2. Diagnosis and Management of Tuberculosis in Transplant Donors: A Donor-Derived Infections Consensus Conference Report”. Morris MI, Daly JS, Blumberg E, Kumar D, Sester M, Schluger N, Kim SH, Schwartz BS, Ison MG, Humar A, Singh N, Michaels M, Orlowski JP, Delmonico F, Pruett T, John GT, Kotton CN. Am J Transplant. 2012 Aug 6.
3. Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation. 2018 Feb;102(2S Suppl 2):S60-S65. doi: 10.1097/TP.0000000000002014. PMID: 29381579.
Thank you, Dr Khan.
A 41-year-old man came forward to donate a kidney to his brother. 000 mismatch, excellent kidney function, no DSA. His GP reported that he had a positive Heaf test.
How would you proceed?
Heaf test is A skin test to determine whether an individual is immune to tuberculosis due to previous exposure, carried out prior to vaccination ,if negative,=> the individual should be vaccinated.
A Heaf gun with disposable single use heads is recommended.
The gun injects purified protein derivative equivalent to 100,000 units per ml to the skin over the flexor surface of the left forearm.
The test is read between 3 and 10 days later.
The injection must not be into sites containing superficial veins.
The reading of the Heaf test was defined by a scale:
Negative – No induration, maybe six-minute puncture scars- avian TB /BCG
Grade 1 – four to six papules (also considered negative)- avian TB/BCG
Grade 2 – Confluent papules form indurated ring (positive)
·Grade 3 – Central filling to form disc (positive)
Grade 4 – severe induration >10 mm with or without blistering (strongly positive)
Grades 1 and 2 may be the result of previous BCG or avian tuberculosis.
Grades 2-4 considered positive and should be managed as latent TB, should send the patients for chest Xray.
The patient should be treated for LTBI by one of the followings:
He should be treated before donation.
Rifampicin 10mg/kg (max 600mg) once daily for 4 months.
Rifampicin 10mg/kg+ Isoniazid 5 mg/kg daily for 3 months.
Isoniazid 5mg/kg daily for 6-9 months or 15mg/kg twice weekly for 6-9 months, to be given with pyridoxine 25-50mg to prevent peripheral neuropathy.
Organs from donors with known active TB infection should be discarded.
If the microbiologic diagnosis of TB in the donor becomes available only after organ transplantation, therapy for active infection should be immediately started in the recipient per local guidelines.
Organs from donors with a history of TB successfully treated for at least 6 months can be transplanted.
Delay donation and give the donor short and effective treatment with 3 months of INH + Rifampicin for latent tb after evaluation
or
Long course: Isoniazid monotherapy for 6 or 9 month with pyridoxine tabs 10-50mg according to The US CDC recommendations .
References:
*American Journal of Transplantation 2012; 12: 2288–2300.doi: 10.1111/j.1600-6143.2012. 04205.
*Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD
*Munoz P, Rodriguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clin Infect Dis 2005; 40: 581– 587.
*Sterling TR, Njie G, Zenner D, et al. Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020. MMWR Recomm Rep 2020;69(No. RR-1):1–11.
*CDC Treatment Regimens for Latent TB Infection
Thank you, MY FRIEND.
Although the multiple puncture technique(heaf ,tine test ) has found favor as a screening
tool, a positive result should be confirmed by Mantoux testing unless vesiculation has
taken place.
Thus, Mantoux testing is the procedure of choice. Mantoux testing has the advantage of
using a standard amount of a standard potency reagent and thus is quantifiable and
reproducible.(1).
Donors with positive test:
Evaluation for TB disease:
History,symptoms,sign and contacts.
CXR.
Patient with symptoms summits 3 sputum samples for TB test.
Search for comorbidities :
— liver disease, neuropathy, and concomitant medications.
Regimens for treatment of TBI are associated with hepatotoxicity; the risk of hepatotoxicity is greatest with isoniazid and less so for the rifamycin-based regimens.
Baseline liver enzyme testing is appropriate for the following nonpregnant adult;
●Patients with heavy alcohol use, liver disease, or chronic hepatitis
●Patients currently injecting drugs
●Patients on potentially hepatotoxic medications
●Patients with history of elevated serum transaminase concentrations
Selecting a regimen :
none of the available treatment regimens has been shown to be superior to any of the others.
Therefore, the choice of regimen is based largely on the likelihood of adherence, the potential for adverse effects, and preference (of the patient, provider, and/or public health program).
Low-incidence settings
low-incidence settings (TB incidence rate <100 per 100,000 population), CDC) and National Tuberculosis Controllers Association (NTCA) in 2020, which favor a rifamycin-based regimen over isoniazid monotherapy.
Given detection of increased levels of nitrosamine impurities in samples of rifampin (RIF) and rifapentine (RPT) announced by the US Food and Drug Administration (FDA) in August 2020 .
isoniazid (INH) monotherapy may be considered as an alternative regimen for adults with newly diagnosed TBI.
INH for 6 months.
High-incidence settings :
TB incidence rate ≥100 per 100,000 population who may warrant TBI treatment consist of close contacts of TB cases.
For these individuals, a rifamycin-based regimen (4R, 3HR, or 3HP) .
the World Health Organization, which favors the regimen of INH daily for six months or
3HP weekly for 12 week.
Reference
1-https://www.bionity.com/en/encyclopedia/BMJ.html.
2_ Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020.
AUSterling TR, Njie G, Zenner D, Cohn DL, Reves R, Ahmed A, Menzies D, Horsburgh CR Jr, Crane CM, Burgos M, LoBue P, Winston CA, Belknap R .MMWR Recomm Rep. 2020;69(1):1. Epub 2020 Feb 14.
3_Food and Drug Administration. FDA Updates and Press Announcements on Nitrosamines in Rifampin and Rifapentine. https://www.fda.gov/drugs/drug-safety-and-availability/fda-works-mitigate-shortages-rifampin-and-rifapentine-after-manufacturers-find-nitrosamine (Accessed on October 06, 2020).
Thank you
Donor with positive head test
Is an old test used before to check that the person exposed to TB before or not , usually was done before vaccination , if it is negative , indicates the need for BCG vaccine.
The reading is performed as a scale from negative to 4 .
Grade 1-2 may be due to previous vaccination , grade 3-4 should proceed for chest X-ray , IGRA to rule out latent or active infection
If confirmed latent TB , should be treated and to postpone donation until treatment
Treatment :
INH daily for 6 months or
Rifampicin alone for 4 months or
INH plus Rifampicin daily for 3 months or
INH and Rifampicin weekly for 3 months
References
Simkins J, Donato-Santana C, Morris MI, Abbo LM, Camargo JF, Anjan S, et al. Treatment of latent tuberculosis infection with short-course regimens in potential living kidney donors. Transplant infectious disease : an official journal of the Transplantation Society. 2020 Apr;22(2):e13244. PubMed PMID: 31923346. Epub 2020/01/11. eng.
