1. A 47-year-old CKD 5 has kidney transplantation from his brother, 111 mismatch, and no DSAs. Excellent kidney function. One year later, he presented with a night fever of 39 C, productive cough, and weight loss. Imaging showed multiple shadows in both lungs.
Would your management differ if the disease was mild and affected one lung?
188 Comments
Theepa Nesam
The patient is a 47-year-old recipient of a kidney transplant from a living donor with a mismatch of 111, no DSAs, and stable graft function who presents one year post-transplant with a fever of 39 degrees Celsius, weight loss, and a productive cough.
The X-ray of the chest reveals reticulonodular shadows in the hilar regions of the bilateral lung fields. Multiple miliary nodular lesions (arrows) were detected throughout the lung parenchyma on the HRCT thorax section imaged.
Based on the presented clinico-radiological picture, miliary tuberculosis is the most likely diagnosis. Nonetheless, the diagnosis must be confirmed, and because the patient is a renal transplant recipient, other differential diagnoses, including pneumonia causes, must be kept in mind.
A thorough medical history and physical examination. The history of prior tuberculosis, the use of induction therapy, and the immunosuppressive regimen employed are particularly significant. Inquire about any recent contact with a patient with tuberculosis, as well as the donor’s own tuberculosis history.
2. Laboratory testing consisting of a complete blood count, renal function tests, liver function tests, C reactive protein, blood culture, chest X-ray, influenza testing (if in influenza season) and other respiratory viral testing (biofire), serum beta-D glucan, serum LDH, and calcineurin inhibitor (CNI) trough levels (if on CNIs).
3. Examination of induced sputum for cytology, Gram stain, acid-fast bacilli (AFB) stain, and culture
high-resolution computed tomography (HRCT) scan of the thorax.
5. CMV PCR testing: to exclude the possibility of CMV infection (although it is unlikely in this context).
Bronchoscopy with bronchoalveolar lavage (BAL) with or without transbronchial lung biopsy: for stain and culture (fungal, AFB) as well as PCR for respiratory viruses, CMV, pneumocystis, and histopathology evaluation.
If the diagnosis of active tuberculosis is confirmed, the treatment consists of a 4-drug regimen of Isoniazid, Rifampicin (or rifabutin), Pyrazinamide, and Ethambutol for the initial 2 months (intensive phase), followed by Isoniazid and Rifampicin (or rifabutin) for an additional 4 months (continuation phase) in immunocompetent patients (2). Ethambutol can be discontinued if the organism’s susceptibility to the other three medications is confirmed (3).
Rifampicin is an inducer of the enzyme CYP3A4, which increases the metabolism of immunosuppressive drugs (cyclosporin, tacrolimus, sirolimus, everolimus, and steroids), necessitating a dose increase (up to 2–5 times for cyclosporine/tacrolimus and 2 times for steroids) and close monitoring of drug levels (4). Rifabutin can be substituted for rifampicin, resulting in a smaller increase in immunosuppressant drug dose than when rifampicin is used (5). Ethambutol and isoniazid appear to have no interaction with immunosuppressive drugs (4).
The optimal duration of treatment has not been determined; however, many specialists recommend 9 months (5). Uncomplicated pulmonary tuberculosis with a negative sputum test after 2 months of treatment requires only 6 months of treatment, whereas a positive sputum test after 2 months of treatment requires 9 months of treatment (2). It is also recommended that patients with bone and joint involvement, central nervous system involvement, or disseminated disease receive treatment for a longer duration (2).
Due to the prevalence of miliary pulmonary nodules in the index patient, there is a high probability of multisystem involvement; therefore, the patient may require 9 months of treatment.
In addition to monitoring drug levels and graft function, liver function tests must also be monitored due to the risk of hepatotoxicity associated with anti-tubercular drugs. Pyridoxine must be administered with isoniazid.
If the patient’s clinical condition deteriorates, the antimetabolite (MMF or azathioprine) dose may need to be decreased or discontinued.
Would your management differ if the disease was mild and affected only one lung?
No, the treatment would remain the same (4-drug regimen) for a duration of 6 months (localized tuberculosis).
Night fever,wt loss and this reticular shadow make milliry TB first differential diagnosis ,cmv pneumonia and PCP pneumonia also could cause this picture
I will took sputum culture and sputum for AAFB ,gene expert
I will start broad spectrum antibiotics till the result is back
then start anti tuberculosis
Would your management differ if the disease was mild and affected one lung?
This is a case of miliary tuberculosis after renal transplant..Patient has fever, night sweats and cough with weight loss…there is evidence of miliary tuberculosis in CT scan with hilar lymphadenopathy….
the other differential diagnosis for miliary mottling in the lung fields are langerhans histiocytosis, viral pneumonumonia, sarcoidosis, histoplasmosis, cryptococcidiomycosis, histoplasmosis and metastasis….
For definitive diagnosis we need to prove TB in the sputum by AFB stain or Gene Xpert MTB…We may need bronchoscopy and BAL for better yield…Bronchoscopy and Transbronchial lymph node biopsy is also needed to establish tissue diagnosis….
According to the American Society of Transplantation, the goal is to eradicate TB completely….The treatment protocol does not vary if there is localized miliary mottling of one lung
the treatment is standard 4 TB drugs namely Tab Isoniazid 10mg/kg, T. Rifampicin 15mg/Kg, combutol 25-30mg/Kg and Pyrazinamide 1000mg/day with addition of pyridoxine 40mg/day
The interaction of rifampicin with immunosuppressive agents require them to change to second line agent like levofloxacin which has less interaction with CNI
In this case, a renal transplant recipient presented with symptoms of fever, productive cough, and weight loss, along with bilateral lung infiltrates and hilar lymphadenopathy on imaging. The differential diagnosis for diffuse nodular opacities in the lung includes conditions such as pulmonary TB, Langerhans cell histiocytosis, diffuse pneumonia (bacterial or viral), silicosis, hypersensitivity pneumonitis, sarcoidosis, and metastatic lung cancer. To definitively diagnose TB, further workup and investigations are necessary, including isolating Mycobacterium TB via culture or acid-fast bacilli in sputum smear, or using nucleic acid amplification testing like the Gene-Xpert test.
Tests like Tuberculin skin test (TST) and Interferon Gamma Release Assay (IGRAs) can support the diagnosis of TB but are less reliable in immune-compromised patients. Other causes of the differential diagnosis should also be ruled out through tests such as urinary or serum antigen for histoplasmosis, CMV PCR, sputum or BAL culture for bacteria and fungi, and B D-glucan.
If TB is confirmed as the diagnosis, a 4-drug regimen is recommended initially for at least 2 months (INH + Rifampin + Pyrazinamide + Ethambutol), followed by a 2-drug regimen for 6-9 months (INH + Rifampin). Management of immunosuppressive medications involves reducing anti-metabolites, increasing the dose of steroids, monitoring therapeutic levels of calcineurin inhibitors (CNI), and adjusting CNI doses due to drug interactions with anti-TB medications. Regular monitoring of renal and liver function tests, medication side effects, and vision changes (in the case of ethambutol) is necessary. Treatment can be stopped after two negative sequential sputum samples by GeneXpert.
Consultation with the infection control team and microbiology team is crucial for appropriate management of the patient. Regular follow-up is important to monitor for TB reactivation and ensure successful treatment.
According to the guidelines provided by the American Society of Transplantation, the treatment approach for both severe and localized non-severe tuberculosis (TB) is the same. The goal is to administer a regimen that ensures complete and thorough treatment, aiming to eliminate the infection and prevent the development of treatment resistance.
Before treatment of LTBI, active TB needs to be excluded. Medications will need to be discontinued or dose adjusted if liver function tests are more than three times the upper limit of normal with symptoms/signs, or more than five times the upper limit of normal without symptoms Treatment of active drug susceptible TB usually involves two months of an initial phase therapy with INH, rifampin/rifabutin, pyrazinamide, +/- ethambutol, followed by a continuation phase therapy of four months of INH and rifampin, with a total duration for six months.
Reference
. Subramanian AK, Morris MI. Mycobacterium tuberculosis infections in solid organ transplantation. Am J Transplant. 2013;13 Suppl 4:68–76. [PubMed] [Google Scholar]
12. Bumbacea D, Arend SM, Eyuboglu F, Fishman JA, Goletti D, Ison MG, Jones CE, Kampmann B, Kotton CN, Lange C, et al. The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement. Eur Respir J. 2012;40:990–1013. [PubMed] [Google Scholar]
● An Immunocompromised recipient with intense immunosuppression due to ABOi presented 1 year after transplantation with weight loss, night fever, and productive cough .
● Radiographic imaging shows perihilar reticulonodular infiltrates that consists with military TB
● Other concomitant infections as fungal, PJP, and viral infections must be rule out .
● For diagnosis we need:
** Staining acid-fast bacilli in the sputum
** Sputum calture
** PCR mycobacterium tuberculosis in blood
** Broncosopy with BAL and lung biopsy
** General teste: CBC,CRP,ESR,liver tests, renal function tests, LDH, and PCR ( CMV,EBV).
● Treatment:
** Duration should be at least 6–9 M
The first-line treatment should be a four-drug regimen containing rifamycin and consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin
** Second-line regimen without rifamycin the 2-month contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a phase of 12–18 months with isoniazid and ethambutol or pyrazinamide. Here a longer period of treatment is recommended
** One challenge is the drug interaction between rifampicin and IS drugs
☆ Rifampicin decrease the levels of CNi , mTORi and affects steroid metabolization,
which increases the risk of rejection
☆ Therefore calcineurin and mTOR inhibitors levels should be monitored and increased three- and five-fold and the glucocorticoid dose should be doubled
☆ An alternative to rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 or fluoroquinolones
● In cases of localized mild condition regimen without rifambicin could be used for 6 months
How do you manage this case? This index case presented with night fever, productive cough and weight loss. CXR and CT lungs showed bilateral lung infiltrates without sub-pleural spare. The clinical picture and radiographic findings points to a pulmonary TB infection. DD: · · Atypical pneumonia. · · CMV pneumonitis. · · PJP Pneumonia Management plan: · Detailed history including history of previous TB exposure and treatment with anti-TB treatment. Beside, recent contact or travel to an endemic area. Also, the history of induction therapy used, and the maintenance immunosuppressive regimen used is of great importance. · MDT approach involving a pulmonologist and ID team · Supportive measures: adequate hydration and antipyretics, nutritional support. CMV Screening for TB: · Sputum microscopy and culture for AFB. · Rapid molecular test (the Xpert MTB/RIF assay) is highly specific. The sensitivity in a smear positive sample is 98% and in smear negative sample is 67% · Exclude other possible causes: CMV PCR, PJP and atypical pneumonia · The treatment is according to the cause. Treatment of active TB infection: · Duration: at least 9–12 months (like our index case with military TB). Longer duration treatment is recommended in patients with disseminated disease, bone, joint and CNS involvement. · First-line treatment is a four-drug regimen containing Rapamycin used in both severe and non-severe cases.
· Standard regimen: 2-month using 4 drugs (intensive phase) including isoniazid, rifampicin (Rifabutin), pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and Rifampicin (Rifabutin can be used instead as it has a lesser effect on cytochrome p450). Pyridoxineshould be given with isoniazid. Adjustment of immunosuppression dose: · Rifampicin is a CYP 450 enzyme inducer increasing the metabolism of immunosuppressive drugs. Therefore, we need to increase the dose of cyclosporine or tacrolimus by2-5 times and steroids by 2 times. This should be coupled with close monitoring of the drug levels. If the clinical status of the patient worsens, antimetabolites (MMF or azathioprine) might require reduction or cessation. · Rifampicin free regimens can be used in non-severe disease or if there is interaction between Rifampicin and other immunosuppressive drugs. Rifampicin free Regimens include: · Regimen A: INH + ethambutol + pyrazinamide or levofloxacin are used for 2 months, followed by INH + either ethambutol or pyrazinamide for 12 to 18 months. · Regimen B : INH + ethambutol + pyrazinamide or levofloxacin are used for 12 months Would your management differ if the disease was mild and affected one lung? · The treatment is the same (4-drug regime). However, a 6 month duration of anti-TB treatment may be given (localized tuberculosis).
References: 1. Sparkes T, Lemonovich TL; AST Infectious Diseases Community of Practice. Interactions between anti-infective agents and immunosuppressant-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13510 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 Feb; 102(2S Suppl 2):S60-S65.
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.
Meije Y, Piersimoni C, Torre-Cisneros J, Dilektasli AG, Aguado JM; ESCMID Study Group of Infection in Compromised Hosts. Mycobacterial infections in solid organ transplant recipients. Clin Microbiol Infect. 2014 Sep; 20 Suppl 7:89-101.
Clinical features and Radiological features are suggestive of Milliary Tuberculosis.
How do you manage this case?
CBC with ESR should be sent.In miliary TB, haematological abnormalities may include anaemia, leukopenia, leukocytosis, monocytosis, agranulocytosis, thrombocytopenia and pancytopenia . Also, ESR is typically high.Sputum test for AFB should be sent.Also if available PCR testing can be done on sputum.If Diagnosis is not confirmed ,BAl fluid examination can be done. Transbronchial lung biopsy can be performed if any doubt exists .
Treatment for TB was initiated with rifampicin (10 mg/kg/day), isoniazid (5 mg/kg/ day), ethambutol (25 mg/kg/day), pyrazinamide (15 mg/ kg/day) and pyridoxine (10 mg/day. Treatment duration should be at least 9 months, based on the results of a few studies that have suggested an association between shorter regimens and greater recurrence and mortality.Cyclosporine /tacrolimus and mycophenolate dose may have to increase by 2 to 5 folds due to drug interaction between rifampicin and Tacrolimus/mycophenolate.
Would your management differ if the disease was mild and affected one lung?
How do you manage this case?
the finding and the history making miliary TB is the diagnosis but other causes as CMV, PJP, and atypical pneumonia
diagnosis:
TB PCR
TB culture
CMV PCR
Treatment
duration 9-12 months as it is disseminated
standard regimen:
4drugs for 2months ( INH, Rifampicin, pyrazinamide and ethambutol) 2drugs ( INH, Rifampicin) Rifabutin can be used instead of Rifampicin as it has lesser effect on cytochrome p450.
Would your management differ if the disease was mild and affected one lung?
the treatment is the same but the duration 6 months
Q1: CXR shows bilateral small nodular shadows indicating miliary TB (probably MDR) and tracheostomy.
History of previous exposure or treatment of active TB and reactivation post-TX and originally or travel to endemic areas of TB should be taken.
Other opportunistic infections such as pulmonary CMV aspergillus, histoplasmosis, PJP and fungal infections should be considered. PCR to detect genetic mutation and smear and staining or culture for acid fast bacilli from induced sputum or BAL fluid should be done.
Imaging studies like bone abdominal and pelvic or brain CT scan or even CSF analysis are necessary for treatment. Start with a four-drug regimen for at least 2 months and continue with at least four months with rifampicin and isoniazid. The optimal treatment duration varies from 6 to 24 months and at least 9 to 12 months. As rifampicin reduces CNI and mTORi levels, the dose of CNIs, mTORi should be increased by three to five times and the glucocorticoid dose should be doubled. Q2: according to AST, the first-time treatment is a four-drug regimen for both severe and non-severe cases. Close monitoring for CNI and mTORi levels is necessary. Rifampicin-free regimens include INH and ethambutol for 18 months, levofloxacin for 6, and pyrazinamide for three months. (if no resistance to INH) Rifabutin is an alternative drug with fewer effects on cytochrome p450, cyp3A4, and p-glycoprotein.
Reference:
Subramanian, A. K., & Theodoropoulos, N. M. (2019). Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious diseases community of practice of the American Society of Transplantation. Clinical Transplantation, 33(9). https://doi.org/10.1111/ctr.13513
How do you manage this case?
The diagnosis is Tuberculosis and other diagnosis is PCP or CMV pneumonia. The mainstay treatment is anti-TB medications. Treatment is with Rifampicin, Isonaizid, Ethambutol and Pyrazinamide for 2-4 months.
Would your management differ if the disease was mild and affected one lung?
Treatment will remain same.
I would perform with a boncoscopy with bronchoalveolar lavage:
– PCR for Tuberculosis and BAAR
– Cultures of mycobacterium and fungis
– Galactomana
– Citologic study
Would your management differ if the disease was mild and affected one lung?
In this case, I would choose to associate the BAL with the performance of a biopsy for histopathological and staining analysis, considering the possibility of malignancy.