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD
The Heaf test is a skin test was used to determine exposure to TB infection, it was discontinued and currently replaced by Mantoux test (PPD).
-Positive results might indicate BCG vaccination or avian tuberculosis.
*Both donor and potential recipient should be evaluated and screened for LTBI and active TB ( especially they are brother) for the following;
– TB remains a relevant public health problem.
– 10% of people with LTBI will progress to developing active TB disease.
– The risk of TB reactivation is higher in immunocompromised individuals.
– TB resulted in significant morbidity and mortality.
Screening for LTBI :
Identify risk factors:
– BCG vaccination ( as it may influence the screening test)
– Previous TST results.
– Exposure to individuals with active TB in the household or workplace
– Prior residence or travel to areas highly endemic for TB.
– Any history of previous TB or TB treatment.
Screening tests;
-There is no gold standard test. WHO recommended the following: TST, IGRA
* Tuberculin skin test (TST) :
– Unreliable advanced CKD and immunosuppressed individuals.
– The result might be falsely positive in previous BCG vaccination
* IGRAs; (QuantiFERON-TB and T-SPOT ):
– High specificity in detecting LTBI in immunocompromised.
– More sensitive than the TST for the diagnosis of LTBI in KTRs.
– Result will not be affected by BCG vaccine.
*The result of these test should be interrupted with caution;
– Both cannot distinguish latent TB infection from active disease.
– Both might be falsely negative or indeterminate results in immunocompromised individual, as they assess the immune response of the body to MTB.
– Neither TST nor IGRAs are recommended for diagnosing active infection.
*Since the sensitivities of TST and IGRA do not overlap fully both modalities preferred to be used in screening in those with high pre‐test probability of LTBI in whom a single positive test result might change clinical management. ( LTBI, previous vaccination, active TB)
*CXR.
*Patients with a prior history of positive TST or IGRA testing to be screened for active TB.
– Signs and symptoms of active TB.
– Sputum for smear, culture, PCR.
*The result of the screening test will further guide the management:
*Active TB in :
– Donor is a contraindication to organ donation. Transplantation should be postponed until the disease is well controlled with adequate treatment and smears are negative.
-Recipient needs to be treated prior to transplant.
LTBI:
Donor:
-Untreated LTBI without evidence of active infection is not a contraindication to donation, but administration of preventive therapy to all recipients should be considered.
-The risk of transmission is low if therapy for LTBI was completed before donation.
Recipient:
-When possible, should be started before transplant, and can often be completed while the patient is on the waitlist.
-If urgent transplant is indicated, the treatment can be held peri-operatively and resumed when medically possible until completion of the originally planned course.
– Caution with rifamycins after transplant.
Regimen AST;
INH 300 mg/d for 9 months, with oral pyridoxine 25 to 50 mg daily or twice weekly by (DOT)
9 months of therapy is preferred over 6months because of better protection.
Monitoring for side effect; hepatotoxicity, neurotoxicity, drug-drug interaction ( IS level)
Alternative regimens
Rifampin for 4 months or INH with rifapentine for 12 weeks.
Can be used in the pre‐transplant setting.
Should be avoided if possible or used with caution post‐transplant due to interactions with IS.
References:
Subramanian, AK, Theodoropoulos, NM; on behalf of the Infectious Diseases Community of Practice of the American Society of Transplantation. Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious diseases community of practice of the American Society of Transplantation. Clin Transplant. 2019; 33:e13513.
Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation. 2018 Feb;102(2S Suppl 2):S60-S65. doi: 10.1097/TP.0000000000002014. PMID: 29381579.
Sundaram M, Adhikary SD, John GT, Kekre NS. Tuberculosis in renal transplant recipients. Indian J Urol. 2008 Jul;24(3):396-400. doi: 10.4103/0970-1591.42625. PMID: 19468476; PMCID: PMC2684355.
Krishnamoorthy S, Kumaresan N, Zumla A. Latent tuberculosis infection and renal transplantation – Diagnosis and management. Int J Infect Dis. 2019 Mar;80S:S73-S76. doi: 10.1016/j.ijid.2019.01.049. Epub 2019 Feb 6. PMID: 30738187.
Great Dr Hadeel. Can expand you on your statement ‘When possible, should be started before transplant, and can often be completed while the patient is on the waitlist.‘
Thank you Prof. Mohsen
Generally for SOT candidate treatment of LTBI preferred to be started and completed before transplantation to decrease the risk of reactivation post-transplantation.
KT candidates on dialysis they can wait, However, this might not be applicable for other SOT if it was indicated urgently as a life saving like in liver transplant.
Heaf test is not accurate to assess immune status for TB.
Assessment of risk for TB:
. History of previous infection with TB , treatment of active TB, or close contact with active TB patient.
.Diagnosis of latent TB IGRA being better TST as it is not affected by previous BCG vaccination .
. In case of donor with latent TB, according to CDC and National Tuberculosis Controller Association, we proceed for 3 month rifampicin regimen such as oral rifampin ,INH and pyridoxine.
Description of Heaf test
Heaf test was historically used in the UK until 2005 and then replaced by Mantaux test. A heaf gun was used to simultaneously inject various serum samples under the skin. The skin was poked with needles that had been soaked in tuberculin pure protein derivative (PPD). A heifer gun with single-use disposable heads was suggested.
On the flexor surface of the left forearm, the gun administered PPD equivalent to 100,000 units per ml in a six-part circular pattern. The exam was graded two to seven days later. Injections were not permitted in places with superficial veins.
The Heaf test score was determined on a scale:
Negative – Absence of induration, maybe six-minute puncture scars
Grade 1 – four to six papules (also considered negative)
2nd grade: confluent papules create an indurated ring (positive)
Grade 3 – Filling the center to form a disc (positive)
Grade 4 – Disc more than 10 millimeters with or without scorching (strongly positive)
Grades 1 and 2 may be caused by BCG or avian tuberculosis instead of a human TB infection.
Approach to clinical scenario
According to WHO guidelines on latent Tb screening, includes 2 tests: Mantoux test and Interferon gamma release assays (IGRAs).
In this case, diagnostic strategy for detecting active and/or latent tuberculosis would be as follows:
Request detailed history of contact with a patient with active TB.
History of prior anti-tuberculosis therapy.
constitutional symptoms such as cough, fever, anorexia, night sweats, and weight loss or other symptoms like hemoptysis.
Therapy of LTBI in the recipient and donor
It is crucial to take all possible precautions to stop the spread of TB infection in such people since TB could directly impair how well an allograft functions. Efforts must be made to detect and treat LTBI and active TB in both the live donor and recipient prior to transplantation. Therapy for LTBI should adhere to WHO 2018 recommendations.