Hx base diagnosis; Miliary tuberculosis most probably
D/D
PCP
Viral pneumonia CMV pneumonia
Fungal pneumonia
Investigation; Peripheral smear, CRP Sputum for AFB, Gene Xpert & culture, PCR in sputum CSF examination if CNS involment study if neurological finding present
Lymph node biopsy if palpable esp neck lymph node
Treatment. First two month 4 anti tuberculous drugs and next 4 month 2 antituberculous drugs with monitoring of mTOR and CNI level
Would your management differ if the disease was mild and affected one lung?
From the given history & radiological findings (multiple miliary mottling shadow affecting both lung field), this patient is suffering from miliary TB.
– Detail history & clinical examination to find out dessiminated TB
Investigations:
-CBC, CRP
– RFT, LFT
– Sputum for AFB, Gene Xpert & culture
– CSF study if neurological finding present
– FNAC of lymp node in case of lymphadenopathy.
Treatment
– Anti TB – 6 month
(Intensive phase – INZ, Rifampicin, ehambutol, PZA for 2 month then continuation phase with INZ & rifampicin for 4 month)
– Monitoring CNI & m TORi level.
– Increase dose of CNI / mTORi to maintain therapeutic range.
– Double the dose of steroid.
– Monitoring liver function 2 weekly for first 2 month then monthly thereafter.
– After completion of Anti TB dose reduction of CNI/mTORi & steroid to previous dose.
Would your management differ if the disease was mild and affected one lung?
How do you manage this case? Chest X-ray showed diffuse bilateral reticulonodular opacities and HRCT chest showed miliary mottling with multiple small nodules involving both lungs 1 year post transplant, having fever, productive cough and weight loss – provisional diagnosis is Miliary Tuberculosis should be made. Other Differential Diagnosis: – PCP – Viral / Bacterial (atypical) / Fungal pneumonia – Hypersensitivity pneumonitis – Histiocytosis X (Langerhans cell histiocytosis) – Lymphangitis carcinomatosa Ø Diagnosis can be confirmed by o Sputum AFB (ZN stain), Sputum Culture (BACTEC) and drug sensitivity; o TB PCR in sputum (Gene X pert / TB-Gold) test · To rule out PJP in sputum Ø Treatment: 1. Minimize immunosuppression and starting ATT Miliary TB being a life-threatening condition, stopping all IS except steroids which can be given in preferably higher dose. Alternately, graded approach of stopping MMF, continuing Tacrolimus and steroid at higher dose –> if symptoms does not improve by 3-4 weeks, stopping Tacrolimus also is imperative. 2. ATT – intensive phase with 4-drugs regimen (INH, Rifampicin, Pyrazinamide, Ethambutol + Pyridoxine) in standard dose. – Intensive phase to continue for minimum of 2-3 months, or till 2 sequential sputum samples become negative. Continuation phase 9-10 months with (INH + Rifampicin + pyridoxine) – Total duration 12 months – can be extended up to 24 months, depending on response and side effects.
– Rifampicin interaction with CNI – needs Tacrolimus dose increase (2-5 folds) to maintain desired trough level. – If initial response to intensive phase (4 drugs regimen) is encouraging, Rifa-sparing regimen (INH + Ethambutol + Moxifloxacin / Levofloxacin) can be tried for 12-24months, with better graft survival. – Rifabutin has less potential for P450 enzyme induction, may be tried in place of Rifampicin. – Regular monitoring RFT (for rejection), CNI drug level, LFT, ATT related side effects. 3. Sputum AFB / culture / Gene X-pert tests to be repeated to monitor treatment response 4. Nutrition – high protein diet
Would your management differ if the disease was mild and affected one lung? – Yes, the management, outcome and complications would differ – IS reduction would have been graded (MMF by 50%) or not required. – ATT regimen: 2months intensive phase with 3-4 drugs, then Rifa sparing regimen for 9-12 months. – Rifa-sparing regimen, al together also may be tried. REFERENCE: 1. Infectious Disease Society of Clinical Practice Guidelines; Tx of drug susceptible TB; Clin infectious diseases 2016 Oct; 63 (7): 147-195.
2. Subramanian AK, Theodor Opoulos NM. Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious disease community of practice of the American Society of Transplantation. Clinical transplantation. 2019 Sep; 33(9): e13513. PubMed PMID: 30817030. Epub 2019/03/01. 3. Sun HY, Munoz P, Torre-Cisneros J, Aguado JM, Lattes R, Montejo M, et al. Mycobacterium tuberculosis-associated immune reconstitution syndrome in solid-organ transplant recipients. Transplantation. 2013 May 15;95(9):1173-81. PubMed PMID: 23435454. Epub 2013/02/26. 4. Abad CLR, Razonable RR. Mycobacterium tuberculosis after solid organ transplantation: A review of more than 2000 cases. Clinical transplantation. 2018 Jun;32(6):e13259. PubMed PMID: 29656530. Epub 2018/04/16. 5. Anand M, Nayyar E, Concepcion B, Salani M, Schaefer H. Tuberculosis in kidney transplant recipients: a case series. World journal of transplantation. 2017;7(3):213.
CBC, ESR, LFT, CRP, RFT QUANTIFERON TB test Sputum for C/S
Isoniazid, ethambutol, pyrazinamide are safe in post transplant patients. Rifampicin reduces the levels of CNI and preferably should be avoided. Ofloxacin, is often added to four-drug regimens. Four-drug regimen: INH and ethambutol (18 months) ofloxacin (nine months) pyrazinamide (three months) The dose of isoniazid and ethambutol should be adjusted according to the degree of renal function.
Would your management differ if the disease was mild and affected one lung?
The management is the same for one lung or both lungs involvement.
●this patient needs to be admitted in the hospital
●monitoring vital signs (RR- saturation– ) ●depending on saturation he may need O2
●laboratory tests (CBC- CRP- ESR – LFT- Crea- ) ● tracheal aspirate and staining for Acid fast bacilli ( the sensitivity low,)
●Culture needs to wait for long time
● bronchoscopy, and BAL assay, and it may need to exclude CMV (PCR) and other bacterial and viral infections
●PCR techniques of tracheal aspiration samples to identify the genetic mutations of MDR-TB
●This case is a severe TB rifamycins are recommended
●Patients receiving a rifamycin-containing regimen should be treated for a minimum of six to nine months.
Would your management differ if the disease was mild and affected one lung?
●non-rifamycin-based regimen in cases of localized (eg, pulmonary) nonsevere TB when there is no suspicion or evidence of isoniazid resistance .
●In patients not receiving a rifamycin, treatment options include a three-drug regimen of INH + ETHAMBUTOL + either pyrazinamide or levofloxacin for 2 months, followed by a two-drug regimen of INH plus ethambutol or pyrazinamide for 12 to 18 months.
● In those receiving a three-drug regimen for the entirety, the duration of treatment can be shortened to 12 months
● if any suspection, of bacterial or CMV infection; empirical antibiotics treatment and starting IV ganciclovir treatment is necessary until the results appear
-1-How do you manage this case?
Imaging (X-Ray Chest and HRCT chest )in the above case showed bilateral reticulo-nodular opacities with perihilar shadowing. Fever in the renal transplant case with night sweats and above findings suggest miliary tuberculosis. Other differentials which need to be considered include viral and fungal pneumonias.
After detailed history and examination, tests which need to be carried out include CBC, ESR, RFT, LFTs Sputum for AFB by stain ,AFB C/S and Genexpert-RIF resistance and if no sputum production then BAL for AFB,AFB C/S and Genexpert-RIF. Viral pneumonias test include PCR for CMV DNA and HZV virus .Tac level to be monitored closely and frequently.
Once the diagnosis is confirmed, patient will be started on weight based standard four drug regimen (rifampicin,Pyrazinamide,INH, myambutol) during the intensive phase but with close monitoring of drug level and side effects .Tacrolimus dose to be increased few days before ATT commencement and MMF to be withheld for few weeks. After 02 months, patient will be started on continuation phase with two drugs and hat to be continued for six months. Duration of ATT also depends on the extent of involvement of the disease. For extensive and cavitatory disease-duration is for 9 months however, for disseminated disease, it is for 12 months.
Would your management differ if the disease was mild and affected one lung?
Treatment will remain the same i.e., standard four drug for mild case for six months and will be different for resistant and extensive disease.IF rifampicin not to be used ,then 02 month regimen , isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by isoniazid and ethambutol or pyrazinamide for 12–18 months. REFERENCE: 1-Sorohan, B.M.; Ismail, G.; Tacu, D.; et al. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens 2022, 11, 1041.
The patient is a post renal transplant within one year who presented with fever cough and night sweats…. He has received kidney transplant from his brother with haplomatch and no DSA…..
CXR shows miliary mottling of both the lungs…. CT scan also shows Miliary mottling with few small nodulo cavitatory lesions….
The most likely diagnosis is Tuberculosis post renal transplant…
The patient management includes investigations and treatment…Investigations include CBC, Renal function test and Liver function test….Procalcitonin and Blood cultures should be done.. Empirical antibiotics should be given… Patient should be asked about the hisotry of LTBI in the donor and recipient if any before transplant…. sputum for AFB, Gene Xpert MTB should be asked for..In this Gene Xpert MTB rifampicin resistance is also detected… So this will help in the treatment also….if the sputum is not sufficient we should encourage them to give induced sputum after 3% saline nebulization…. ideally 3 sputum AFB samples in the morning is recommended as per RNTCP program in our country… but in transplant patients even one sample of AFB positivity is enough…. sometimes adequate sputum sample is needed and may not be able to procure….We have to start treatment empirically given the clinical scenario in this patient…. We need to look into tacrolimus level as a baseline…
The treatment of the above include 4 drug regimen ….Namely Rifampicin, Isoniazid, Combutol and Pyrazinamide with pyridoxine…. The treatment duration is generally continued for 9 to 12 months depending on the severity of the disease..6 months of treatment is sufficient of extra pulmonary TB but not for miliary TB treatment .. Every country has a different protocol for the treatment of TB…In our country, We need to start the 4 medicines and continue them for 9 months… the treatment for miliary TB is minimum 9 to 12 months in immunocompromised patient….The first 2 months include the intensive phase namely all the 4 drugs followed by remaining months of INH and Rifampicin
Rifampicin is an enzyme inducer and it can reduce the levels of Tacrolimus and steroids….Hence another alternative is to give non rifampicin based regimen, which include Isoniazid, PZA, ethambutol and Levofloxacin….
Another alternative is to use Rifabutin which is a less powerful enzyme inducer, but there are hardly any trials or enough data to support the use in renal transplants….
The liver functions need to be monitored for the hepatotoxicity of the medicines
The management should not differ if the disease is localized or mild and affecting one lung as the recommendations from Infectious disease society of America and WHO guidelines suggest disease treatment for 9 months or as far as possible in order to avoid disease treatment and eradication
Diagnosis:
Millary TB
INVESTIGATION:
CBC, ESR, LFT, CRP, RFT
QUANTIFERON TB test
Sputum for C/S
Isoniazid, ethambutol, pyrazinamide are safe in post transplant patients.
Rifampicin reduces the levels of CNI and preferably should be avoided.
Ofloxacin, is often added to four-drug regimens. Four-drug regimen: INH and ethambutol (18 months) ofloxacin (nine months) pyrazinamide (three months) The dose of isoniazid and ethambutol should be adjusted according to the degree of renal function.
· How do you manage this case? · This is a case of immunocompromissed patient with history of solid organ transplantation. He is around (20-74)18.5% more at risk of developing opportunistic infection then normal population. · If latent disease there is 80-100% risk of developing reactivation. · According to the history post-transplant, immunocompromissed, no history of prophylaxes, history fever, productive cough of some infection, X-ray chest looks like miliary mottling. · Further to confirm the diagnosis. Baseline investigation including ESR, CRP, procalcitonine, blood culture, sputum culture, and for AFB, · May need BAL, · HRCT, · Gene Xpert, Management; General management, Treat as pulmonary tuberculosis and also look for dissemination. First line therapy for Tb is same as general population, initially full dose with four drugs for two months, with frequent monitoring of CNI drugs level, keep CNIs in 2 folds higher level, The standard dose is four month continuation of two drugs, but it varies according to organ involvement up-to 18 months. If difficulty in drug level achievement can switch to mTORi , or quinolones.
· Would your management differ if the disease was mild and affected one lung? · The management is the same for one lung or both lungs involvement.
Investigations: Sputum AFB. Gene Xpert. ESR. Liver function tests for baseline values. Eye examination for baseline evaluation.
Treatment:
-Counselling [disease, duration of taking medications; need for adherende; possible side effects to expect; regular checks to get blood levels of the immunosuppresants]
-Isolation if smear positive till patient has three negative smear sputums
-Medicines: The recommendation for treatment of tubeculosis infection in transplant recipients, who are on immunisuppression, is the same as the recomendation for the general population, except that the regimen will change, and the duration. Regimen change is because the Rifamycin family [Rifampicin, Rifabutin or Rifapentine] do interact with the immunosuppresants [the CNIs, MTORi’s, and costicosteroids].
Treatment is with Rifampicin, Isonaizid, Ethambutol and Pyrazinamide for twomonths, and then continue with Rifampicin and Isonaizid for four more months. With the use of Rifampicin, the dose of the CNIs should be increased 3-5 fold, and the levels closely monitored.
Rifabutin can be used in place of Rifampicin, as it is a weker inducer of CytochromeP450, but levels of the immunosuppresants should still be monitored.
Would my management differ if it was mild disease or one lung affected?
No it wont. MAnagement is the same whether its a mild disease or affects one lung only
References José María Aguado, Julián Torre-Cisneros, Jesús Fortún, Natividad Benito, Yolanda Meije, Antonio Doblas, Patricia Muñoz, David R. Snydman, Tuberculosis in Solid-Organ Transplant Recipients: Consensus Statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology, Clinical Infectious Diseases, Volume 48, Issue 9, 1 May 2009, Pages 1276–1284, https://doi.org/10.1086/597590
Guidelines for the prevention and management of Mycobacterium tuberculosis infection and disease in adult patients with chronic kidney disease
This immunocompromised below 50-year-old recipient with high suspension to have miliary TB, as the CT is not suggestive of viral or fungal infection.
Investigations required:
· Blood and urine cultures.
· sputum culture, stain, AFB. If sputum not obtained bronchoscope for BAL should be done.
· Mycobacterial culture: Conventional and Rapid culture techniques
· Xpert MTB/RIF assay.
Treatment of active TB:
The treatment of active TB should be started immediately once the diagnosis has been established.
the duration of treatment is recommended to be at least 9–12 months Traditional regimen (≥6 months):
· intensive phase of two months and continuation phase of at least four months, includes the drugs isoniazid, rifampin, pyrazinamide, and ethambutol
· If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.
· when a rifampicin-based regimen is used, CNI and mTORi levels should be closely monitored, the dose of CNI and mTORi should be increased between 3-5-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
· after the rifampicin is stopped, the immunosuppression doses should be reduced to the value before the start of rifampicin and then adjusted to obtain the therapeutic target
· Reduction of immunosuppression in this case of severe TB should be considered.
Would your management differ if the disease was mild and affected one lung?
in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present
this case scenario findings (both clinical and radiological ) make a high suspicious of military TB , at the same time should think about other differential diagnosis such such viral, fungal infections, and extensive micro metastasis….
workup : sputum or BAL for AFB & culture
require a co-ordination between nephrologist, pulmonologist and microbiologist
Rx.:
starting anti TB (initial 2 months 4 agents and next 6 -9 months 2 agent )
increasing the dose of steroid and CNI
decreasing the dose of Mycophenolate
close monitoring of renal function, side effects and drug levels
Radiological picture is classical of disseminated miliary TB involving both lungs.
There must be milliary lesions all over the body
differential diagnosis could be viral or fungal pneumonia , ARDS,diffuse pulmonary haemorrhage
diagnosis
Even the CXR is pathognomic of TB in endemic area like India
sputum- AFB smear or Gene xpert test
treatment
reduction in immunosuppression is must
considering the gravity of disease all drugs can be stopped except steroid
involvement of respiratory and infectious disease specialist is done early after the suspicion of TB
AKT- anti koch treatment of 4 drugs( INH REFAMPICIN ETHAMBUTOL PYRIZINAMIDE ) for 2 months and 2 drugs for 6-8 months as per guideline of national TB programme
CNI serum level is monitored closely if at all it is on due to interaction with refampicin
involvement of one lung only make respiratory management easy but TB protocol will remain same in line of miliary TB
· With above scenario with Chest X-ray and CT showed miliary mottling involved bilaterally. My provisional diagnosis is Miliary TB · Differentials are pneumonia caused by virus, bacteria and fungus or lymphangitis carcinomatosa. · Diagnosis should be confirmed prior treatment by sending sputum for AFB, Sputum for Gene X pert TB test · Once confirmed that it is Miliary TB, first step should be to minimize immunosupression. · From chest x-ray patient expected to be in life threatening condition, I will go either stopping all IS except giving higher dose of steroids or stopping MMF and continue Tacrolimus and steroid at higher dose. · 2 months of intensive treatment with the combination of 4 dru; isoniazid (INH), rifampicin, pyrazinamide, and ethambutol till 2 sequential negative sputum samples then followed by 7-9 months of continuation phase with INH and rifampicin. · Treatment duration can be extended up to 24 months · Rifampicin interaction with CNI s should be kept in mind and if used dose of Tacrolimus should be increased 3-5 fold and similarly decreased once drug is stopped. · For minor disease or single lung involvement RIF sparing protocol can be considered. REFERENCE: (i) UpToDate (ii)Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017. can be considered
The radiological findings of milletlike Numerous small, nodular lesions combined with clinical manifestation of night fever, productive cough and weight loss strongly suggest military TB
The differential diagnosis includes the following:
Pneumocystis carinii pneumonia
Bacterial pneumonia
Community-acquired pneumonia
Fungal pneumonia
Viral pneumonia
Other problems to be considered include the following:
Histiocytosis X (Langerhans cell histiocytosis)
HIV-related pulmonary opportunistic infections
Lymphangitic spread of cancer (eg, thyroid carcinoma, malignant melanoma)
Acute respiratory distress syndrome
Blastomycosis
Hypersensitivity pneumonitis
Investigation
CBC, LFT, KFT, UEC, CNI level
Sputum for acid fast bacilli
BAL for cytology, culture and geneXpert
Treatment: quadruple anti-TB therapy for 2 months with Rifampicin, isoniazid, pyrazinamide and ethambutol, followed by 4 months of isoniazid and rifampicin.with increasing steroid and CNI doses up to 2 and 3-5 fold respectively with careful monitoring of liver enzymes
Rifabuntin is a less enzyme inducer and can be used as an alternative to rifampicin
the same regimen would be applied for unilateral affection
The duration of treatment is not clear with some guidelines and experts recommending longer duration esp if rifampicin has been excluded of possibly 12-18/12 continuation phase – ECSMID guidelines
Pyridoxine is to be given for the duration of time the patient is on isoniazid.
Rifabutin to be given instead of rifampicin where possible as it is a less enzyme induction on cytochrome P450.
Immunosuppression ; RIS with possible reduction of antimetabolites by 50% or withdrawal in life threatening conditions, higher steroids doses, In consideration of drug interactions, increase CNI doses x2-5 and monitor trough levels while on rifampicin.
Follow up – Monitor labs for SE while on treatment – FHG, LFTS, UECS, Rpt sputum after intensive and continuation treatment if initially positive to determine duration of treatment.
Stop treatment after x2 negative gene xpert results.
MILD DX AFFECTING ONE LUNG.
Same treatment more efficacious to avoid resistance.
REF
Subramanian et al ;MTB in SOT- Guidelines from infectious disease community practice of AST.Clin Transplant 2019,33.
Bumbacea et al ;Risk of TB in transplant candidates and recipients ;A TBNET consensus statement Eur.2012,40,990-1013
Infectious Disease Society Of Clinical Practice Guidelines ;Tx of drug susceptible TB;Clin infectious dx,Vol 63,issue 7,1 oct 2016,pg e147-e195.
The CXR and CT show widespread, random, bilateral micro nodular infiltrates.
The Differential Diagnosis includes Miliary TB, Fungal infections such as Histoplasmosis, Metastatic lung disease, Sarcoidosis. Given this patients risk factors and presentation, Miliary TB is most likely.
Management:
I would mange this patient with a thorough clinical and laboratory evaluation while starting appropriate treatment early. History of contact with a TB positive patient, history of TB on the donor if not evaluated pre-transplant. I would check if the patient had evidence of Latent TB pre transplant and if they got prophylaxis. Other symptoms such as chills, rigours, night sweats are worth noting. I would check for Lymphadenopathy, ascites and hepatosplenomegaly.
I would evaluate with basic labs including FBC, U&E/Creat, LFT, ESR, CRP. Sputum to be sent for MCS, AFB and Gene Xpert analysis. If the sputum tests are negative, as they may be in immunocompromised patients, I would consider Bronchoscopy with BALF and transbronchial biopsy.
I would treat with ATT as per our national TB treatment protocol. In Botswana we use a weight based four drug regimen (RHZE) for two months of the intensive phase, followed by a four month two drug (RH) consolidation phase.
Special consideration when transplant patient is on ATT:
Monitor CNI and M-TORi drug level. Rifampicin is a powerful CYP4503A inducer which may lower the drug levels leading to rejection
Consider rifabutin instead of Rifampicin, as it is a weaker inducer of CYP450 but with equivalent efficacy
Monitor for increased drug toxicities such as liver injury and myelosuppresion caused by INH and antiproliferative medications
I would manage the patient in the same way for mild disease
Miliary TB usually presents with bilateral lung findings as it is from haematogenous spread. I would question the diagnosis if unilateral and seek definitive answer from sputum, BAL or transbronchial biopsy
References
Andreu J, Mauleón S, Pallisa E, Majó J, Martinez-Rodriguez M, Cáceres J. Miliary lung disease revisited. Curr Probl Diagn Radiol 2002;31:189–197.
Munoz PRodriguez CBouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants.Clin Infect Dis. 2005; 40: 581-587
How would you manage this case? One year post-kidney transplant presented with fever, productive cough and weight loss. CXR showed diffuse bilateral reticular-nodular opacities and CT scan showed mottling with multiple nodules. Most likely diagnosis: miliary TB. Differential diagnosis: Bacterial pneumonia Fungal pneumonia Viral pneumonia Metastatic malignancy. Investigation CBC, RFTs SE LFTs and Tac trough level AFB on sputum. BAL Cytology and culture (MDR AND XDR) Treatment Four drug combination of Isoniazid, Rifampicin, pyrazinamide and ethambutol for 2 months along with pyridoxine and monitoring LFTs fortnightly. Followed by 4-6 months of two agents’ combination isoniazid and rifampicin. Total duration of treatment 6-9months. CNI during ATT should be closely monitored and usually be scale up upto 4 folds and increasing Steroids from 5mg to 10mg/day.
Rifabuntin can be used as an alternative for rifampicin because of less potent inducer of P450 than rifampicin. Monitoring ; close monitoring of Tac level, monthly liver function and Renal function. Would your management differ if the disease was mild and affected one lung? I will treat the same way.
The above image on left is cxr and on right is coronal slice of CT scan. Correlating both the images with the patient’s history, the most likely diagnosis is Miliary tuberculosis.
Other DDs like pneumonia, viral infection, fungal infection can be kept but is very unlikely. This appears to be classical book picture of miliary TB.
When we compare the pathogenesis of two forms of pulmonary tuberculosis viz, Miliary TB and Ghon focus (PPC), then it is well established that miliary TB is seen in immunocompromised patients and undernourished children.
Investigations:
Sepsis work up
Sputum for AFB
Gene xpert
Treatment:
Each country has somewhat different treatment protocols.
India is an endemic country for tuberculosis. So we use CB-NAAT as gold standard for diagnosis which also detects rifampin resistance.
We have a national program governed by GOVT which is RNTCP (revised national tuberculosis program).
Our treatment recommendations:
First-line therapy for transplant candidates with active TB disease is the same as for immunocompetent subjects with TB
Treatment duration for uncomplicated pulmonary TB in kidney transplant candidates or recipients is at least 9 months
A longer period of treatment (upto 18 months) may be needed if the rifampicin is excluded from the regimen
In KTRs who are on CNIs and/or mTORi, rifampicin can be substituted with a once a day quinolone (levofloxacin or moxifloxacin)
In KTRs with TB who are treated with rifampicin, the CNI and/or mTORi dose should be increased and monitored frequently to ensure they stay in the therapeutic range
When possible, TB should be treated fully before transplant. However transplant is possible once the 2 month intensive phase of the treatment is completed.
Longer treatment courses are recommended if second-line drugs are used or if there is resistance to Rifampicin ± other drugs.
American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP):
the first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases
This standard regimen is similar to that used for the general population and consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin.
The optimal period of treatment could vary from 6 to 24 months and in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months,
In case of severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months
Specifically, rifampicin usage decrease the levels of CNI, mTORi and affects glucocorticoids metabolization, which increases the risk of rejection. Therefore, when a rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin and mTOR inhibitor should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
REF:
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review Bogdan Marian Sorohan 1,2,* , Gener Ismail 2,3, Dorina Tacu 1 , Bogdan Obris, că 2,3 , Gina Ciolan 4 , Costin Gîngu 1,2, Ioanel Sinescu 1,2 and Cătălin Baston
Clinical scenario with radiological evidence is suggestive of active tuberculosis (Miliary) while other differential are;
· Viral infection
· Fungal infection
· PTLD Active tuberculosis in SOT;
Active TB in SOT is well described particularly beyond first year mainly due to reactivation of latent TB. Median incidence is 2.37% and up to 15% in endemic areas. [1] Investigation
CBC, RFTs SE LFTs and Tac trough level AFB and geneXpert on sputum. BAL Cytology, geneXpert and culture (MDR AND XDR) Treatment
Four drug combination of Isoniazid, Rifampicin, pyrazinamide and ethambutol for 2 months along with pyridoxine and monitoring LFTs fortnightly. Followed by 4-6 months of two agents’ combination isoniazid and rifampicin. Total duration of treatment 6-9months. CNI during ATT should be closely monitored and usually be scale up upto 5 folds and increasing Steroids from 5mg to 10mg/day.
Rifabuntin can be used as an alternative for rifampicin because of less potent inducer of P450 than rifampicin. Monitoring ; close monitoring of tac level, monthly liver function and Renal function. Would your management differ if the disease was mild and affected one lung? I will treat the same way.
References 1. Abad CLR, Razonable RR. Mycobacterium tuberculosis after solid organ transplantation: A review of more than 2000 cases. Clin Transplant. 2018 Jun;32(6):e13259. doi: 10.1111/ctr.13259. Epub 2018 May 7. PMID: 29656530. 2. UpToDate
How would you manage this case?
One year post-kidney transplant presented with fever, productive cough and weight loss. CXR showed diffuse bilateral reticular-nodular opacities and CT scan showed mottling with multiple nodules.
Most likely diagnosis: miliary TB.
Differential diagnosis: Bacterial pneumonia
Fungal pneumonia
Viral pneumonia
Metastatic malignancy.
Management should be multidisciplinary including chest physicians, transplant physicians and infectious disease specialist.
Workups:Sputum for AAFB and Gene Xpert
BAL for cytology, microscopy, culture and Gene Xpert
Blood works up: CBC, UEC, LFT, Tacrolimus trough levels
Treatment: 4 drug regimen with Rifampicin, isoniazid, pyrazinamide and ethambutol for 2 months intensive phase, followed by 4 months of isoniazid and rifampicin. Total duration of 6-9 months.
Increment of the CNI 3-5 fold and doubling steroids.
Monitoring of the liver enzymes bi weekly in the intensive phase then monthly there after.
Rifabuntin is a less potent cytochrome P450 thus can be used as an alternative for rifampicin due to drug interactions.
Would you manage this case differently if this was mild and affected one lung?
No, the regimen would be the same only difference would be a short duration of 6 months.
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
I appreciate clarity of your thought process in managing this clinical problem and I quote your comment in italics: No, the regimen would be the same only difference would be a short duration of 6 months.
This patient presented with symptoms of pneumonia and weight loss, ct chest show mottling and reticulnodular shadow which go most likely with pulmonary tuberculosis, so we need to confirm the diagnosis by sputum test for TB(pcr or gene expert),sputum culture,ESR ,CMV screening and BVL for pcp screening
if it confirmed well start 4 drugs combined regimen (Rifampicin ,INH,pyrthinamide and ethambutol for 2 months then continue with rifampicin and INH for the next 4 month with follow up by sputum test
Would your management differ if the disease was mild and affected one lung?
No the regimen is a same but me be different in prognosis
Most important point to increase the dose of immunosuppressive medication because anti TB are enzyme inducers
I appreciate clarity of your thought process in managing this clinical problem.
However, I suggest you to 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.
47-year-old CKD 5 has kidney transplantation after One year, he presented with a night fever of 39 C, productive cough, and weight loss. Imaging showed diffuse bilateral infiltrate suggestive of military TB
How we will manage such patient
Probably the most challenging situation lies on the clinical suspicion of active infection.
TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin.
Diagnosis
The definitive diagnosis of pulmonary TB is established by isolation of M. tuberculosis .
It can be done from
>>> body secretion or fluid through
culture of sputum
bronchoalveolar lavage
pleural fluid
>>> tissue through pleural biopsy or lung biopsy
>>> Additional diagnostic tools include
sputum acid-fast bacilli (AFB) smear
nucleic acid amplification (NAA) testing; a positive NAA test (with or without AFB smear positivity) in a person at risk for TB (who has no prior history of treatment for pulmonary TB) is considered sufficient for diagnosis of TB .This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively.
>>> Radiographic studies are important supportive diagnostic tools.
Note that Neither TST nor IGRAs are recommended for diagnosing active infection.
Treatment
Many specialists recommend that treatment of active TB duration should be at least 9 months.
A 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB. 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin .In the context of SOT, many factors should be carefully considered and must be well educated to the patient especially the risk of hepatotoxicity related to the antituberculous treatment and drug interactions of rifampicin and CNIs.
Two-to 5-fold increments in the daily dose of cyclosporine, tacrolimus, and mammalian target of rapamycin inhibitors are generally necessary to maintain trough levels of the drug in the therapeutic range.
Although enzyme induction start within hours after the first dose of rifampin, maximum effect is reached in about 1 to 2 weeks and slowly declines over 2 weeks after stopping its use. Thus, therapeutic drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption, all to reduce of graft rejection or even loss.
Would your management differ if the disease was mild and affected one lung?
According to AST-IDCOP, the first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases.
Compared to AST-IDCOP, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) suggests a standard regimen used for a period longer than 6 months, and, in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present .
If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide. Additionally, if second-line drugs are used, a longer period of treatment is recommended.
Reference
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
one year
post kidney transplant
Night Fever
weight loss
Productive cough
CXR and CT suggestive of miliary mottling
The first diagnosis is Miliary TB
The possibility of other pneumonia s like viral , bacterial and fungal should also be kept in mind.
Diagnosis should be confirmed by sending sputum for AFB
Sputum for Gene X pert /RIF assay
Once confirmed that it is Miliary TB, first step should be to minimize immunosupression.
The radiological pic looks very scary and one can think of stopping all immunosuppressants and pump steroids a bit
A four drug regimen should be introduced and kept for two months followed by RIF and INH for another 7 months.Pyridoxine should be given alongside.
Rifampicin interaction with CNI s should be kept in mind and if used dose of Tac should be increased four fold and similarly decreased once drug is stopped
For minor disease or single lung involvement RIF sparing protocol can be considered
How do you manage this case?
This 47 years male
Post transplant
On immune suppression
Have excellent kidney function
Presented with chronic productive cough for 1 year
Also presented with night fever
Loss of weight
From the above history the diagnosis is most probably Miliary tuberculosis . other differential :
malignancy (metastatic lung disease)
viral pneumonitis(cmv.covid 19)
bacterial pneumonia.
Fungal pneumonia
We need to share this case with pulmonologist and infectious disease team
Then we need to take history of any past diagnosis of TB,history of contact ,or even travelling to endemic area.
Then examination of any extra pulmonary TB.
Investigation :
Sputum for detect AAFB(acid alchol fast bacilii) by culture on ZN stain.
Sputum culture for gram staining for bacterial.
Gene expert test of sputum or BAL.
CMV PCR. Treatment
The first-line treatment should be a four-drug regimen. Standard regimen consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed bya4-month continuation phase of isoniazid and rifampicin as in general.
With this regimen included rifampcin , must be monitoring the CNI,also monitoring for hepatotoxicity ,neurotoxicity ,cytopenia ,visual disturbances ,skin lesions,hyperuricaemia,and interstitial nephritis.
If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.
In this case which is sever symptoms and signs reducing immune supressions is mandatory . Would your management differ if the disease was mild and affected one lung?
No ,treatment same. references
1.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. [CrossRef]
2. 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.
3.Bolt, H.M. Rifampicin, a Keystone Inducer of Drug Metabolism: From Herbert Remmer’s Pioneering Ideas to Modern Concepts. Drug Metab. Rev. 2004, 36, 497–509. [CrossRef
1. A 47-year-old CKD 5 has kidney transplantation from his brother, 111 mismatch, and no DSAs. Excellent kidney function. One year later, he presented with a night fever of 39 C, productive cough, and weight loss. Imaging showed multiple shadows in both lungs.