LTBI treatment options
– Six months of isoniazid monotherapy (recommended in countries with high & low TB incidence).
– 3 months of daily Rifampicin and Isoniazid therapy (for children and adolescents under 15 years old).
– Weekly Isoniazid and Rifapentine for three months.
Thank you for the comprehensive answer. Can you please explain who will have weekly INH and Rifampicin for three month?
How would you proceed?
Heaf test is a skin test to diagnose latent TB, was used in UK, it is a spring-loaded instrument with six needles arranged in a circular formation which was inserted in the wrist or shoulder, the needles were dipped with purified protein derivative and pricked in to the skin.
The reading of the Heaf test was defined by a scale:
· Negative – No induration, maybe six minute puncture scars- avian TB /BCG
· Grade 1 – four to six papules (also considered negative)- avian TB/BCG
· Grade 2 – Confluent papules form indurated ring (positive)
· Grade 3 – Central filling to form disc (positive)
· Grade 4 – Disc >10 mm with or without blistering (strongly positive)
Grades 2-4 considered positive and should be managed as latent TB, should send the patients for chest Xray.
The patient should be treated for LTBI by one of the followings:
Rifampicin 10mg/kg (max 600mg) once daily for 4 months.
Rifampicin 10mg/kg+ Isoniazid 5 mg/kg daily for 3 months.
Isoniazid 5mg/kg daily for 6-9 months or 15mg/kg twice weekly for 6-9 months, to be given with pyridoxine 25-50mg to prevent peripheral neuropathy.
He should be treated before donation.
References:
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD
How would you proceed? According to the guidelines both donor and recipients should be screened for LTBI or possible active TB as part of the transplant workupactive MTB is a contraindication for donation and should follow local protocol for treatment as the general populationMedical history including epidemiological history is he from an endemic area with a higher rate of TB including previous history of TB or treatment history for active TB, any BCG scar, any history of exposure or contact with an active case of TB at the workplace, or social history if he is homeless, refugee, alcoholic abuse, malnutrition or working in humanitarians, travel history in the last 2 years to an endemic area, previous TST or IGRA testing positive or treated for LTBIPhysical examination focus on LAP and chest examination, CXR for any fiberoptic apical lesion, calcified lymph node, or pleural thickeningHeaf test for TB
heaf test, it’s six needle guns sterilized by flaming. puncture skin test after cleaning the skin of the forearm cleaned isopropyl alcohol and p.p.d was applied by dropper and spread with the end-plate of the gun before firing usually wait for 7 days to interpret the test results and grades from 0-4
The positive Heaf test appears to be too sensitive. Both a negative and grade 1 positive should be negative and not significant and these children are given the B.C.G. vaccine. 4 or more palpable skin papules of at least 1 mm grade 2, grade 3 papules forming a ring in the middle, and grade 4 vehicular ulceration should be regarded as significant and the children investigated for M. tuberculosis infection.
he will be considered high risk for LTBI if confirmed he is from the endemic area then in addition to TST will do IGRA test as it will increase the sensitivity of the screening if positive will be treated on the line of LTBI provide he is asymptomatic with negative cxr with INH 300mg /day and pyridoxin 25 – 50mg for total 6 months and the transplantation will be postponed till he completed the course. some preferred 9 months of treatment with a lower rate of recurrence especially in the endemic area.
Alternative treatment
Rifampin in a dose of 600 mg for 4 months.
INH+ weekly rifapentine for 3 months.
References
1. Galbraith NS, Hanson A, Shoulman R, Andrews DW, Lee DB. Interpretation of positive reactions to Heaf tuberculin test in London schoolchildren. Br Med J. 1972 Mar 11;1(5801):647-9. doi: 10.1136/bmj.1.5801.647. PMID: 4622617; PMCID: PMC1787811.
2. Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis recommendations for solid organ transplant recipients and donors. Transplantation. 2018;102(2) Suppl 2:S60–SS5.
3.Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD
The reading of the Heaf test is defined by a scale:
Grades 1 and 2 may be the result of previous BCG or avian tuberculosis.
Children who have a grade 3 or 4 reaction
I would proceed in following manner:
https://gpnotebook.com/simplepage.cfm?ID=644546568
Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation. 2018 Feb;102(2S Suppl 2):S60-S65. doi: 10.1097/TP.0000000000002014. PMID: 29381579.
How would you proceed?
Check for risk factors for TB (1)
Country of origin
· Immigrants from TB endemic countries (incidence>100/100000)
Social risk factors
· Close contacts of individuals with TB disease,
· homelessness,
· injection drug use,
· work or residence in facilities (e.g. homeless shelters, correctional facilities)
Medical risk factors
· History of untreated TB
· Radiographic evidence prior TB
· If previously treated for either TB disease or LTBI, anti-TB drug(s), treatment duration, and adherence should be verified.
Look for active disease (pulmonary and extrapulmonary) (2)
· Symptoms like chronic cough, night sweats, weight-loss, fever, anorexia
· CXR
· Induced Sputum for ZN stain, (NAAT) Xpert MTN/RIF
· USG Whole abdomen
· CT/ MRI (when indicated)
Consider treatment as LTBI if no active disease (1)
Defer donation till completion of treatment (1)
Treatment of LTBI should follow WHO 2018 guidelines (3)
· INH monotherapy- 6 months
· Rifampicin + INH daily- 3 months
· Rifapentine and Isoniazid weekly for 3 months
My preference would be Rifampicin plus INH daily for 3 months, pyridoxine 25-50mg and close monitoring for hepatotoxicity.
References:
👉 Heaf test represents an immunological reaction to TB antigen, which can give false positive result in case of prior BCG vaccine or living in high endemic area for TB.
👉 Heaf test or now what is called manteau test is used to diagnose latent TB infection, so we must proceed to IGRA test which is more sensitive and not give false positive results to exclude latent TB.
👉 In addition, epidemiological data regrading the residence or travel to endemic areas, contact with open TB cases or exposure to infection or past history of treatment from TB are essential steps in evaluation.
👉 In addition, CXR and HRCT are needed to exclude any pulmonary affection.
👉 Exclusion of active TB by sputum analysis for AFB, culture on BACTEC system, geneXpert study are essential to exclude active TB
👌 Active TB is absolute contraindication to donation, and therapy should be started immediately and must be isolated till clearance of sputum from his brother.
👌 Latent TB should be treated prior to consideration as donor by 4 months oral rifampin, or 6 months of INH or 3 months of combined INH and rifampin.
The Heaf test: is a skin test, to see the exposure to tuberculosis infection in the past.
Defined by a scale:
I would proceed with detail History of past TB disease, or close contact with TB infected person or working in highly prevalent area and living with high-risk groups (prison inmates, homeless, drug abuser)
Important Investigations in pretransplant period of both Donor and Recipient: –
-Chest x-ray/ Chest CT scan.