Issues/ concerns
– 47yo, CKD 5, kidney transplant, excellent kidney function
– donor – brother, 111 mismatch, no DSAs
– 1yr later fever 39, productive cough, weight loss
– detailed history: – drenching night sweats, TB contact, INH prophylaxis, induction therapy, maintenance immunosuppressive therapy, previous TB infection, history of LTBI in both the donor and the recipient
– sputum smear, gene xpert, sputum m/c/s or BAL fluid gene xpert
– gene xpert MTB/ RIF assay is highly specific and sensitive, it allows for detection of rifampicin resistance
– screen for routine bacterial, fungal (PCP, aspergillosis), CMV, Covid, VZV, and other respiratory viral infections
– IGRA and TST do not distinguish between active and latent TB; can be falsely negative in immunocompromised patients
– Treatment: –
depends on local epidemiological data and resistance patterns
in total, 6-9 months of treatment are usually recommended
Intensive phase involves 2months of Rifampicin, Isoniazid, Pyrazinamide, Ethambutol (RHZE) plus pyridoxine. Pyrazinamide and ethambutol are dosed depending on the kidney function
Continuation phase consists of 4months of Rifampicin and Isoniazid (RH) plus pyridoxine
some experts recommend at least 9months of treatment in all SOT recipients since shorter treatment duration may be associated with increased mortality (1)
duration of treatment can be extended in patients with severe disseminated disease (6-9months), bone disease (6-9months), joint disease(6-9months) , CNS disease (9-12months), cavitary disease with a positive sputum culture after 2 months of treatment (9months) (1)
increase the dose of CNI or mTORi by 3-5fold if rifampicin is being used, monitor the trough levels closely (2)
CYP3A4 induction by rifampin takes several days to occur, peaks within a week and lasts for days to weeks (3)
monitor LFTs for cases of drug induced liver injury (DILI) – anti-TBs should be withheld if the patient has deranged LFTs with or without symptoms
Rifamycin-based regimens have a potent sterilizing activity and prevent emergence of resistance – hence rifamycins are preferred for both severe and localized non-severe TB in SOT recipients (4)
SOT patients with non-severe and localized TB without suspicion/ evidence of INH resistance use a rifamycin-based regimen similar to what is used in immunocompetent patients. (4)
SOT patients with severe (e.g., multilobar or cavitary) or disseminated TB or in case of suspected or evident INH resistance, use a rifamycin-based regimen similar to what is used in immunocompetent patients. (4)
Rifamycins especially rifampicin, induce cytochrome p450 isoenzyme CYP3A4 resulting in a reduction in the serum concentration of CNIs (tacrolimus, cyclosporine), mTORi (sirolimus, everolimus). This can lead to graft rejection if the doses are not adjusted appropriately and if trough levels are not monitored carefully. (4)
Rifamycin have also been noted to reduce the level of glucocorticoids
If the patient has severe/ life-threatening disease, consider reducing the antimetabolite dose by 50% or stopping it altogether
Rifabutin is an alternative to rifampin – it has similar activity against M. TB but is a weaker cytochrome p450 inducer. Unfortunately, there is less experience with rifabutin in the treatment of TB among SOT recipients. Based on expert opinion, treatment with Rifabutin should be continued for at least 6-9months. (4)
if rifamycin is not part of the regimen, then the intensive phase should consist of 2months of isoniazid, pyrazinamide, ethambutol, levofloxacin followed by a continuation phase of 12-18months of isoniazid, pyrazinamide, ethambutol
if there is rifamycin resistance, 2nd line agents are used and the duration of treatment is extended
anti-TBs reverse the immunosuppressive effects associated with TB infection increasing the risk of paradoxical IRIS which manifests as worsening of pulmonary infiltrates, effusion (pleural or pericardial), lymphadenopathy, fever (5)
– incidence of TB among transplant recipients is higher than in the general population (6)
– active TB usually occurs in the 1st year post -transplantation
– reactivation of latent TB within the first year is a common occurrence (7)
– 30-50% of the cases of TB in post-transplant patients are extrapulmonary/ disseminated. This is a much higher rate than that seen among immunocompetent individuals (8)
– TB in transplant recipients remains a diagnostic and therapeutic challenge
– the treatment is challenging given the drug interactions and side effects
– hence screening for LTBI (using IGRA and TST) prior to transplantation and consequent INH prophylaxis is essential
– false negative TST and IGRA is common in patients with an impaired immune system (11)
– Risk factors for LTBI: – older age, lack of BCG vaccination, immunosuppression, positive DSAs
– TB-related mortality is higher among transplant recipients compared to immunocompetent persons
– screening methods: –
TST and IGRA, both have lower sensitivity in immunosuppressed patients compared to immunocompetent persons (12)
in order to detect the pathogen, TST and IGRA rely on the patient’s immune response to the pathogen (12)
-if a potential kidney transplant recipient tests positive for TB, they should complete TB treatment unless there is an urgent underlying need for transplant
Would your management differ if the disease was mild and affected one lung?
– no, management would remain the same i.e., for SOT patients with non-severe and localized TB without suspicion/ evidence of INH resistance use of a rifamycin-based regimen similar to what is used in immunocompetent patients is recommended (4)
References
1. Aguado JM, Herrero JA, Gavaldá J, Torre-Cisneros J, Blanes M, Rufí G, et al. Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Spanish Transplantation Infection Study Group, GESITRA. Transplantation. 1997 May 15;63(9):1278-86. PubMed PMID: 9158022. Epub 1997/05/15. eng.
2. Aguado JM, Torre-Cisneros J, Fortún J, Benito N, Meije Y, Doblas A, et al. Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2009 May 1;48(9):1276-84. PubMed PMID: 19320593. Epub 2009/03/27. eng.
3. Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivistö KT. Pharmacokinetic interactions with rifampicin : clinical relevance. Clinical pharmacokinetics. 2003;42(9):819-50. PubMed PMID: 12882588. Epub 2003/07/29. 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. Sun HY, Munoz P, Torre-Cisneros J, Aguado JM, Lattes R, Montejo M, et al. Mycobacterium tuberculosis-associated immune reconstitution syndrome in solid-organ transplant recipients. Transplantation. 2013 May 15;95(9):1173-81. PubMed PMID: 23435454. Epub 2013/02/26. eng.
6. Abad CLR, Razonable RR. Mycobacterium tuberculosis after solid organ transplantation: A review of more than 2000 cases. Clinical transplantation. 2018 Jun;32(6):e13259. PubMed PMID: 29656530. Epub 2018/04/16. eng.
7. Anand M, Nayyar E, Concepcion B, Salani M, Schaefer H. Tuberculosis in kidney transplant recipients: a case series. World journal of transplantation. 2017;7(3):213.
8. Fiske CT, Griffin MR, Erin H, Warkentin J, Lisa K, Arbogast PG, et al. Black race, sex, and extrapulmonary tuberculosis risk: an observational study. BMC Infect Dis. 2010 Jan 22;10:16. PubMed PMID: 20096113. Pubmed Central PMCID: PMC2823615. Epub 2010/01/26. eng.
9. Muñoz P, Rodríguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2005 Feb 15;40(4):581-7. PubMed PMID: 15712081. Epub 2005/02/16. eng.
10. Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1998 Nov;27(5):1266-77. PubMed PMID: 9827281. Epub 1998/11/25. eng.
11. Diel R, Loddenkemper R, Niemann S, Meywald-Walter K, Nienhaus A. Negative and positive predictive value of a whole-blood interferon-γ release assay for developing active tuberculosis: an update. American journal of respiratory and critical care medicine. 2011;183(1):88-95.
12. Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K. Updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection – United States, 2010. MMWR Recommendations and reports : Morbidity and mortality weekly report Recommendations and reports. 2010 Jun 25;59(RR-5):1-25. PubMed PMID: 20577159. Epub 2010/06/26. eng.
Clinical Scenario: Renal transplant recipient (Living donor, no DSAs, 1-1-1 Mismatch) presented one-year post transplantation with: night Fever, productive cough, loss of weight. He had a chest x-ray done showing: Bilateral lung infiltrates with bilateral hilar lymph adenopathy.
CT chest showed: bilateral small nodular infiltrates.
DD of diffuse nodular opacities in the lung:
1- Pulmonary TB (Miliary TB) —à fits with the index clinical scenario.
2- Langerhans cell Histoplasmosis.
3- Diffuse pneumonia (Bacteria or viral like CMV)
4- Silicosis.
5- Hypersensitivity pneumonitis.
6- Sarcoidosis.
7- Metastatic lung cancer.
A- Definitive diagnosis of TB needs further work up and investigations that include:
· Any positive test from the following is sufficient for diagnosis of active TB infection:
1- Isolation of Mycobacterium TB via culture of sputum or Broncho-alveolar swab, or pleural fluid.
2- Isolation of acid-fast bacilli in sputum smear.
3- Nucleic acid amplification testing, like Gene-Xpert test which is 98% sensitive, and results will available within 2-4 hours.
· The following 2 tests are used to support diagnosis in suspicious cases:
Tuberculin skin test (TST) and Interferon Gamma Release Assay (IGRAs) depend on patient’s immune response which makes their interpretation in immune-compromised patients (HIV infected or SOT recipients on IS) less reliable and can’t be used for diagnosis of active TB.
TST:
Advantages: 1- less expensive. 2- doesn’t need laboratory analysis.
Disadvantages: 1-Requires ID injection, follow up in the clinic to be reviewed by well-trained staff within 48-72 hours.
2- False positive results can happen following BCG vaccination or non-tuberculous mycobacteria.
3-False negative results can happen because of immune-suppression state.
4- Serial TST interpretation can be complicated by potential boosting.
5- TST can lead to adverse reactions like blistering and ulceration.
IGRAs:
Advantages: 1- doesn’t require follow up visits for interpretation. 2- doesn’t give false positive results because of previous BCG vaccination.
Disadvantages: 1- Costlier than TST because of Lab, sampling, reagents.
2- Results would be available after 24hours at least.
3-False negative results can happen because of IS.
4-Serial IGRAs interpretation is complicated by frequent conversions and spontaneous reversions and lack of consensus about the optimum threshold.
B- Work up to rule other causes of DD:
· Urinary or serum antigen for histoplasmosis with >90% sensitivity.
· CMV PCR.
· Sputum, BAL Culture for bacteria, fungi.
· B D-glucan.
Treatment if TB is the diagnosis:
1- 4-drug regimen is the appropriate therapy: (INH + (Rifampin or Rifaputin) + Pyrazinamide + Ethambutol) for at least 2-months then 6-9months of 2-drug regimen (INH + Rifampin).
2- Rifaputin has less enzyme inducing effect than Rifampin.
3- Add B6 50mg po od.
4- Rifamycins are recommended for severe (cavitary or multi-lobar disease) or disseminated TB or with suspected or documented INH resistance.
5- Second-line drugs (quinolones, aminoglycoside and clarithromycin) can be used in case of resistance or side effects to first line medications or poor clinical condition or infection with atypical mycobacteria.
Management of IS medications:
1- Reduction of IS maintenance medications: at least 50% reduction of anti-metabolites (MMF or Azathioprine) with potential withdrawal if progressive infection not responding to treatment.
2- Increase the dose of steroids.
3- Monitoring the therapeutic level of CNI because of drug interaction with anti-TB medications which tend to reduce the level of CNI exposing the patient to the risk of rejection.
4- Anti-TB are enzyme inducers, so CNI or m-TOR inhibitors level will be low and dose usually increase by 2-5 folds while being on anti-TB.
Monitoring of treatment:
1- Monitor renal and liver function tests.
2- Monitor for side effects of medications.
3- Monitor vision before and after starting ethambutol.
4- Regular follow up for reactivation of TB.
5- Anti-TB treatment can be stopped after having 2 negative sequential sputum samples by GeneXpert (NAAT).
6- Consult infection control team and microbiology team.
Would your management differ if the disease was mild and affected one lung?
The treatment will be the same according the American society of transplantation, both severe and localized non-severe TB should be treated with the same regimen to ensure radical treatment and prevent resistance to treatment.
After 1 year of renal transplant, he presented with fever, wt loss, and productive cough and chest X-ray showing reticulonodular opacities in both lung field and HRCT shows multiple scattered modular lesions, so this picture is pointing to miliary TB while other Differential diagnosis:
viral infection : CMV , influenza
Bacterial
Fungal : pneumocystis jirovecii
The management:
Proper history taking , full examination
Lab test: CBC, RFT , LFT, ESR, CRP, blood cultures , CMV PCR , serum B D Glucan, drug level
Sputum culture , cytology , gram staining , TB PCR ,
Bronchoalveolar lavage
Radiology: chest X-ray , HRCT
Treatment:
Anti TB drugs as :
First line INH, , Rifampicin or rifabutin , Pyrazinamide and Ethambutol are used for 2 months then INH and Rifabutin for 4 months may total duration up to 9 months
Rifampicin is more enzyme inducer than rifabutin , so drug level must be carefully monitored and the dose may be increased up to 2-5 folds
B6 must be given with INH
2. Would your management differ if the disease was mild and affected one lung?
No, the treatment will be the same
References:
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.
Anand M, Nayyar E, Concepcion B, Salani M, Schaefer H. Tuberculosis in kidney transplant recipients: a case series. World journal of transplantation. 2017;7(3):213.
This 47-year-old post-RTX for 1 year presented with typical features and high suspicious of pulmonary TB , HE IS HAVING FEVEER WITH SWEATING and wt loss
his chest x-ray showed bilateral chest mottling and HRCT of bilateral scaTTERED LUNG NODULE.
In such cases, we need to di fukk routine tests like CBC, CMP, LFT and ESR, which is giving us a good clue to pulmonary TB as usually > 3 figures in favour of pulmonary TP.
we need to know from the history if he has HX of TP or contact with TP patients.
The donor status and if he has latent TB.
We need to know the area of the patients and the donor if ist is endemic in TB .
Once the diagnosis is made the patient should start the treatment to prevent complications.
the treatment of pulmonary TB is for 6 months in case not complicated but may extend to 9 months in case of a cavitary lung lesion or disseminated disease.
The first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases. Bone and CNS TB may need a longer course of treatment up to 9 to 12 months.
Monitoring of LVT and RFT during treatment adding close observation for CNI level as it will be affected by anti TB treatment and may increase the risk of rejection to 30%
1. How do you manage this case?
The clinicoradiological features of this patient goes with the diagnosis of miliary TB , although other differential diagnosis must be considered.
DDX include:
Bacterial infection , viral like CMV , fungal , pneumocystis.
The management plan start from detailed history of endemic area, history of TB , history of treatment of latent TB , close contact to index case, details about the donors , any history of TB , details about IS .any history of travel to highly endemic areas.
Physical examination and investigation like : CBC, ESR, CRP, LFT ,RFT
CXR , HRCT, induced sputum for cytology and gram stain and Z-N stain for AFB , or BAL and bronchoscopical examination, PCR for CMV and pneumocystis.
The treatment of active TB should be started immediately after the diagnosis has been established.
The epidemiological features from the area of patient’s origin and drug resistance patterns should be assessed .
The optimal period of treatment could vary from 6 to 24 months and, in some cases, the duration of treatment is recommended to be at least 9–12 months .
in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months .In case of severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months .Patients with central nervous system involvement should be treated for at least 9–12 months.
the first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases.
Rifamycin is recommended for its effectiveness and also to reduce the risk of resistance .
2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin .
a regimen without rifampicin could be used if no resistance to isoniazid is present .
If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide. Additionally, if second-line drugs are used, a longer period of treatment is recommended .
One challenge in the treatment of KT recipients with active TB is the drug interaction between rifampicin and transplant-associated immunosuppression .Rifampicin, a potent inducer of cytochrome P450 3A4 interferes with immunosuppression metabolization .
Specifically, rifampicin usage decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection .Therefore, when a rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin and mTOR inhibitor should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target. Additionally, after the rifampicin is stopped, the immunosuppression doses should be reduced to the value before the start of rifampicin and then adjusted to obtain the therapeutic target .
An alternative to rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy .Likewise, even in rifabutin-based regimens, immunosuppression doses could be modified, and levels should be closely monitored .Another safe and effective alternative to rifampicin in KT recipients is treatment with fluoroquinolones .
Another challenge is linked to the adverse effects of TB therapy, which are more frequent than in the general population. Therefore, some first-line drugs could not be used, and consequently, the treatment period will be increased .Patients treated with anti-TB drugs should be closely monitored for hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol), neurotoxicity (isoniazid, ethambutol), cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol), visual disturbances (rifabutin, ethambutol), skin lesions (rifampicin), hyperuricemia (pyrazinamide) or interstitial nephritis (rifampicin, pyrazinamide) .The most common adverse event associated with anti-TB therapy is hepatotoxicity; therefore, liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter .
Treatment adherence could also be an issue in KT recipients.
An additional caveat is that patients with KT could have different degrees of graft function and therefore is very important to evaluate creatinine clearance and adjust the doses for pyrazinamide and ethambutol .
Reduction of immunosuppression in the case of severe TB or when a vital organ is involved should be considered.
2-Would your management differ if the disease was mild and affected one lung?
No, but the duration for 6 months . Reference:
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
Bogdan Marian Sorohan 1,2,* , Gener Ismail 2,3, Dorina Tacu 1, Bogdan Obris, că 2,3 , Gina Ciolan 4, Costin Gîngu 1,2, Ioanel Sinescu 1,2 and Cătălin Baston
This patient has night fever of 39 C, productive cough, and weight loss. The chest X ray shows diffuse nodular shadowing with tracheostomy tube in situ. On X ray it is difficult to comment on mediastinal lymphadenopathy. CT scan axial view shows wide spread scattered nodules indicating miliary tuberculosis.
A detailed history of any previous Tuberculosis, exposure or use of ATT should be taken. A thorough physical examination is mandatory to rule out any lymphadenopathy.
Investigations
Blood CP/ESR. Renal and liver functions , CRP,
Diagnostic tests for tuberculosis will include –
Sputum for AFB smear and AFB culture
Molecular tests based on NAA
FNAC of any palpable lymph node
Treatment
As there is clinical suspicion , Anti tuberculosis treatment should be started.
AST- IDCOP guidelines recommends 4 drug regimen
Initial two months of 4 drugs- Rifampicin, ethambutol, INH and pyrazinamide
Next 4 months with INH and Rifamicin
AST- IDCOP guidelines recommends 6 months treatment in case of uncomplicated tuberculosis
AST- IDCOP guidelines recommends 9 months treatment if there are cavitating lesions or persistently positive sputum 2 months post initiation of drug therapy.
CNS involvement 9-12 months
In the index case there is suspicion of miliary tuberculosis, so 9 months treatmnet should be considered.
Regular monitoring of liver functions, graft functions
Pyridoxine should be use to prevent neuropathy
If situation worsens then antimetabolites can be reduced
Would your management differ if the disease was mild and affected one lung?
Treatment will be same with four drugs . Total duration 6 months
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
Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: treatment of drug-susceptible tuberculosis. Clin Infect Dis. 2016;63(7):e147-e95.
The scenario of fever and night sweats, cough, and weight loss combined with transplantation (immunosuppression), in addition to somehow typical military pattern that seems consistent with TB. Control of CBC, CRP, ESR, LDH, acid-fast staining, sputum culture, TBC staining, and culture is needed.
Treatment is the same as immunocompetent patients except for special considerations regarding drug interaction.
** AST states that Rifamycine containing regimen used for severe and nonsevere localized infections because of potency of treatment and prevention of resistance. rifamycines are good option especially in cavitary infection. Tretemenof our case needs to be as long as 12 months.
Management should be in cooperation with pulmonologist and or infectious diseases.
**If the lesions were localized or in one side , I prefer the same potent treatment.
Paying attention to drug interaction or Rifampicin and CNIs is essential
…
Interms of immunosuppression we should balance the severity and life threting situation. In case of localized infection we can sustain IS but with severe infection like our case , we should minimize and monitor RFTs.
1- The onset, clinical picture and chest imaging are highly suggestive of miliary TB.
Management include:
proper history taking: hx of previous T>B, review of pre-transplant data for latent TB, travelling or contact with infected persons.
Investigations: CBC, RFT, LFT, CRP
microscopic examination of the sputum for acid fast bacilli and culture for TB
specific test: TST and IGRA
check for extra-pulmonary infection: renal us
start anti-tuberculous treatment:
-The first-line treatment should be a four-drug regimen c
– Consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and
ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin
-Duration of treatment can be extended up to 24 months till clinical improvement
and negative smear.
reduction of immunotherapy
during tratment: monitor kidney function, liver function every 2 weeks for 2 months then monthly and IS drug level
2- In mild cases: there is no need to reduce IS treatment.
This patient presented with symptoms suggestive of TB .
Needs detailed history of contact with the patient diagnosed as case of TB or Contact with patient has chronic cough
Past medical history of TB .
Ask about donor screening from TB at the time of transplant .
Full clinical examination
Investigations:
CBC
ESR
CRP
LFT
RFT
Sputum for culture and sensitivity.
Gene xpert MTB /rif assay .Histology for biopsy or aspirate acid fast bacilli
Test for latent TB infection :
TST and IGRA
Renal US
Treatment of active TB:: Commonly used anti-tuberculosis drugs are are isoniazid, rifampicin, pyrazinamide and ethambutol and one of the quinolones. .The first three are called essential first-line drugs and are the mainstay of short-term treatment. The latter two are first-line adjuvants. Second-line drugs are highly toxic and are only used when resistance to first-line drugs develops.
Isoniazid, ethambutol, pyrazinamide are safe drugs. Rifampicin, an essential drug in the ATT regimen, induces the cytochrome-c P450 microsomal enzyme system responsible for the metabolism of cyclosporine, sirolimus and prednisolone. This unpredictable interaction has been associated with acute rejection in 30% of cases and graft loss in 20% of cases and should therefore be avoided in solid organ transplantation.
Doses of calcineurin inhibitors may need to be increased two to five times to overcome this effect. Ofloxacin, a quinolone withantimycobacterial properties, is often added to four-drug regimens. It is considered as effective as ethambutol and has fewer side effects.
. Duration of therapy: Four-drug regimen: pyrazinamide (three months); ofloxacin (nine months); INH and ethambutol (18 months). The dose of isoniazid and ethambutol should be adjusted according to the degree of renal function. The dose of prednisolone should be doubled if rifampicin is given to patients not taking ciclosporin
References :
1. John GT. Infections after renal transplantation in India. Indian J Nephrol. 2003;13:14. [Google Scholar]
2. Sakhuja V, Jha V, Varma PP, Joshi K, Chugh KS. The high incidence of tuberculosis amongrenaltransplantrecipients in India. Transplantation. 1996;61:211. [PubMed] [Google Scholar]
3. Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid organ transplantation recipients: Impact and implications for management. Clin Infect Dis. 1998;27:1266. [PubMed] [Google Scholar]
4. John GT, Date A, Mathew CM, Jeyaseelan L, Jacob CK, Shastry JC. A timetable of infectionsaftertransplantation in the tropics. Transplantation. 1996;61:970. [PubMed] [Google Scholar]
5. John GT, Shankar V. Mycobacterial infections in organ transplant recipients. Seminar Res Infect. 2002;17:274. [PubMed] [Google Scholar]
The most likely diagnosis is miliaryTB and productive cough means open TB. therefore, hospitalization with isolation in a -ve pressure room is necessary pending the final diagnosis.
infection control notification.
pulmonologist consultation.
Lab. tests including CBC, ESR, CRP, Liver function tests, renal chemistry & electrolytes, sputum examination for AFB, TB culture, TB PCR and also for rpoB gene for drug resistance. baseline trough CNI levels should also be available.
Tuberculin and INF gamma tests for active TB infection. -ve results don’t exclude infection.
Screening of all contacts.
in case of multi-drug resistance TB (MDRTB), isolation in a -ve pressure room should be maintained for 2 weeks with antibiotic ttt.
in case of non- MDRTB, isolation can be done in a separate room for the same period of 2 weeks with antibiotic ttt.
First line ttt include 4 antibiotics for the first 2 months : Rifampicin, Isoniazide, Ethambutol and Pyrezinamide. then Isonizide and Rifampicin for the remaining months according to the local protocol. the short protocol include total 6 months of ttt.
Second line ttt for MDRTB include quinolone, Capreomycin, Cyclserine,…
both Rifampicin and INH are hepatic microsomal enzyme inducers. therefore, increasing the dose of CNI is needed with follow-up of trough levels and also renal chemistry.
other supportive ttt as Vit. B complex for peripheral neuropathy of Isoniazide. baseline nerve conduction study should also be available.
follow-up of liver function tests for possible hepatoxicity of anti-tuberculous ttt.
Would your management differ if the disease was mild and affected one lung?
The index patient is a 47-year-old living donor renal transplant recipient, with 111 mismatch, no DSAs and stable graft function, now presenting 1 year post-transplant with fever of 39 degree Celsius, weight loss, and productive cough.
Chest X ray shows reticulonodular shadows in bilateral lung fields with hilar prominence. HRCT chest section shown revealed multiple miliary nodular lesions (arrows) throughout the lung parenchyma.
In view of the clinico-radiological picture presented, the first possibility is miliary tuberculosis. Nevertheless, the diagnosis need to be confirmed, and the patient being a renal transplant recipient, other differential diagnosis, including causes of pneumonia should be kept in the differential diagnosis (1).
3) Bacterial: community acquired like streptococcus, tuberculosis etc.
4) Parasitic
5) Non-infectious: mTOR inhibitor associated
The management of the index case involves:
1. A detailed history and clinical examination. History regarding prior tuberculosis, induction therapy use, and the immunosuppressive regime being used is especially important. History of recent contact with any patient with tuberculosis, and history of tuberculosis in the donor should also be elicited.
2. Laboratory testing including complete blood count, renal function tests, liver function tests, C reactive protein, blood culture, chest X ray, influenza testing (if in influenza season) and other respiratory viral testing (biofire), serum beta D Glucan, Serum LDH, Calcineurin inhibitor (CNI) trough levels (if on CNIs).
3. Induced sputum examination for cytology, gram stain and acid-fast bacilli (AFB) stain, and culture.
4. High resolution computed tomogram (HRCT) of chest.
5. CMV PCR testing: To rule out CMV infection (although unlikely in this setting).
6. Bronchoscopy with bronchoalveolar lavage (BAL) with or without transbronchial lung biopsy: For stain and culture (fungal, AFB), as well as PCR for respiratory viruses, CMV, pneumocystis, and histopathological analysis.
Treatment: If the diagnosis of active tuberculosis is confirmed, the treatment involves 4-drug regimen of Isoniazid, Rifampicin (or rifabutin), Pyrazinamide, and Ethambutol for first 2 months (intensive phase) followed by Isoniazid and Rifampicin (or rifabutin) for 4 more months (continuation phase), as advised in immunocompetent patients (2). Ethambutol can be stopped if it is confirmed that the organism is susceptible to the other 3 drugs (3).
Rifampicin is an enzyme CYP3A4 inducer, leading to increased metabolism of immunosuppressives drugs (cyclosporin, tacrolimus, sirolimus, everolimus, and steroids) thereby requiring an increase in the doses (upto 2-5 times for cyclosporine/ tacrolimus, and 2 times for steroids) and close monitoring of the drug levels (4). Rifabutin can be used in place of Rifampicin, with the resultant required immunosuppressant drug dose increase being less than that with use of rifampicin (5). Ethambutol and isoniazid do not appear to interact with the immunosuppressive medications (4).
The optimal duration of treatment has not been defined, with many specialists recommending a duration of 9 months (5). Uncomplicated pulmonary tuberculosis showing sputum negativity after 2 months of treatment can be given treatment for 6 months only, while a positive sputum test for tuberculosis after 2 month treatment warrants treatment for 9 months (2). Longer duration treatment is also recommended in patients with bone and joint involvement, central nervous system involvement, or a disseminated disease (2).
Considering the presence of miliary pulmonary nodules in the index patient, there is high probability of multisystem involvement in the patient, hence patient may require treatment for 9 months.
In addition of monitoring of drug levels and graft function, liver function tests are also required to be monitored in view of risks of hepatotoxicity with the anti-tubercular medications. Pyridoxine should be given with isoniazid.
If the clinical status of the patient worsens, dose of antimetabolite (MMF or azathioprine) might require reduction or cessation.
2. Would your management differ if the disease was mild and affected one lung?
No. The treatment would remain same (4-drug regime) with 6 month duration of antitubercular treatment (localized tuberculosis).
References:
1. Dulek DE, Mueller NJ; AST Infectious Diseases Community of Practice. Pneumonia in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13545. doi: 10.1111/ctr.13545. Epub 2019 Apr 23. PMID: 30900275; PMCID: PMC7162188.
2. 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.
3. 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.
4. Sparkes T, Lemonovich TL; AST Infectious Diseases Community of Practice. Interactions between anti-infective agents and immunosuppressants-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13510. doi: 10.1111/ctr.13510. Epub 2019 Apr 23. PMID: 30817021.
5. 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.
Rapid nucleic acid amplification technique (NAAT) test like Xpert MTB/RIF (Cepheid Inc) can be used to increase the sensitivity and rapidity to diagnose tuberculosis, in addition to finding resistance to rifampicin (1).
Rifampicin free regimens can be used in following conditions:
1) Localized, non-severe TB with no resistance to isoniazid (2). Patients can be given 3 drugs (Isoniazid, Ethambutol and pyrazinamide or levofloxacin) for 2 months followed by 2 drugs (isoniazid with ethambutol or pyrazinamide) for 12-18 months. Another regimen used includes use of 3 drug regimen (Isoniazid, Ethambutol and pyrazinamide or levofloxacin) for 12 months.
2) Use of rifabutin in place of rifampicin in transplant recipient on CNI .
3) Patient with latent tuberculous infection (LTBI): Isoniazid monotherapy for 9 months (3).
References:
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.
Meije Y, Piersimoni C, Torre-Cisneros J, Dilektasli AG, Aguado JM; ESCMID Study Group of Infection in Compromised Hosts. Mycobacterial infections in solid organ transplant recipients. Clin Microbiol Infect. 2014 Sep;20 Suppl 7:89-101. doi: 10.1111/1469-0691.12641. PMID: 24707957.
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.
A 47-year-old CKD 5 has kidney transplantation from his brother, 111 mismatch, and no DSAs. Excellent kidney function. One year later, he presented with a night fever of 39 C, productive cough, and weight loss. Imaging showed multiple shadows in both lungs.
How would you manage this case?
The CXR => showed bilateral reticulo-nodular shadows with peri-hilar infiltrate and opacities represent mediastinal LNs. The CT Thorax => showed numerous small sized nodules distributed throughout both lungs, (most likely military TB). (Active pulmonary TB ; most probably 2ry to reactivation of LTBI in recipient). DD: – PJP pneumonia – Aspergillosis – PTLD – CMV pneumonitis – Drug induced pneumonitis if he was treated with m TOR. – Other bacterial and opportunistic pneumonia. Prevalence of TB after solid organ transplantation:
It significantly higher than general population, it differs according to geographic area, it ranges from 1.2-2.6% in developed countries and in 10-15% in endemic regions, around 95% of cases occur at 1 mouth to 1 year after transplantation, Donor-derived TB usually occur earlier compared to activation of latent TB. Mode of transmission:
– Activation of latent TB (the most common) – Acquiring the disease from the graft (donor derived) – Acquiring new infection through air born transmission C/P: – Fever occurs in 91% of disseminated TB, and in 64% of localized TB cases. – Night sweats and weight loss are commonly seen. – The presentation differs from immunocompetent patients in the following. – Atypical presentation is more common (pyomyositis, tenosynovitis, skin ulcers or abscess) – Around 30-50% of cases present with extra pulmonary or disseminated TB (much higher than immunocompetent hosts). Investigations:
The diagnosis of TB requires a high index of suspicion based on the epidemiological risk, personal history, manifestations, and imagistic lesions,
-Rapid Molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test (Xpert® MTB/RIF) could provide false negative results when mycobacterial load is low, which is highly predictive of MDR-TB.
-Tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not useful in the diagnosis of active TB.
-Probability of association with other co-infections, so further investigations r/o other fungal or viral infections (CMV-EBV-HIV).
-Sputum for AFB smear, Culture and drug sensitivity (it will take long time and decision need to be taken rapidly).
-BAL Fungal infection cultures, staining and PCR.
Screening for donor:
-His brother should be screened for latent TB infection if it has not been done prior to KT using (TST/IGRA).
-Recognizing latent infection or undiagnosed active TB in the kidney donors is critical in preventing post-transplant infection.
–A careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors.
–Current guidelines provide recommendations for latent TB screening in all KT candidates and donors before transplantation. -Patients should be isolated until he is improving clinically, or after 3 consecutive negative sputum smear results (guided by I.C. recommendation)
-The treatment of active TB should be promptly started immediately after the diagnosis has been established.
-The epidemiological features from the area of patient’s origin and drug resistance patterns should be assessed.
-The optimal period of treatment could vary from 6 to 24 months and, in some cases, based on experts’ opinion, the duration of treatment is recommended to be at least 9–12 months. Other work up:
-Drug level (CNIs, mTORs), monitor drug level frequently every 3 days keeping trough at lower target (trough around 5 for tacrolimus), I will keep lower Therapeutic dose of MMF and steroid.