-Sputum AFB, Culture & Gene- Xpert.
-QuantiFERON-TB-Gold In-Tube test (QFT).
–ESR, CRP.
Treatment of Latent TB infection in Donor
-Rifampin daily for 4 months
-INH + Rifampin daily for 3 months
-INH only daily for 6 – months.
Check investigation after treatment and before donation.
If diagnosed active TB, donation should be cancelled and start treatment of the donor.
References:
1-Galbraith NS, Hanson A, Shoulman R, Andrews DW, Lee DB. Interpretation of positive reactions to Heaf tuberculin test in London schoolchildren. Br Med J. 1972;1(5801):647-649. doi:10.1136/bmj.1.5801.647.
2-Singh, N., & Paterson, D. L. (1998). Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clinical infectious diseases, 27(5), 1266-1277.
Thank you Dr Manal Malik
Excellent.
How did you confirm that this donor has L TB and not only due to vaccination?
Introduction;
–Current guidelines provide recommendations for latent TB screening in all KT candidates and donors before transplantation.
–There are no gold standard tests for diagnosing latent TB accurately in KT candidates, but IGRA seems to present some advantages over TST in patients with ESRD.
–The incidence and prevalence of latent TB in KT recipients is higher than in KT candidates and therefore KT recipients should be more frequently screened.
-The importance of diagnosis is supported by the fact that undiagnosed and untreated latent TB after KT significantly increases the risk of active TB.
–Treatment of latent TB should be considered only after active TB has been excluded.
–Treatment of KT recipients with latent TB is important for preventing the risk of reactivation.
-Treatment in KT patients is indicated in one of the following conditions:
*A positive TST or IGRA test,
*History of untreated TB,
*History of recent contact with an active TB patient,
*When the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB.
How would you proceed?
The following history will be obtained from the donor:
–History of staying in country with high TB incidence > 3 months,
–History of close contact with open TB infection,
–History of working with high-risk groups (prison inmates, homeless, drug abuse)
–Past history of infection or treatment for LTBI or active TB,
-Past history of anti TB medications & duration of treatment,
-Past history of BCG vaccination,
-Family history for active or LTBI.
Work Up;
–Heaf test was used to assess individual immune status for TB ,but it is not accurate test and should not depend on it in this case.
-Positive Heaf test indicates presence of immune response to TB protein either BCG vaccine or latent infection.
-Sputum sample for AFB stain
-IGRA (Quantiferon test)
-CXR
-LFTs (before starting anti TB medications)
Treatment;
-Donor should be referred to Pulmonology for clearance before proceeding for KT.
–In the KT setting, the preferred treatment of latent TB is;
(Isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6.
-A regimen based on rifampicin is not recommended.
-Evaluation of liver enzymes during treatment, initially bi-weekly for 6 weeks and monthly thereafter, is recommended.
References;
–Bumbacea, D.; Arend, S.M.; Eyuboglu, F.; Fishman, J.A.; Goletti, D.; Ison, M.G.; Jones, C.E.; Kampmann, B.; Kotton, C.N.; Lange, C.; et al. The Risk of Tuberculosis in Transplant Candidates and Recipients: A TBNET Consensus Statement. Eur. Respir. J. 2012, 40, 990–1013.
–Subramanian, A.K.; Theodoropoulos, N.M. Mycobacterium Tuberculosis Infections in Solid Organ Transplantation: Guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation. Clin. Transplant. 2019, 33, e13513.
–Meije, Y.; Piersimoni, C.; Torre-Cisneros, J.; Dilektasli, A.G.; Aguado, J.M. Mycobacterial Infections in Solid Organ Transplant Recipients. Clin. Microbiol. Infect. 2014, 20 (Suppl. 7), 89–101.
–Shu, C.-C.; Tsai, M.-K.; Lin, S.-W.; Wang, J.-Y.; Yu, C.-J.; Lee, C.-Y. Latent Tuberculosis Infection Increases in Kidney Transplantation Recipients Compared With Transplantation Candidates: A Neglected Perspective in Tuberculosis Control. Clin. Infect. Dis. 2020, 71, 914–923.
Thank you Dr Mohamed Abou Elenein
Well done for the detailed answer.
Can you clarify the exact role of BCG vaccine in the donor if he fulfils the above criteria such as staying in a country with high TB incidence > 3 months OR
–History of close contact with open TB infection,
–History of working with high-risk groups (prison inmates, homeless, drug abuse).
Thanks; our prof
Positive Heaf test indicates presence of immune response to TB protein either BCG vaccine or latent infection.
This potential kidney donor seems to be excellent, with zero mismatch, young with no DSA. However, he has positive Heaf test. This could mean previous vaccination, latent or active TB. To differentiate between them we need to take detailed history of vaccination, current or previous symptoms of TB, treatment of TB or contact with TB patients. Also we need to know how strong was the positivity. If all are negative, then we need to do a chest ray, CRP to make sure no active disease, especially if Heaf was grade 3-4 positive. If no active disease, then to diagnose latent TB, we need to do Mantoux test or IGRA. 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).
If confirmed to have latent TB (LTBI), WHO 2018 guidelines outline the following treatment options for LTBI (WHO, 2018b):
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 of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone.
In our center we use INH with pyridoxine for 9 months.
References:
1-S. Krishnamoorthy et al. / International Journal of Infectious Diseases 80 (2019) S73–S76
Thank you Dr Muntasir Mohammed. Whilst your answer was very detailed I feel I’m lost. You referred to:
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.
Then you mentioned
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
So you referred to 6 month and 9 month of INH monotherapy in low incidence countries. I do not know even what is the difference numerically between high and low incidence countries.
Would you be able to simplify your recommendation for this case please?
Will delayed the donation and give the donor short and effective treatment with 3 months of INH + Rifampicin for latent tb after evaluation.
History of exposure to active tb, previous tb, treatment for tb
chest x ray, sputum for afb1,2,biopsy or fnac of any lymph node, lft, crp, rft, uric acid
If diagnosed active TB, donation should be cancelled and start treatment of the donor.
References
Sterling TR, Njie G, Zenner D, et al. Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020. MMWR Recomm Rep 2020;69(No. RR-1):1–11. DOI: http://dx.doi.org/10.15585/mmwr.rr6901a1
Simkins J, Donato-Santana C, Morris MI, Abbo LM, Camargo JF, Anjan S, Natori Y, Guerra G. Treatment of Latent Tuberculosis Infection with Short-Course Regimens in Potential Living Kidney Donors [abstract]. Am J Transplant. 2019; 19 (suppl 3).
Galbraith NS, Hanson A, Shoulman R, Andrews DW, Lee DB. Interpretation of positive reactions to Heaf tuberculin test in London schoolchildren. Br Med J. 1972 Mar 11;1(5801):647-9. doi: 10.1136/bmj.1.5801.647. PMID: 4622617; PMCID: PMC1787811.
Thank you for simple and straight forward answer. What about vaccination as a cause of +ve Heaf test?
Yes, BCG vaccination can cause +ve heaf test. thank you
A skin test to determine whether or not an individual is immune to tuberculosis due to previous exposure ,carried out prior to vaccination if negative, the individual should be vaccinated.
Heave test is classified into 4 grades.
Grades 1 and 2 may be the result of previous BCG or avian tuberculosis.
Children who have a grade 3 or 4 reaction require X-ray and follow-up.
MY approach to this case :
-History (prior TB exposures, history of active TB, travel or residence in en-demic regions and past TST results), physical examination(pneumonia, unexplained cachexia or lymphadenopathy),IGRAs test , sputum cultures and nucleic acid amplification tests , thoracic imaging (old granulomatous disease,apical scarring, new infiltrates).
– IGRAs have been shown to be of increased specificity antigens derived from M. tuberculosis compared with TST .
-Since he is a living donor the transplant can be delayed until a full evaluation of possible latent or active TB is performed.
Recommendations for the management of LTB :
Short course regimens include:
-Three months of once-weekly isoniazid plus rifapentine.
-Four months of daily rifampin.
-Three months of daily isoniazid plus rifampin .
Long course : Isoniazid monotherapy for 6 or 9 month with pyredoxine tabs 10-50mg according to The US CDC recommendations .
-In our center we used INH monotherapy for 6month.
Reference :
1.American Journal of Transplantation 2012; 12: 2288–2300.doi: 10.1111/j.1600-6143.2012.04205.x
2. CDC Treatment Regimens for Latent TB Infection
I like your detailed summary. I appreciate your debate regarding the uncertainty on optimal duration of therapy
Thank you prof Ajay .
Heaf test was used to assess individual immune status for TB ,but it is not accurate test and should not dedpend on it in this case.
Assess patient riskfor TB
1- History of orevoius TB infection , treatment or close contact with patient with active TB.
2- For diagnosis of latent TB either TST or IGRA is recommended with IGRA being better option asit is not affected by previous BCG vaccination .
3- If the donor was latent TB , CDC and national tuberculosis controller association prefers 3 month rifampicine based regimen such as oral rifampin + INH and pyridoxine 25 mg .
Short and sweet
But ‘previsous’ is mistyped as ‘orevious’ !!
The Heaf test: is a diagnostic skin test, was long performed to determine whether or not children had been exposed to tuberculosis infection which is not used since 2005.
The reading of the Heaf test was defined by a scale:
Our case came positive Heaf test:
We should cover all points:
-History of staying in a tuberculous endemic area > 3 months and history of close contact with TB infected person.
-Working with high-risk groups (prison inmates, homeless, drug abuse)
-Past history of infection or treatment for TB, drugs used, and duration.
Investigations:-
-Chest x-ray/ Chest CT scan.
-Sputum AFB, Culture & Gene- Xpert.
-QuantiFERON-TB-Gold In-Tube test (QFT).
-BAL if possible for a higher yield of sputum analysis.
-ESR, CRP.
Might be active or latent TB:
Treatment of Latent TB infection
This clinical state needs to be treated even if he is not donating kidney as 80-90% of LTBI will reactivate if not treated.
Treatment plan will be one of the following:
-Rifampin daily for 4 months
-INH + Rifampin daily for 3 months
-INH only daily for 6 – months.
Check investigation after treatment and before donation.
If diagnosed active TB, donation should be cancelled and start treatment of the donor.
References:
1-Galbraith NS, Hanson A, Shoulman R, Andrews DW, Lee DB. Interpretation of positive reactions to Heaf tuberculin test in London schoolchildren. Br Med J. 1972;1(5801):647-649. doi:10.1136/bmj.1.5801.647.
2-Singh, N., & Paterson, D. L. (1998). Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clinical infectious diseases, 27(5), 1266-1277.
You mention 3 possible options for prophylaxis against latent TB in recipients. Which one would you choose for your patients?
Thanks prof, Sharma.
I would prefer options contain Rifampicin because regimens containing
this drug have a stronger sterilizing activity.
Multipuncture methods (including the Tine test and the Heaf test) should not be used; they may be easier to administer but are not accurate because it is not possible to precisely control the amount of tuberculin
Exclude TB disease prior to treatment of TB infection
Prior to starting treatment for TB infection, we ensure that there are no signs or symptoms of TB disease (previously termed active TB) based on history (eg, fever, cough, weight loss, night sweats), physical examination, and chest radiography. This evaluation is important to avoid inadvertent undertreatment of TB disease, which can lead to emergence of drug resistance.
Testing for TB infection (previously termed latent TB infection) is reserved for individuals who are at increased risk of developing TB disease and would thus benefit from treatment
●Individuals at increased risk of recent infection (eg, close contacts of persons with untreated TB disease
●Individuals at high risk of reactivation if infected (eg, immunocompromised individuals)
●Individuals at moderate or slightly increased risk of reactivation who reside in an area where TB is prevalent
In general, either IGRA or TST may be used; , particularly for patients who are unlikely to return to have the TST read and for patients with a history of Bacille Calmette-Guerin (BCG) vaccination administered after 12 months of age.
.
Only those who would benefit from treatment of LTBI should undergo testing, so a decision to test presupposes a decision to treat if the test is positive.
If the first test is negative, close contacts of patients with active pulmonary TB should undergo a second test eight weeks later. Many TB programs test casual contacts only once at eight weeks after exposure.
FOR OUR CASE POST PONE UNTIL TB SCREEN FOR BOTH DONOR -Recipient
IGRA is preferable if available
NOT DEPEND ON RESULT OF HEAF TEST
TREATMENT LATENT TB
Typing whole sentence in capitals amounts to shouting.
-Heaf test is a skin test used to detect if an individual is immune to tuberculosis, it is used to be done before vaccination. If positive it indicates that the case is immune needs no vaccine and if negative means that the case needs to receive BCG vaccine
Current international guidelines recommend using TST and/or IGRAs for LTBI screening for donors and recipients , infact IGRAs are more specific with higher r positive and negative predictive values but are more expensive
A history of untreated LTBI without active infection in the donor is not a contraindication for donation. The risk of transmission is low if LTBI therapy course was completed before organ donation and transplant recipients from such donors can be clinically monitored without receiving LTBI therapy.
Therefore both donor and recipeint have to undergo screening for LTBI
So this donor can be accepted but treated first and after confirmation of full clearance of TB donation can proceed .
LTBI therapy includes oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
9 months of therapy provides better protection compared to 6 months .