-Pan CT with contrast to assess the extent of the disease. Treatment:
The treatment of TB in SOT is challenging due to the following.
Drug-drug interaction between rifampicin (the corn stone of TB treatment) and immunosuppressive medications used in transplantation.
Loss of host immune response to TB due to the use of immunosuppressive drugs
Nephrotoxicity and other side effects related to the use of anti –TB medications.
Protocols used in treatment of TB:
I- Rifampicin containing regimen:
Regimen A– 4-drug regimen of Rifampicin+ INH+ ethambutol + pyrazinamide for 2 months, followed by a 2-drug regimen of Rifampicin + INH for 4 months. It is recommended to increase the duration of treatment to at least 9 months if one of the following is present.
Disseminated disease.
Cavitary disease with positive sputum culture after 2 months of treatment
Bone and joint disease
CNS disease.
Some recommends extending the duration of treatment to 9 months in all SOT recipients since there is improvement in the mortality when using extended duration.
II- Rifampicin free regimen:
Regimen A – 3-drug regimen of INH+ ethambutol + pyrazinamide or levofloxacin are used for 2 months, followed by a 2-drug regimen of INH + either ethambutol or pyrazinamide for 12 to 18 months.
Regimen B – 3 drugs (INH+ ethambutol + pyrazinamide or levofloxacin are used for 12 months
Regimen C – Rifabutiun can be used instead of rifampicin due to its lesser effect on cytochrome p450, so minimal drug-drug interactions but experience is little when using this drug in transplantation, although it seems effective in HIV TB patients.(9)
It is strongly recommended to use Rifampicin containing regimen especially in patients with severe (cavitary or multilobar) or disseminated disease or if there is an evidence of INH resistance.
In non-severe cases with no evidence of INH resistance, Rifampicin is sometimes avoided due to its intense drug-drug interactions with immunosuppressive drug with subsequent increase in the risk of rejections, so it is better to use rifampicin free protocols.
Induction of CYP3A4 with rifampicin takes several days to occur and peak at 1 week after initiating the drug. Once rifampin is used, it is recommended to increase the dose of CNI or rapamycin 3-5 folds, with close follow up of serum level.
In SOT it is recommended to save Rifampicin for severe and resistant cases, and avoid streptomycin due to its nephrotoxicity.
Avoid extreme reduction of the immunosuppressive agents to decrease the possibility of anti-tuberculous therapy – induced immune reconstitution inflammatory syndrome (IRIS). IRIS occur due to flare of immunity after the start of anti-TB drugs, manifested as worsening of fever, pulmonary infiltrates, lymphadenopathy, pleural and pericardial effusions (10). In one study evaluating transplant recipient s with TB, IRIS occur after 1.5 month of initiating anti-TB drugs in 14% of cases. (10) risk factors associated with IRIS includes liver transplantation, CMV infection and use of Rifampicin.
TB in SOT is associated with around 20% graft and patient loss, poor prognostic factors include the use of ATG, OKT3, previous rejection and disseminated disease.
Would your management differ if the disease was mild and affected one lung?
Yes, at this time I will avoid Rifampicin and use one of the Rifampicin free regimens.
Diagnosis of latent TB:
-Recipients with latent TB are at high risk of conversion to active TB after transplantation, on the other hand, if the donor has latent TB and did not receive treatment it carry a risk of transmission to the recipient.
-So, all recipients and donors should both be undergo careful evaluation of the risk, history, examination and CXR, together with test for latent TB
-In general, all transplant recipients and donors should be evaluated for the presence of latent TB and once detected treatment should be received.
-2 tests are used to detect latent TB, tuberculin skin test (TST) and IGRA, both are usually negative in immunosuppressed patients due to their dependence on the host immune response which is impaired in these sets of patients.
-Patient and donor should have no symptoms, CXR should be normal and no evidence of exra-pulmonary TB to settle the diagnosis of latent TB.
Which test to use?
-In low-risk transplant recipients, it is it is preferred to use IGRA over TST due to its higher sensitivity in these sets of patients.
-In low-risk donor, either of both tests can be used, with the preference of IGRA in patients with previous vaccination.
-In high-risk transplant recipients and donor (patient who are living in country with high TB prevalence, contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), it is better to do both tests to maximize sensitivity, at that time IGRA should be done either at the same time of before TST to avoid TST-mediated IGRA response.
-All transplant recipients and donors should have thorough history taking and CXR.
Interpretation of the result:
If TST is negative the test should be repeated after 7-10 days to detect posted effect
If IGRA is negative treatment is considered only in high-risk transplant recipients
If the TST is positive (Induration ≥5 mm in recipient or > 10 mm in donor), there is a history of positive TST, or IGRA is positive, the patients is considered to have latent TB provided that the CXR is normal and the patient is asymptomatic
If radiology is suspicious for TB (apical fibronodular lesions, calcified solitary nodule, calcified lymph nodes, or pleural thickening) thorough evaluation including microbiological assessment is indicated to exclude TB as a cause.
If TB diagnosed in the recipient transplantation should be delayed till complete treatment of TB
If TB is diagnosed in the donor donation should be postboned till successful treatment is given for at least 6 months.
Indications of treatment of latent TB in transplant recipient and donor:
Positive TST (> 5mm in recipient, > 10 mm in donor) or a positive IGRA
History of positive TST or pervious history of TB
Negative TST and/or IGRA in a patient with close contact to an active TB case
If the donor has latent TB and did not receive treatment (treat the recipient), but if the donor received treatment there is no need to treat the recipient.
Protocol for treatment of latent TB:
The preferred regimen in renal transplant candidate is the use of INH in a dose of 5 mg/kg (maximum dose 300 mg) together with oral pyridoxine 50 mg daily for 6-9 months (9 months is preferred).
Rifampin in a dose of 600 mg for 4 months
INH+ weekly Rifampin for 3 months
Regimen should be started before transplantation, but if it started after transplantation, Rifampicin containing regimen should be avoided.
Patient should be monitored for liver enzymes and bilirubin at baseline, every 2 weeks for 6 weeks then monthly, if there is 3 fold rise of liver enzymes with symptoms or 5 fold rise without symptoms, INH should be stopped
References:
* Lopez de Castilla D, Schluger NW. Tuberculosis following solid organ transplantation. Transpl Infect Dis 2010; 12:106.
* Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clin Infect Dis 1998; 27:1266.
*Aguado JM, Torre-Cisneros J, Fortún J, et al. Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clin Infect Dis 2009; 48:1276.
*Abad CLR, Razonable RR. Mycobacterium tuberculosis after solid organ transplantation: A review of more than 2000 cases. Clin Transplant 2018; 32: e13259.
* Muñoz P, Rodríguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clin Infect Dis 2005; 40:581.
*Torre-Cisneros J, Doblas A, Aguado JM, et al. Tuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort. Clin Infect Dis 2009; 48:1657.
DD could be: miliary TB,CMV pnemonitis, pneumocystis pneumonia, PTLD and other bacterial, fungul, and opportunistic pneumonia.
To confirm TB:
History of TB disease, contact with TB patient or travel to endemic area. Clinical examination to look for extrapulmonary TB.
Sputum C&S with Z-N stain to detect acid fast bacilli ,BACTEC.
Sputum C&S for Bacterial, fungal, PCP
Gene Xpert of sputum or BAL.
Bronchoscopy, BAL and PCR for PCP
CMV PCR.
Drug treatment:
Start anti TB protocol with Rifampicin, INH& Ethionamide ( all for 9 months) and Pyrazinamide for 2 months
Several protocols are available including treatment from 9 months up to 18 months.
Rifampicin is P450 cytochrome inducer causing reduction in CNI levels, so we need to monitor CNI levels and increasing of CNI dose.
Alternative to Rifampicin, we can use: INH for18 months, Ethambutol for 18 months, Pyrazinamide for 3 months and Levofloxacin for 6 months.
Monitoring of graft function is warranted..
If the disease is mild and affecting one lung:
According to ESCMID guidelines: in cases of localized mild TB, a rifampicin free regimen could be used if no resistance to isoniazid. Rifabutin; rifamycin having weaker inducer of cytochrome P450 3A4, is an alternative for rifampicin or fluoroquinolones. Immunosuppression drugs doses could be modified, and levels closely monitored.
This image most probably suggests tubercular infection post-transplant.
Mangement:
2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin
Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with immunosuppression metabolization
Specifically, rifampicin usage decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection
Therefore, when a rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin and mTOR inhibitor should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
The most common adverse event associated with anti-TB therapy is hepatotoxicity; therefore, liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter
Reduction of immunosuppression in the case of severe TB or when a vital organ is involved should be considered
if the disease was mild and affected one lung?
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) suggests in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present
If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.
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.
How do you manage this case?
rifamycin-containing regimen- treatment should be continued for at least nine months
In general, the approach to antimicrobial therapy for treatment of miliary TB consists of the traditional regimen (≥6 months) for treatment of pulmonary TB .
MANAGEMENT OF ACTIVE TUBERCULOSIS
the 2019 guidelines of the American Society of Transplantation (AST) , and the 2014 guidelines of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID)
The AST, ESCMID, and TBNET have all recommended that the approach to the treatment of TB in SOT recipients be similar to immunocompetent hosts However, the following important issues specific to SOT recipients should be noted:
●The AST states that a rifamycin-containing regimen is strongly preferred for both severe and localized nonsevere TB due to the potent sterilizing activity of such regimens and the importance of preventing the emergence of resistance
●TBNET and ESCMID suggest a non-rifamycin-based regimen in cases of localized (eg, pulmonary) nonsevere TB when there is no suspicion or evidence of isoniazid (INH) resistance . In patients not receiving a rifamycin, treatment options include a three-drug regimen of INH plusethambutolpluseitherpyrazinamideorlevofloxacin for 2 months, followed by a two-drug regimen of INH plus ethambutol or pyrazinamide for 12 to 18 months. In those receiving a three-drug regimen for the entirety, the duration of treatment can be shortened to 12 months.
●Experts agree that rifamycins are indicated in patients with severe (eg, cavitary or multilobar disease) or disseminated TB or when there is suspicion or documentation of INH resistance
●Rifampin should be used with caution due to significant interactions between this class of drug and the calcineurin inhibitors and rapamycin (sirolimus). The rifamycins (especially rifampin) reduce serum concentrations of tacrolimus, cyclosporine, rapamycin (sirolimus), and everolimus via induction of the cytochrome p450 isoenzyme CYP3A4, and the combination of a rifamycin with these drugs has been associated with the development of rejection . Rifamycins also reduce levels of glucocorticoids, although this has been less well characterized
●If rifampin is used, the dose of the calcineurin inhibitor or rapamycin should be increased approximately three- to fivefold, and serum concentrations should be monitored . Rifabutin has similar activity against M. tuberculosis but is a weaker inducer of cytochrome p450
●Patients receiving a rifamycin-containing regimen should be treated for a minimum of six months. However, duration should be extended in patients with severe disseminated disease, treatment should be continued for at least nine months in all SOT recipients, since a shorter duration may be associated with increased mortality in this population
●Caution is advised against the overzealous reduction in immunosuppression while treating post-transplant TB given the challenge of immune reconstitution inflammatory syndrome (IRIS).
Antituberculous therapy reverses the immunosuppressive effects associated with TB infection, and IRIS may manifest with a paradoxical worsening of pulmonary infiltrates, fever, pleural or pericardial effusion, or lymphadenopathy
Would your management differ if the disease was mild and affected one lung?
YES
TBNET and ESCMID suggest a non-rifamycin-based regimen in cases of localized (eg, pulmonary) nonsevere TB when there is no suspicion or evidence of isoniazid (INH) resistance . In patients not receiving a rifamycin, treatment options include a three-drug regimen of INH plusethambutolpluseitherpyrazinamideorlevofloxacin for 2 months, followed by a two-drug regimen of INH plus ethambutol or pyrazinamide for 12 to 18 months. In those receiving a three-drug regimen for the entirety, the duration of treatment can be shortened to 12 months
The diagnosis of the current scenario most probably is disseminated TB with imaging showed pulmonary TB with general manifestations of wight loss, night fever and sweat. In renal transplant patients on immunosuppression and history of induction with lymphocyte depleting agents, these patients represent a high-risk to develop TB infection either localized or disseminated. The source of infection either reactivation of latent infection or TB transmission from the donor allograft to the recipient (The reactivation of latent tuberculosis in organ transplant recipients within the first twelve months is the most common manifestation).
In addition to imaging findings of disseminated TB, blood Mycobacterium tuberculosis PCR test must be done to confirm TB infection. bronchoscopy with bronchoalveolar lavage or lung biopsy may be needed for diagnosis. Sputum should be sent for acid-fast bacilli staining and culture and histopathology.
Treatment with antituberculosis treatment consisting of rifampicin, isoniazid, pyrazinamide, and ethambutol to be started immediately for 2 months, followed by a two-drug regimen of INH plus ethambutol or pyrazinamide for 12 to 18 months. .In addition to hold MMF and target tacrolimus level of 5-7 (rifampin reduce serum concentrations of tacrolimus, cyclosporine, rapamycin , and everolimus via induction of the cytochrome p450 isoenzyme CYP3A4). the dose of the calcineurin inhibitor or rapamycin should be increased approximately three- to fivefold, and serum concentrations should be monitored.
screening for latent tuberculosis infection prior to transplantation and consequent prophylaxis with isoniazid is essential. Available screening tests for latent tuberculosis, including interferon gamma-release assays (IGRA) and tuberculin skin tests (TST), are limited in patients with chronic kidney disease, as the tests rely on an intact immune response. Would your management differ if the disease was mild and affected one lung? suggested a non-rifamycin-based regimen in cases of localized (eg, pulmonary) nonsevere TB when there is no suspicion or evidence of isoniazid (INH) resistance.
The index scenario is a KTR with night fever, productive cough and weight loss. CXR and CT lungs showed bilateral lung infiltrates without subpleural spare. Symptoms and radiographic findings are highly suggestive of TB infection.
The differentials for this scenario:
· Pulmonary TB.
· Atypical pneumonia.
· CMV pneumonitis.
· Pneumonia due to PJP.
Management plan:
1. Supportive measures; full hydration, good nutrition and anti-pyretic.
2. General investigations: CBC, RFT, LFT, CRP, RBG, Urinalysis and LDH.
3. Screening for TB:
· sputum microscopy and culture for AAFB.
· Rapid molecular test(the Xpert MTB/RIF assay) is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively(1).
4. Screening tests for CMV(CMV IgG & IgM) and PJP.
5. Treatment of the causative agent; in case of active TB infection(2):
a) The optimal period of treatment could vary from 6 to 24 months. Recommended to be at least 9–12 months.
b) According to AST-IDCOP, the first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases.
c) The standard regimen is similar to that used for the general population and consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin.
d) Adjustment of immunosuppression as Rifampicin reduces the level of CNIs and mTORi:
· the dose of CNIs and mTORi should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
Would your management differ if the disease was mild and affected one lung?
· The treatment will differ only in the duration of therapy from 6 -24 months. In case of mild disease 6-9 months may be adequate. Not less than 6 months.
· According to AST-IDCOP, the first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases(2).
References
1. 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.
2. 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.
How do you manage this case?
the indexed case of an immunocompromised patient after kidney transplantation from his brother with a history of fever around 1 year after transplantation with wt loss, night sweat, and CXR on the RT side showed bilateral diffuse reticular nodular shadows with an endotracheal tube( tracheostomized patient ), which indicate the possibility of active TB and probably MDR – resistant MBT complicated by miliary TB as the radiological images including CT chest highly suggestive of miliary TB, we need to ask more history about the previous exposure or previously treated on the line of active pulmonary TB or LTBI and reactivation after transplantation which is the commonest source of infection, also need to ask about recent contact or travel to an endemic area or his originally might be from an endemic area. Did he receive anti-TB treatment and now with complications my concern about MDR – MBT with superadded invasive infections like fungal infection, CMV, aspergillosis
histoplasmosis Diagnosis of MDR -MBT
Genotypic (or molecular) methods have revolutionized the diagnosis of MDR-TB. These methods generally use polymerase chain reaction techniques to detect the genetic mutations that are known to confer resistance to drugs in his case will get tracheal aspiration for gene expert, molecular methods will be better than culture, as will get the results faster, and cultures need to wait for weeks, also direct staining for from tracheal aspirate for Acid fast bacilli but the sensitivity low, bronchoscopy, and BAL assay, a positive molecular test for rifampicin resistance can be considered diagnostic for MDR-TB because, in most countries, greater than 90% of rifampicin-resistant strains are also resistant to isoniazid.