INH should be monitored for hepatotoxicity by checking liver function tests every
2 weeks for 6 weeks, then monthly afterwards .
Other regimens containing rifamycins can be used including Rifampicin 600 mg daily for 4 months or INH and rifapentine weekly for 12 weeks.
Fluoroquinolones (± ethambutol) have been proposed for LTBI therapy but less efficient
Reference
-Meinerz G, Silva CKD, Dorsdt DMB, et al. Latent tuberculosis screening before kidney transplantation in the South of Brazil. J Bras Nefrol. 2021;43(4):520-529. doi:10.1590/2175-8239-JBN-2020-0189
-Santoro-Lopes G et al . Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation 2018 , Volume 102 , Number 2S-2
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.
Heaf test
Was the test used till 2005 and then discontinued and substituted by the Mantoux test
Used for determining the previous exposure to M.TB
How proceed
First, the donor and recipient should be screened against latent TB (the recipient will be immunocompromised so he has a high risk for reactivation post-transplantation);
Treatment of LTBI in donor and recipient (WHO 2018)
Donations can be conducted after cure of the disease
References;
Aguado JM, Herrero JA, Gavaldá J, et al. Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain, Transplantation, 1997, vol. 63 (pg. 1278-86)
2Muñoz P, Rodriguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants, Clin Infect Dis, 2005, vol. 40 (pg. 581-7)
3Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management, Clin Infect Dis, 1998, vol. 27 (pg. 1266-77)
4s l. Guidelines for the prevention and management of infectious complications of solid organ transplantation, Am J Transplant, 2004, vol. 4 (Suppl 10)(pg. 37-41)
I like your summary, and analysis.
You mention 3 possible options for prophylaxis against latent TB in recipients. Which one would you choose for your patients?
A 41-year-old man came forward to donate a kidney to his brother. 000 mismatch, excellent kidney function, no DSA. His GP reported that he had a positive Heaf test.
==================================================================
Other Tests
How would you proceed?
1- Medical history
2- Physical examination
3- Chest x-ray/CT.
3- And other laboratory tests
Microbiology
4- Full blood count
5- Tuberculin Skin Test (TST)
6- Interferon Gamma Release Assay (IGRA)
Indications
Test Selection
====================================================================
A decision to test should presuppose intention to treat LTBI if detected.
High risk for developing TB disease fall into two categories:
====================================================================
Latent TB Infection
But A Person with TB Disease
====================================================================
Treatment options recommended for LTBI include:
However, the Panel could not reach a consensus and voted on the equivalence of
===================================================================
Reference
I like your clinical approach that is well-referenced. I appreciate a judicious use of investigations. Typing whole sentence in bold or typing in capitals amounts to shouting.
Many Thanks Prof.Sharma
Positive Heaf test indicates presence of immune response to TB protein either BCG vaccine or latent infection. It is improtant to confirm the diameter of induration and use IGRA assay depends on the local protocol.
Both D and R to be assessed thouroughly and treated for any active or latent TB before proceed to transplant.
Short and sweet
How would you proceed?
A potential kidney donor with positive Heef test (TST)
All renal transplant donors should undergo screening for LTBI and active TB disease prior to transplantation
First rule out active TB
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, and homeless)
Test for LTBI with either Tuberculin skin test (TST) or IGRA assays
TST test:
o Is carried out by injecting intradermal purified protein derivate (PPD) in the forearm of an individual. An induration reaction of 15mm or larger, read after 48 or 72h, is considered indicative of past or current mycobacterial infection. TST is based on delayed-type hypersensitivity (DTH) skin reactivation to tuberculin PPD
o Affected by a complex array of factors such as age, nutritional and immunological status, the time interval between antigen exposure and the test performance, BCG vaccination (positive in the BCG-vaccinated individual), immunosuppression, genetic background, and cross-reactivity with environmental nontuberculosis mycobacteria and perhaps other pathogens
Advantages of IGRAs:
1. Avoid interpreting bias
2. Reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination
3. More sensitive in candidates with CRF and advanced cirrhosis
Limitations of IGRAs:
1. The NPV of IGRAs is not optimal to rule out infection in patients considered to be at high risk for LTBI
2. Higher cost
3. Frequent occurrence of conversions and reversions of test results when serial screening is performed (may complicate the interpretation of their results among SOT candidates)
o In low-risk patients: do only IGRAs, because the use of a more specific test might reduce the rate of false-positive results and, consequently, the number of patients who will unnecessarily be exposed to LTBI therapy
o In high-risk patients: do both tests (IGRA should be performed before or concurrently with TST placement to avoid TST-mediated boosting of subsequent IGRA responses), and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening
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)
Treatment of LTBI in donor (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
Monitor for hepatotoxicity with at least serum ALT checked every 2 weeks for 6 weeks, then monthly thereafter
So, for the index case, I will do the following:
o I will ask for high risk of TB (contact with active TB, recently arrived from travel abroad, drug users, incarcerated persons, and homeless) and history of vaccination
o Exclude active pulmonary and extra pulmonary TB (history, symptoms, investigations, clinical examination, and imaging)
o As TST is susceptible to false-positive results (BCG vaccine), I will do IGRA test (TSPOT.TB or QuantiFeron). It is more sensitive and specific for diagnosing LTBI (generally do only IGRAs in areas of high incidence of TB, and both tests in areas of low incidence)
o If confirmed to be LTBI, I will treat with Isoniazid monotherapy for 6 months with close monitor for hepatotoxicity with at least serum ALT checked every 2 weeks for 6 weeks, then monthly thereafter (there are other options)
o Treat living donor with LTBI before transplantation
References
1. Carranza C, Pedraza-Sanchez S, de Oyarzabal-Mendez E and Torres M (2020) Diagnosis for Latent Tuberculosis Infection: New Alternatives. Front. Immunol. 11:2006. doi: 10.3389/fimmu.2020.02006
2. Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020
3. Krishnamoorthy S, Kumaresan N, Zumla A. Latent tuberculosis infection and renal transplantation – Diagnosis and management. Int J Infect Dis. 2019 Mar;80S:S73-S76. doi: 10.1016/j.ijid.2019.01.049. Epub 2019 Feb 6. PMID: 30738187.
4. Santoro-Lopes, Guilherme, Subramanian, Aruna, Molina, Israel, Aguado, José María, Rabagliatti, Ricardo, Len, Osca. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation 102(2S):p S60-S65, February 2018.
I like your clinical approach that is well-referenced. I appreciate a judicous use of investigations.
Persons with no known risk factors for TB may be considered for treatment of LTBI if they have either a positive IGRA result or if their reaction to the TST is 15 mm or larger.
In this scenario, a positive heaf test is suggestive of a latent infection and should be treated before transplantation. Thorough history and investigation of donor should also be done to rule out active tuberculosis.