This patient should be in negative pressure room isolation, get ID consultation and consider second-line anti-TB to cover for possible MDR – resistant TB Patients who are infected with strains resistant to isoniazid and rifampicin, called multidrug-resistant (MDR) TB, are practically incurable by standard first-line treatment. And carry a high mortality rate, with increased frequency in endemic areas of up to 20% and even more in those with a previous history of TB of up to 50%.
Would your management differ if the disease was mild and affected one lung?
For patients with drug-susceptible TB, standard treatment based on isoniazid and rifampicin, the two most powerful drugs, results in excellent cure rates but need frequent monitoring for hepatotoxicity and drug interaction with CNI including, cyclosporine, tacrolimus everolimus, sirolimus, rifampicin is an enzyme inducer induction of cytochrome 450, cyp3A4, and can significantly reduce the level even to undetectable level and need dose adjustment by 3-5 folds and frequent drug monitoring to avoid the risk of rejection vs drug toxicity References
1.Seung KJ, Keshavjee S, Rich ML. Multidrug-Resistant Tuberculosis and Extensively Drug-Resistant Tuberculosis. Cold Spring Harb Perspect Med. 2015 Apr 27;5(9):a017863.
the main challenge in post-transplantation TB is the late diagnosis due to atypical and nonspecific findings, I have two cases of laryngeal TB after kidney transplantation one in Iraq just a few months after transplantation with hoarseness of the voice, and another Omani female patient two years back presented to us with 8 months history of fever of unknown origin with wt loss and also hoarseness of the voice later on complicated by stridor ( 12 years after commercial TX in Pakistan ), she underwent extensive work up in the regional hospital then referred for expert opinion during her admission she had a respiratory arrest, intubated and again tracheal aspirate was positive for MBT and improved with anti-TB medications.
Thankyou for the exellent answer.
Thankyou for sharing your cases, the Omani lady after 12 years this is probably a new infection as it is too late for activation of a latent one.
Post transplant patient with night fever, cough, and dyspnea having Ct chest finding of bilateral reticulonodular lesions is consistent with miliary TB. But other DD could be
CMV pnemonitis
PTLD
Pneumocystis pneumonia
Other bacterial, Fungul, and opportunistic pneumonia.
For confirmation of Milliary TB
Previous history of TB disease, contact with TB patient or travel to endemic area would be important but not necessary. Detail examination to look for sign and symptoms of extrapulmonary TB.
Sputum C&S with Z-N stain to detect acid fast bacilli.
Sputum C&S for Bacterial, fungal, PCP
Gene Xpert of sputum or BAL for TB
Bronchoscopy, BAL and PCR for PCP
CMV PCR.
CBC, LDH, ESR, CRP
Treament options
Start anti TB protocol with
– Rifampicin for 9 months
– INH for 9 months
– Ethunamide for 9 months
– Pyrazinamide for 2 months
Duration of treatment: Several protocols are available including treatment from 9 months up to 18 months.
As Rifampicin is P450 cytochrome inducer leading to reduction in CNI levels therefore if 4 drugs mentioned above are to be used, we have to closely monitor CNI levels and upscaling of CNI would be required.
If Rifampicin is to be avoided to maintain the CNI in study stat, we have to give.
INH for18 months
Ethambutol for 18 months
Pyrazinamide for 3 months
Levofloxacin for 6 months
Close Monitoring of graft function during this therapy is recommended. Adverse effects of TB therapy:
1. Hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol)
2. Neurotoxicity (isoniazid, ethambutol)
3. Cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol)
4. Visual disturbances (rifabutin, ethambutol)
5. Skin lesions (rifampicin)
6. Hyperuricemia (pyrazinamide)
7. Interstitial nephritis (rifampicin, pyrazinamide)
Would your management differ if the disease was mild and affected one lung?
o ESCMID guidelines treatment: in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid (the 2-month intensive phase contains isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide)
o Rifabutin, a rifamycin with weaker inducer of cytochrome P450 3A4 and P-glycoprotein, is an alternative for rifampin (as effective as rifampin for the treatment of TB in trials conducted in non-transplant patients). Immunosuppression doses could be modified, and levels should be closely monitored.
o Another safe and effective alternative to rifampicin is treatment with fluoroquinolones
References
1- Bednarova K, Slatinska J, Fabian O, Wohl P, Kopecka E, Viklicky O. Tuberculosis dissemination in kidney transplant recipient treated with anti-CD40 monoclonal antibody: a case report. BMC Nephrol. 2022 Aug 19;23(1):290.
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 Feb;102(2S Suppl 2):S60-S65.
3- Machuca I, Vidal E, de la Torre-Cisneros J, Rivero-Román A. Tuberculosis in immunosuppressed patients. Enferm Infecc Microbiol Clin (Engl Ed). 2018 Jun-Jul;36(6):366-374. English, Spanish.
Starting TB treatment is challeninging without confirmatory diagnosis , but once suspected tretment should be started immediately .
According to AST-IDCOP, the first-line treatment should be a four-drug regimen containing rifambycin used both in severe and non-severe cases.
2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin .
If a regimen without rifambycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide .
AST-IDCOP guidelines recommends that in case of active uncomplicated pul- monary TB, treatment duration should be at least 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treat- ment may be extended to 9 month .
In case of severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months .
Patients with central nervous system involvement should be treated for at least 9–12 months.
Immunosuuprsion medication like tac,cyclosporine should be incresed by 2-5 fold during treatment with rifambycin as its apotent enzyme inducer to cytochrome 450 so levels may be too low , so monitoring should be regulary checked .and after stoppage of tretment by 2 weeks
also steroid dose should be doubled to the same reason.
regular checking of liver panel every two weeks due to hepatotoxic side eeffcts of anti TB drugs .
Symptoms of night fever, productive cough, and weight loss and radiological features in a post-transplant period is highly suggestive of pulmonary TB (other co-infection should be considered)
Chest x ray showed: bilateral hilar shadows and bilateral reticulnodular shadows of both lungs CT chest showed: bilateral reticulonodular shadows with well-defined scattered small nodules (military TB) with possible cavitatory lesions
Active Tuberculosis: usually occurs in the first year after KT (a median time of 11.5 months) in the case of reactivation (the most common cause) and earlier in the case of donor-derived infection (in the first 3 months). Diagnosis is by detection of M. tuberculosis bacilli by direct observation, culture, and NAT
Screening of active TB and other extra-pulmonary TB History of previous TB infection,contact with active TB patient, travel to area with high endemic of TB, prophylaxis and vaccination, and donor LTBI
Symptoms: Chronic cough, weight loss, night sweats, and anorexia. Symptoms of extrapulmonry involvement (urinary, neurological and others)
Clinical examination: full examination of the chest, examine for lymph nodes, and exclude other extra pulmonary TB
Investigations: CBC, CRP, RFT, LFT, sputum microscopy for AFB and culture, molecular tests based on rapid nucleic acid amplification techniques, lymph nodes aspiration and urinary tract where indicated
Imaging:Chest x ray/CT chest, renal ultrasound, spinal MRI and CT/MRI brain where indicated
TST and IGRA are not useful in the diagnosis of active TB
Treatment of pulmonary TB (at least 9–12 months) AST-IDCOP guidelines recommend:
1. Active uncomplicated pulmonary TB (treatment duration should be at least 6 months)
2. if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy (9 months)
3. Severe disseminated disease or bone and joint disease (at least 6–9 months)
4. CNS involvement (at least 9–12 months)
AST-IDCOP guidelines treatment:
First-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases (2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by isoniazid and rifampicin)
Rifampicin-immunosuppression interaction:
o Rifampicin and transplant-associated immunosuppression interaction
o Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein
o Rifampicin decrease the levels of CNIs, mTOR inhibitors, and affects glucocorticoids
o CNIs and mTOR inhibitors levels should be closely monitored during rifampicin-based regimen
o The dose of CNIs and mTOR inhibitor should be increased between 3-5 folds and the glucocorticoid dose should be doubled during treatment
Adverse effects of TB therapy:
The most common adverse event is hepatotoxicity (liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter)
1. Hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol)
2. Neurotoxicity (isoniazid, ethambutol)
3. Cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol)
4. Visual disturbances (rifabutin, ethambutol)
5. Skin lesions (rifampicin)
6. Hyperuricemia (pyrazinamide)
7. Interstitial nephritis (rifampicin, pyrazinamide)
Severe TB or when a vital organ is involved:
Reduce immunosuppression (risk of immune reconstitution inflammatory syndrome, which is associated with the reduction of immunosuppression and the use of rifampicin)
Would your management differ if the disease was mild and affected one lung?
o ESCMID guidelines treatment: in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid (the 2-month intensive phase contains isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid ande thambutol or pyrazinamide)
o Rifabutin, a rifamycin with weaker inducer of cytochrome P450 3A4 and P-glycoprotein, is an alternative for rifampin (as effective as rifampin for the treatment of TB in trials conducted in non-transplant patients). Immunosuppression doses could be modified, and levels should be closely monitored
o Another safe and effective alternative to rifampicin is treatment with fluoroquinolones
References
1. Sorohan, B.M.; Ismail, G.; Tacu, D.; Obris ,ca˘, B.; Ciolan, G.; Gîngu, C.; Sinescu, I.; Baston, C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens 2022, 11, 1041. https://doi.org/10.3390/ pathogens11091041
2. 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.
The CXR shows multiple small nodules characteristic of miliary TB. His symptoms of night fevers, productive cough and weight loss are characteristic of TB. He is post-transplant and studies have shown that patients post-transplant have a higher risk of developing compared to the general population
The differential diagnosis is:
Fungal infections – especially endemic mycosis like histoplasmosis
Bacterial pneumonia
Bronchoalveolar carcinoma
Sarcoidosis
Viral pneumonitis – less likely as it does not have a miliary picture
Management of the case:
He will need further investigations:
Sputum for AAFBs and Gen xpert
BAL for cytology, AAFBs and gen xpert (to assess for rifampicin resistance)
CBC
ESR
LFTs – Its important to get baseline LFTs as the antiTBs have been known to cause drug induced liver injury (DILI)
Tacrolimus levels – There is significant drug to drug interaction with rifampin and the CNIs and mTOR inhibitors
Treatment:
Once the diagnosis is confirmed, he will need to be started on rifafor (Isoniazid, rifampin, pyrazinamide and ethambutol) with pyridoxine. The rifafor dose is weight based
The dose of the CNI will need to be monitored very closely as the rifampin will increase the metabolism of tacrolimus reducing the levels. In most cases, the dose tacrolimus is doubled to achieve the appropriate trough concentrations.
The patient will also need to be informed that his body secretions will change color – due to the antiTBs
His liver function need to be monitored
After 2 months and appropriate clinical response, the patient gets the continuation phase of the Tb regimen – isoniazid and rifampicin for four months
The management is the same even if only one lung was affected. The therapy will be:
Intensive phase for 2 months and continuation phase for four months
The CXR and CT: bilateral fine nodular opacities, which is typical of millet. In addition there is rounded perihilar shadowing (LNs)
Based on the presence of fever, night sweats, occurring in renal transplant recipient 1 year post transplantation, miliary TB is highly suggestive.
Other differential diagnoses to be considered
Viral pneumonias especially HZV and CMV Fungal pneumonias, histoplasmosis Bronchoalveolar carcinomaLymphangitic carcinomatosisHistory:
In the recipient: DM, LTBI, past history of active TB or contact with a patient with active TB and history of travel to an endemic area and duration of stay.In the donor: history of untreated and latent TB.Type of IS treatment, any AR.Examination
· Looking for lymph nodes elsewhere, or primary malignancy
Laboratory
CBC, ESR, CRPRFT, LFT Exclude other differential by PCR for HVZ , CMV in respiratory samplesFor fungal staining, PCR and cultures in respiratory samples and serology. Sputum for AFB by stain and send for culture and drug sensitivityRespiratory samples also tested for cytology BAL samples may be needed if sputum is not yielding The rapid molecular testing, Xpert MTB/RIF assay, this test is highly specific.Treatment
· For active TB, the recommendation is to follow the local guide lines for the general population.
4-drug regimen is recommended in most cases INH and rifampicin are the first-line drugs against TB.
Rifampicin leads to a reduction in the blood levels ta crolimus, cyclosporine, sirolimus, everolimus, and corticosteroids. A lower blood level of these drugs is associated with higher risk of graft rejection. Rifabutin, which has a weaker enzyme induction is an alternative for rifampin. It has been demonstrated to be as effective as rifampin for the treatment of TB in non-transplant patients. When rifabutin is used, drug monitoring of immunosuppressive is also indicated as for rifampicine Looking for side effects of anti tuberculous medications, importantly is hepatic toxicity, peripheral neuropathy( pyridoxine is given with INH) and ethambutol optic neuropathy The optimal length of treatment of disseminated TB as in this index case treatment duration should be at least 9 months. The response to treatment should be followed closely and treatment should be shared with an expert in management of TB. How would the treatment differ if it is a milder form:
May use a riampicine free regimen if there is no local INH resistance. The regimen should be longer than 6 month. Always we should involve experts who are familiar with the local guidelines and drug resistancebof TBI.
1-How do you manage this case? Regarding clinical approach of this case; -CXR—–showed bilateral reticulonodular shadows with perihilar infiltrate and opacities represent mediastinal LNs. -HRCT—showed numerous small sized nodules distributed throughout both lungs, (most likely military TB). For confirmation Diagnosis; –The diagnosis of TB requires a high index of suspicion based on the epidemiological risk, personal history, manifestations and imagistic lesions,
-Molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test (Xpert® MTB/RIF) could provide false negative results when mycobacterial load is low, –Tuberculin skin test (TST) and interferongamma release assay (IGRA) are not useful in the diagnosis of active TB. -Probability of association with other co-infections, so further investigations r/o other fungal or viral infections (CMV-EBV-HIV). My Impression; (Active pulmonary TB ; most probably 2ry to reactivation of LTBI in recipient). Treatment; –Patients should be isolated until he is improving clinically, or after 3 consecutive negative sputum smear results (guided by I.C. recommendation)
-The treatment of active TB should be promptly started immediately after the diagnosis has been established.
-The epidemiological features from the area of patient’s origin and drug resistance patterns should be assessed. –The optimal period of treatment could vary from 6 to 24 months and, in some cases, based on experts’ opinion, the duration of treatment is recommended to be at least 9–12 months. (AST-IDCOP) guidelines:
-The first-line treatment should be a four-drug regimen containing rifamycin.
-Intensive phase (for 2 months) of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by;
-Continuation phase (for 4 months) of isoniazid and rifampicin,
-Recommends that in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months,
-But if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months. (ESCMID) guidelines:
-Suggests a standard regimen used for a period longer than 6 months, and, in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present. If a regimen without rifamycin is used,
-Intensive phase (for 2 months) of isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by,
-Continuation phase (12–18 months) with isoniazid and ethambutol or pyrazinamide. Challenges in the treatment of KT recipients with active TB:
1-Drug interaction between rifampicin and transplant-associated immunosuppression.
-An alternative to rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy , another safe and effective alternative to rifampicin in KT recipients is treatment with fluoroquinolones.
-Rifampicin usage decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection.
-When a rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin and mTOR inhibitor should be increased between 3-5 fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
-After the rifampicin is stopped, the immunosuppression doses should be reduced to the value before the start of rifampicin and then adjusted to obtain the therapeutic target.
2-Patients treated with anti-TB drugs should be closely monitored for hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol), neurotoxicity (isoniazid, ethambutol), cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol), visual disturbances (rifabutin, ethambutol), skin lesions (rifampicin), hyperuricemia (pyrazinamide) or interstitial nephritis (rifampicin, pyrazinamide). During Treatment protocol of TB;
-Closely monitoring liver enzymes with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter ; as the most common adverse event associated with anti-TB therapy is hepatotoxicity.
-Creatinine clearance and adjust the doses for pyrazinamide and ethambutol.
-Reduction of immunosuppression in the case of severe TB should be considered. Screening for donor; -His brother should be screened for latent TB infection if it has not been done prior to KT ; using (TST/IGRA). –Recognizing latent infection or undiagnosed active TB in the kidney donors is critical in preventing post-transplant infection. –A careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors. –Current guidelines provide recommendations for latent TB screening in all KT candidates and donors before transplantation. 2-Would your management differ if the disease was mild and affected one lung? -The same treatment if no proven drug resistance , but the duration may be different;
-According to AST-IDCOP, the first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases.
-Rifamycin is recommended for its sterilization capacity and efficiency but also to reduce the risk of resistance.
-(AST-IDCOP) guidelines recommends that in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months. –Severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months.