In some TB endemic countries, routine donor screening for latent tuberculosis is not usually done since it is likely to be positive. Therefore, all post-transplant patient are placed on INH prophylaxis for 6 months.
reference
Deciding When to Treat Latent TB Infection | TB | CDC. https://www.cdc.gov
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.
How would you proceed?
The Heaf test is a diagnostic skin test was used in the past to determine whether or not children had been exposed to tuberculosis infection and need for BCG vaccination.
The Mantoux test or tuberculin sensitivity test, or (PPD test for purified protein derivative) is a tool for screening for tuberculosis (TB) and for tuberculosis diagnosis.
According to the guidelines published by Centers for Disease Control and Prevention in 2005, interpretation of Mantoux test as the following:
Baseline test: ≥10 mm is positive .0 to 9 mm is negative
Serial testing without known exposure: Increase of ≥10 mm is positive
Known exposure:
≥5 mm is positive in patients with baseline of 0 mm
≥10 mm is positive in patients with negative baseline or previous screening result of >0
Recently interferon gamma release assays (IGRAs) have become common in clinical use in the 2010s.
In current practice in renal transplant units The QuantiFERON-TB Gold blood test is routinely used ,it measures the patient’s immune reactivity to the TB bacterium, and is useful for initial and serial testing of persons with an increased risk of latent or active tuberculosis infection. Guidelines for its use were released by the CDC in December 2005.
The target now to screen for latent TB infection (LTBI) in the potential living donor: Since the latent infection can be transmitted to recipient,screening is very important to avoid a deadly infection after kidney transplantation:
Screening includes previous TB history, chest radiograph findings, and tuberculin test (TST) ,interferon-gamma release assays (IGRAs) results and /Or QuantiFERON gold test results (There is no gold standard test to diagnose LTBI).
-In the current scenario ,if screening for latent TB came positive ,So LTBI treatment is recommended after transplantation for recipients with a donor’s positive screening.
-The recommended drug for LTBI treatment is INH 5-10mg/kg/day (maximum 300mg), to be initiated within 30 days of transplantation and maintained for 6 to 12 months (preferably 9 months).
-Monitoring for liver toxicity is mandatory which defined as an increase in aminotransferases above 3 times the normal value with symptoms (nausea, abdominal pain, jaundice) or above 5 times the normal reference values.
References:
Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis recommendations for solid organ transplant recipients and donors. Transplantation. 2018;102(2) Suppl 2:S60–SS5.
Thankyou well done
Positive Heaf test denotes probable latent infection with TB.
Additional serologic test with Quantiferon TB gold to support the diagnosis .
Post transplant TB is drastic infection with risk of dissemination and miliary tuberculosis consequent development. General incidence of post transplant recipient tuberculosis is 6% , 4% out of 6% is attributed to donor transmission via the donated allograft.
In these circumstances its better to clear the donor by treating his latent TB with protocol short course of anti-TB :
1] INH and Rifapentine for 3 months of weekly dosing.
2] Daily Rifampin for 4 months.
3] INH and Rifampin daily dosing for 3 months.
If the patient is non compliant and there is no other donor for this patient, then the option would be to proceed with transplant and commence on prophylactic anti TB as per the protocols mentioned, with close observation of CNi trough level and monitoring for any toxicity.
References:
1] M.I.Moris et al .Diagnosis and Management of Tuberculosis in Transplant Donors: A Donor-Derived Infections Consensus Conference Report.American journal of transplantation:06 August 20122] Treatment Regimens for Latent TB Infection | TB | CDC
https://www.cdc.gov › tb › topic › treatment › ltbi
.
Thankyou but you have to be more strict :
rule out a LTBI in the recipient as well, as it’s activation is the commonest cause of TB disease in the R.
You are using low incidence country protocols.
If R is negative and you agreed not to wait then what is your policy.
How will you proceed
The heaf test was long used in the UK to test if children have been exposed to tuberculosis and its use was stopped in 2005. It is now replaced by the Mantoux test
A positive result could be grade 1 to grade 4
Grade 1 and 2 means previous BCG vaccine or avian tuberculosis
Grades 3 and 4, must be referred for further workup
The following history will be obtained from the donor
Investigations
The outcome of the investigation could be:
Treatment of Latent TB infection
This clinical state needs to be treated even if he is not donating kidney as 80-90% of LTBI will reactivate if not treated.
Any of the following regimens could be used for treatment
References
WHO states there are 1.7 billion cases of latent TB world wide ie 1/6 of world population 2017.
10% can progress to active TB
So 80-90% is over rated
How would you proceed?
In general, all donors should be evaluated for the presence of latent TB
2 test are used to detect latent TB, tuberculin skin test (TST) and IGRA, any one of them can be used for donor assessment, but patients who have received BCG vaccination in early life (especially if the vaccine is received in the primary school) can have false positive TST, so they should be evaluated by IGRA
On the other hand, if there is history of previous vaccination, I will order IGRA
Treatment of donor latent TB is impotent since If the donor has latent TB and did not receive treatment it carry a risk of transmission to the recipient and if that happen the recipient should be treated for latent TB before possible progression to active disease
Protocols for treatment of latent TB
Patient should be monitored for liver enzymes and bilirubin at baseline then monthly
So … In the current patient I will do IGRA (if the patient is not vaccinated), CXR, sputum for AFP (if IGRA is positive)
Thankyou remember to start the donor is the brother so the option to wait is there.
you are right TST can be also due to BCG vaccine but IGRA is due to interferon gamma release assay, and Quantiferon are not.
THe criteria to treat the brother depends on many factors among which is ,is the country in question of high incidence or low incidence which can dictate the treatment protocols.
So councelling the couple is needed.
This donor is heaf positive indicating patient previously vaccinated and has immunity against tuberculosis but recipient post kidney transplant may develop latent TB so the QuantiFERON-TB-Gold In-Tube test (QFT) is widely used for assessing latent TB; however, it is currently unclear whether the pre-KT QFT of the recipient and donor can predict post-KT TB.
interferon-gamma release assays (IGRA) is superior to tuberculin test; If positive indicates recipient with high risk of reactive TB ( 1-15% in incidence), and should be counselling regarding activation of tuberculosis.
So better to cancel this donor
However there is currently no gold standard for LTBI diagnosis.
Thankyou your sentence is correct.
Both brothers have to be screened thoroughly for LTBI .Decision will depend on the results.
·How would you proceed?
Introduction
WHO recommends 2 tests for screening for LTBI:
My diagnostic approach to for detection of active & latent tuberculosis in this scenario would be as follows:
History:
Clinical examination:
Investigations:
Screen the potential recipient for LBTI:
Other indications for screening include:
Treatment of LTBI in donor & recipient:
Treatment options for LTBI (WHO 2018 guidelines):
For LTBI treatment in countries with low TB incidence, the following alternatives to 6 months of isoniazid monotherapy are advised:
References
Sriram Krishnamoorthya, Natarajan Kumaresana , Alimuddin Zumlab, Latent tuberculosis infection and renal transplantation – Diagnosis and management, International Journal of Infectious Diseases 80 (2019) S73–S76
Thankyou this is an excellent answer.
regimen of weekly rifapentine plus isoniazid. Daily
– Some people may react to the TST even though they are not infected with M. tuberculosis. The causes of these false-positive reactions may include, but are not limited to, the following: Previous TB vaccination with the Bacillus Calmette-Guérin (BCG) vaccine.
Living donors should be evaluated like transplant recipients.
According to CDC general population standards, live donors’ TSTs should be positive or negative.
The first step is to look into QFT as an alternative. can differentiate between positive secondary to BCG vaccine or ( latent or active infection).
-Starting with a symptom evaluation and chest x-ray, MTB infection should be ruled out
Before organ donation,
Recent TST or IGRA converts with a latent TB infection should be treated before donation(oral INH 300 mg daily for 9 months).
Donors with active TB should not donate organs.
In transplant candidates who have had BCG immunization, IGRA testing may be preferable to TST since BCG does not affect IGRA findings.
References:
Singh, N., & Paterson, D. L. (1998). Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clinical infectious diseases, 27(5), 1266-1277.
Thankyou well done .so your options are depending on
LTBI in donor only
LTBI in D,R (remember they are brothers with possible proximity)
After councelling if the D only has LTBI ,they don’t want to wait how will you manage that.
Donors with distant MTB infection are at risk for transmission, but at lower risk for active disease due to decreased reactivation rate.
Donors with a history of LTBI or active tuberculosis should be excluded from donation until further treatment can be performed.
Latent TB-positive TST or Interferon gamma release assay found during pre-transplant evaluation.
consider deferring transplant if possible until donor has taken some/all of chemoprophylaxis and consider chemoprophylaxis of recipient; monitor clinically.
Bennett DE, Courval, JM. Prevalence of tuberculosis infection in the Unites States population: the national health and nutrition examination survey, 1999-2000. American Journal of Respiratory and Critical Care Med 2008; 177 (3):348-355 2008
WHO (2010). Global tuberculosis control 2010. Geneva, World Health Organisation: 1-218.
Diagnosis and Management of Tuberculosis in Transplant Donors: A Donor-Derived Infections Consensus Conference Report”. Morris MI, Daly JS, Blumberg E, Kumar D, Sester M, Schluger N, Kim SH, Schwartz BS, Ison MG, Humar A, Singh N, Michaels M, Orlowski JP, Delmonico F, Pruett T, John GT, Kotton CN. Am J Transplant. 2012 Aug 6.
Thankyou well done
Donor assessment
Source; TB recommendation for SOT recipient & donors (Guilherme Santoro-Lopes et al.)
Thankyou options for treatment depends upon wether they are in a low or high incidence country.ie, if you are in Canada or Yemen where TB is very prevailant.
Thnxs prof
The currently FDA-approved screening methods for LTBI in the United States include the Tuberculin skin tests (TST) and the IGRAs: QuantiFERON-TB Gold in Tube assay (QFT) and T-SPOT TB. None of these tests differentiates active from latent TB, and it is not uncommon for any of these tests to be negative during times of active infection.
However, recent U.S. guidelines recommend using IGRA instead of the TST for diagnosing LTBI. IGRA is especially recommended as the preferred test for persons who have received BCG. Although IGRA is more expensive than the TST, health economics analyses have found that the tests are cost-effective as they reduce the number of individuals needing unnecessary chemoprophylaxis and monitoring while on drug therapy. Therefore, IGRA has been increasingly replacing the TST for screening LTBI.
So, since this donor has positive Tuberculin skin tests (TST) and he is asymptomatic, he should be investigated further for latent TB.
Ref. Moon SM, Park IA, Kim SM, Park SJ, Lee SO, Choi SH, Kim YS, Woo JH, Kim SH, Jung JH, Kim YH. Living donor and recipient screening for latent tuberculosis infection by tuberculin skin test and interferon-gamma releasing assay in a country with an intermediate burden of tuberculosis. Journal of Infection and Chemotherapy. 2013 Jan 1;19(5):1009-13.
Thanks, Fakhriya
Therefore, you will do IGRA to confirm latent TB or it could be just a vaccination?
Since he is a donor, yes, I will do IGRAs. Accordingly, if positive, then active TB infection must be excluded. If no active disease is evident, he might have LTB.
A history of untreated LTBI without evidence of active infection is not a contraindication to donation, but the administration of preventive therapy to all recipients should be considered.
The risk of transmission is estimated to be low if therapy for LTBI was completed before organ donation and, therefore, transplant recipients from such donors can be clinically monitored without receiving LTBI therapy.
Ref. Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis recommendations for solid organ transplant recipients and donors. Transplantation. 2018 Feb 1;102(2S):S60-5.
I would just watch.
Heaf test is not used in Brazil and was formerly used to define whether there was previous exposure to the vaccine and the need for an extra dose of vaccine against Tuberculosis.
This model later fell into disuse with methods that were easier to interpret, such as the PPD, but it is no longer used to define whether there is a need for an extra dose of the vaccine.
The positivity of this test only suggests that the patient has been previously vaccinated and has an immune response against tuberculosis.
Thanks, Filipe, but you have to do something. Could it be a latent TB?
Brazil is an endemic country for Tuberculosis.
Here, the Ministry of Health suggests chemoprophylaxis for latent tuberculosis if the skin test (PPD) is greater than 10 and the patient is in the context of immunosuppression (anti-TNF alpha, HIV, transplantation).
Chest X-ray is sufficient to rule out disease activity and proceed with LTBI instead of classical treatment.
Both a negative and grade 1 positive should be regarded as not significant . Heaf grades 2, 3, and 4 should be regarded as significant and investigated for M. tuberculosis infection.
Diagnosis of LTBI includes either an interferon-gamma release assay (IGRA) or a TST.
To check for active TB before starting LTBI treatment using-
History
physical examination
chest radiography
bacteriologic investigations like sputum for AFB,HYNES or TB GOLD test
sos HRCT chest
Treatment for latent infection
Isoniazid monotherapy 6 or 9 months, daily
Rifampicin monotherapy 3–4 months, daily
Isoniazid +Rifampicin 3–4 months, daily
Interpretation of positive reactions to Heaf tuberculin test in London schoolchildren
N S Galbraith et al
Vishwakarma D, Bhoi S R, Rannaware A (March 02, 2023) Latent Tuberculosis in India: An Overview. Cureus 15(3): e35706. doi:10.7759/cureus.35706
natural history