-Patients with central nervous system involvement should be treated for at least 9–12 months. References; –Morris, M.I.; Daly, J.S.; Blumberg, E.; Kumar, D.; Sester, M.; Schluger, N.; Kim, S.-H.; Schwartz, B.S.; Ison, M.G.; Humar, A.; et al. Diagnosis and Management of Tuberculosis in Transplant Donors: A Donor-Derived Infections Consensus Conference Report. Am. J. Transplant. 2012, 12, 2288–2300. –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.
Thankyou for an exellent review but please note:
The picture is very suggestive of miliary TB which is usually not open so depending on sputum culture is not always helpful, but all other criteria are useful to take the decision.
If that shown lesion is unilateral then it is difficult to categorise it as miliary and other pathologies should be excluded.
Well done.
Active TB usually appears in the first year after KT, at a median time of 11.5months in the case of reactivation after latent infection and earlier in the case of donor derived infection (in the first 3months
The diagnosis of Pulmonary TB relies on the detection of M. tuberculosis bacilli by direct observation, by culture and nucleic acid testing.
A-Confirm the diagnosis. – Thorough historyincluding; contact with active TB, previous history of TB and TB treatment, being in endemic areas, previous TST result.
– Full examination to rule out extrapulmonary TB.
Work up:
– CBC, ESR, CRP.
– Kidney function and LFT.
– Drug levels.
– Sputum for AFB smear, Culture and drug sensitivity ( it will take long time and decision need to be taken rapidly).
– BAL may be required it will increase the yield of diagnosis.
– Rapid molecular test (Xpert MTB/RIF assay): It is highly specific and sensitivity and allows detection of rifampicin resistance, which is highly predictive of MDR-TB.
-Exclude fungal infection cultures, staining and PCR.
– Viral screening; EBV, CMV, VZV and HIV.
– Neither TST nor IGRAs are recommended for diagnosing active infection as both test may be falsely negative in immunocompromised patients and in active TB, as these test assess the immune response of the body to MTB.
Treatment of Active TB:
– Treatment depend on epidemiological data and the pattern of local resistance.
– The recommendations for 1st line therapy in the transplant patient are the same as for the immunocompetent host.
Intensive phase (2 months) First line 4‐drug regimen; of isoniazid, rifampin (or rifabutin) pyrazinamide, and ethambutol Continuation phase: isoniazid and rifampin alone for an additional 4 months
-Ethambutol can be discontinued once susceptibility to isoniazid, rifampin, and pyrazinamide is confirmed.
-Moxifloxacin and levofloxacin; currently listed as second‐line agents for active TB treatment – Rifamycin‐containing regimen is strongly preferred due to sterilizing activity. It is enzyme inducer metabolize most IS drugs.
– Rifabutin if available can replace rifampin as it has similar activity against but is a much less potent enzyme inducer, which make IS easier to maintain
-If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.
– INH should be co-administered with pyridoxine Treatment duration
– Treatment durations of active TB after SOT reported in the literature range between 6 and 24 months.
– Longer durations considered if the response to treatment is slow, if second‐line drug replacements are used or if there is resistance to rifampin ± other drugs. AST-IDCOP recommendation:
– Uncomplicated pulmonary TB is at least 6 months.
– But longer course (9 months)for cavitary disease or disease with persistent sputum culture‐positive status after 2 months of therapy
– Bone and joint disease (6‐9 months), CNS (9‐12 months), and severe disseminated disease (6‐9 months)
Immunosuppression management:
– In sever TB , vital organ involved, fatal infection not responded to treatment, we may reduce IS, reduce antimetabolite by 50 % or can be stopped completely.
– Rifampicin usage decrease the levels of CNI, mTORi and affects glucocorticoids metabolization, which increases the risk of rejection
– Increase CNI by 3-5 fold, monitored by the level.
– Double the dose of glucocorticoid dose. Monitor:
– Immunosuppressant levels must be closely monitored closely at the start and end of rifamycin therapy SOT.
– IS should be adjusted during and after completion of therapy.
– Graft function as there is a risk of rejection
– Hepatotoxicity serious side effect, therfore monitor LFT regularly and more frequently.
– Treatment adherence; DOT programs are recommended for transplant recipients.
– Screen household contact for LTBI.
Would your management differ if the disease was mild and affected one lung?
-Treatment should be guided by drug susceptibility.
– AST-IDCOP and ESCMID suggests a standard regimen used for a period longer than 6 months, and, in cases of localized non-severe TB.
– Regimen without rifampicin could be used if no resistance to isoniazid is present. Options include:
-INH and ethambutol and pyrazinamide or levofloxacin are used for 2 months, followed by INH and either ethambutol or pyrazinamide for 12 to 18 months –INH and ethambutol and pyrazinamide or levofloxacin are used for 12 months.
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.
Well done Dr Hadeel Badawi. Points of excellence:
1- Radiological description of lesions
2-Difference between Rifampicin and Rifabutin
3-The need to start treatment pending results of investigation which can take longer time
You referred to hepatotoxicity but did not refer to potential side effects of other anti TB medications other than Rifampicin. Clearly this patient requires counselling. One of the important piece of information from history is his donor history of TB.
From this radiological findings, do you think this patient is at high risk of any other organ involvement and what haemodynamic complication would be?
donor source of TB more in DD as usually living donor will be thoroughly investigated including IGRA test for latent TB infection as part of the protocol for screening the donor and recipient, in addition, if his brother the source it would be present earlier with the introduction of IS, i think in history here we should focus on recipient previous history of TB or LTBI and previous treatment of TB and now presented with MDT complicated course
Other side effects definitely need to be monitored and patient should counselled in this regards.
S/E includes:
-Hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol).
-Neurotoxicity (isoniazid, ethambutol), cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol)
-Visual disturbances (rifabutin, ethambutol).
-Skin lesions (rifampicin).
-Hyperuricemia (pyrazinamide) or interstitial nephritis (rifampicin, pyrazinamide)
The most common sites of involvement include lungs (>50%) the lymphatic system, bones and joints, liver, CNS (15-20%) , and adrenal glands (1% reported cases, however, 40 % in autopsies).
Hemodynamic complications:
– Multiorgan system failure.
– ARDS
– Adrenal insufficiency ( crises with hypotension and shock)
– Syndrome of septic shock
References:
– Ahuja SS, Ahuja SK, Phelps KR, Thelmo W, Hill AR. Hemodynamic confirmation of septic shock in disseminated tuberculosis. Crit Care Med. 1992 Jun;20(6):901-3. doi: 10.1097/00003246-199206000-00031. PMID: 1597048.
How do you manage this case?Through history and examination to exclude extrapulmonary TB (blood pressure, meningeal sign, encephalopathy.
Relevant history- prior history of TB, history of TB in donor pre and post donation, BCG vaccination
Care Airway Breathing and circulation (some time present with adrenal insufficiency)
O2 inhalation, protect airways, care of blood pressure.
Investigation
Sputum AFB1, AFB 2, (Z-N staining), C&S(BACTEC or L and J)
PCR for MTB in sputum or blood
Xene expert in drug resistant area
Montoux test
if sign of meningeal irritation- CSF( tlc, dlc, sugar, protein,ldh, ADA, pcr, cob web on standing)
serum cortisol if hypoglycemia, hypotension
LFT- disseminated TB or base line LFT before starting treatment.
uric acid-before starting treatment can in BY pyrazinamide.
Duration of treatment : 9 month if brain involvement 9-12 month
Adjuvant- steroid, pyridoxine in high acetylation population
Monitoring for adverse drug effects such as hepatotoxicity, peripheral neuropathy (INH), optic atrophy (ethambutol), monitor graft function.
Immunosuppressive agents
Tacrolimus- need to increase the dose to (3-5 fold) and monitor trough level after starting and after stopping (interaction with rifampicin and INH)
MMF- though AUC is changed in withdrawal of rifampicin dose is not change in clinical practice but can be hold till sputum comes negative till 2 to 4 weeks
increase dose of steroid if in chronic use-
Screening of donor with IGRA- to rule out latent tuberculosis if he had not manifested the disease.
Would you manage differ if the disease was mild and affected one lung?
Duration of treatment – 6 months-short
Can use less interaction drugs – HZE with or without fluroquinolone in intensive phase and continuation phase HE (18 month) or HE plus z or levofloxacin for 12 months
z (pyrazinamide) H isoniazid E ethambutol
Reference
José María Aguado, Julián Torre-Cisneros, Jesús Fortún, Natividad Benito, Yolanda Meije, Antonio Doblas, Patricia Muñoz, David R. Snydman, Tuberculosis in Solid-Organ Transplant Recipients: Consensus Statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology, Clinical Infectious Diseases, Volume 48, Issue 9, 1 May 2009, Pages 1276–1284, https://doi.org/10.1086/597590
Annapandian VM, Fleming DH, Mathew BS, John GT. Mycophenolic acid area under the curve recovery time following rifampicin withdrawal. Indian J Nephrol. 2010 Jan;20(1):51-3. doi: 10.4103/0971-4065.62091. PMID: 20535273; PMCID: PMC2878413.
Thank you for comprehensive answer. You referred to Relevant history- prior history of TB, history of TB in donor pre and post donation, BCG vaccination. This piece of information is vital but what did you mean history of TB pre and post donation? I understand pre and what about post?
You mentioned care airway in many occasions do you suspect this patient will suffer from airway obstruction?
You referred to ‘Can use less interaction drugs – HZE with or without fluroquinolone in intensive phase’
I’m not clear about less interaction drugs? Do you think INH would be enough with short course in a case similar to this?
Thank you for the question, sir and suggestion –
1)If the donor had TB post donation – we can think he might have latent tb in him before donation.
2) Taking care of airway- i mean to say patient need to be well oxygenated, if spo2 is low need to supplement. (Will take care next time sir will try to write so that it will be easily understandable.)
3)INH only will not be enough but to use this drug with combination with other drug like pyrazinamide, ethambutol, moxifloxacin, levofloxacin, linezolid which are less interacting than rifampicin with tacrolimus.
How do you manage this case? Pulmonary tuberculosis is the most likely diagnosis in this case based on the following:
Time since transplant: over 2/3rd reported cases of active tuberculosis in transplant recipients present within the first year, with median time between 6 to 11 months. (1,2) Signs/symptoms: Night fever, productive cough, and weight loss CXR and CT chest: Bilateral, diffuse involvement of lungs. CT film suggestive of tree in bud appearance
Confirmation of diagnosis:
High index of suspicion
Careful history taking:
Previous exposure to individuals with active TB in household or workplace.
Prior residence or travel to high endemic areas.
Prior history of active TB, duration, and treatment type
Confirmation on expectorated sputum:
ZN staining for acid fast bacilli.
NAAT (Xpert MTB/RIF): increase the sensitivity and decrease the time to diagnosis.
TB culture
Treatment (3):
First-line treatment for active tuberculosis: same as for immunocompetent hosts
Intensive Phase (First 2 months): four-drug regimen of isoniazid, rifampin (or rifabutin), pyrazinamide, and ethambutol
Continuation phase (additional 4 months): isoniazid and rifampin alone
Second Line agents:
Fluoroquinolones including moxifloxacin and levofloxacin, for those
who have hepatotoxicity on standard TB therapy or
who have poor liver function.
Daily administration of active TB therapy
Recommended
Reduce the risk of relapse in comparison to twice or thrice weekly administration.
Longer therapy in cases of:
Cavitary disease
Disease with persistent sputum culture-positive status after 2 months of therapy
If the response to treatment is slow
If second line drug replacements are used
If there is resistance to rifampin ± other drugs.
DOT program
Recommended for transplant recipients.
Pyridoxine
to be added
Main Challenges in treating TB in post-transplant:
Potential of anti TB drugs hepatotoxicity
Major drug-drug interaction with rifampin and immunosuppressive medications
Rifampin is a potent inducer of the microsomal enzymes (CYP450 3A4)
Effect metabolism of calcineurin inhibitors, mTOR inhibitors and may also interfere with corticosteroid metabolism.
Despite this, rifamycin containing regimen is strongly preferred due to the potent MTB sterilizing activity of this drug class.
Overcoming challenges with Anti TB drugs in post-transplant period
Doses of cyclosporine, tacrolimus, and sirolimus will have to be increased at least two to fivefold. (4)
Can replace rifampin with rifabutin (5)
activity against MTB is similar to rifampin,
much less potent inducer of CYP450 3A4,
immunosuppressant levels are typically easier to maintain.
experience is limited as rifabutin is generally not available in parts of the world in which TB is more common.(2)
With either rifampin or rifabutin, immunosuppressant levels must be closely monitored at the start and end of rifamycin therapy.
Would your management differ if the disease was mild and affected one lung?
I would like to treat it in similar fashion as mentioned above
References:
Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clin Infect Dis. 1998;27(5):1266-1277.
Lopez de Castilla D, Schluger NW. Tuberculosis following solid organ transplantation. Transpl Infect Dis. 2010;12(2):106-112.
Subramanian AK, Theodoropoulos NM, Infectious Diseases Community of Practice of the American Society of T. 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(9): e13513.
Lewinsohn DM, Leonard MK, LoBue PA, et al. 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;6 4(2):111-115
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;12(9):2288-2300.
McGregor MM, Olliaro P, Wolmarans L, et al. Efficacy and safety of rifabutin in the treatment of patients with newly diagnosed pulmonary tuberculosis. Am J Respir Crit Care Med. 1996;154(5):1462-1467.
postrenal transplant recipient presents with productive cough, night fever, and weight loss.CTscan and CXR showed a bilateral reticulonodular shadow all this picture goes with miliary pulmonary T.B at the top of the list of our differential diagnosis so other possibilities:
Drug-induced pneumonitis, CMV pneumonitis, and aspergillosis.
investigation search for the cause of sputum for Acid fast bacilli(z-n stain),gamma interferon and PCR for mycobactruim T.B
send sputum for bacterial and fungal culture
CBC and differential,ESR,C RP
other lab such as KFT,LFT ,Drug level and PCR for CMV
VBG if the patient has respiratory failure
investigation to exclude other organ involvement as milliary T.B is hematogenous spread such as :
CTscan of the head,abdominal U/S, and CT scan for adrenal gland(cortisol level )
vital signs if patient has a shock or maintains Bp,po2 , RR, and PR and according to vital signs need isolation ward or ICU
The T.B treatment regimen depends on local resistance and epidemiology of the individualized patients.
in such cases as the disease is severe and multilobular disseminated disease experts agree that rifampcin is indicated in the regimen of the treatment although is an enzyme inducer so reduces the level of TAC and also can cause rejection.
Rifampcin also reduces level of glucocorticoids although this has been less well characterized.
when use Rifampcin we should have to increase the dose of TAC 3 to 5fold and conc should be monitored carefully.
RIfubtin is an alternative to rifampicin as is a weaker enzyme inducer but less experience in the treatment of T.B transplant recipients
Rifampcin regimen therapy duration of therapy in sever cases and immunocompromized is for total 9 month but non -a rifampicin regimen should be 12 to 18 months
first 2 month of therapy Rifampicin, INH, ethambutol, and pyrazinamide
the remaining months 2 therapy INH and Rifampcin
the role of corticosteroid in management of miliary T.B has limited data .
Would your management differ if the disease was mild and affected one lung?
the American society of transplantation guidelines 2019 based on randomized trials for the treatment of active Transplant recipients based on large randomized trials in immunocompromised hosts use non -rifampicin in less severe and localized diseases including INH plus ethambutol plus either pyrazinamide or levo floxacin for 2 months followed two-drug regimen of INH plus ethambutol or pyrazinamide for 12 to 18month
This kidney recipient presented with night fever, cough, dyspnea and both CXR and Ct chest show diffuse bilateral reticulonodularv lesions , He mostly have pulmaonary TB.
Other DD
1- PTLD
2- PJP pneumonia
3- CMV pneumonitis
4- Drug induced pneumonitis , if he was treated with m TOR.
5- Other bacterial and opportunistic pneumonia.
I- To confirm diagnosis of TB
1- History : previous TB disease , vaccination , contact with TB patient or travel to endemic area.
2- Thourou history and examination to exclude extrapulmonary TB .
3- Sputum C&S with Z-N stain to detect acid fast bacilli .
4- PCR for TB in sputum or blood .
5- Investigation for other causes as PJP with bronchoscopy ,BAL and PCR
6- CMV PCR .
II- Treament
A- IS drugs modification : stop antiproliferative drugs and increase steroid dose.
B- Start anti TB protocol :with
– Rifampicin
– INH
– Ethunamide
– Pyrazinamide
– Duration of treatment : Several protocols with variablr durations exist ,but its better to continue treatment for 9 months to prevent relapase.
– Monitoring for adverse drug effects such as hepatotoxicity ,specially during first 2 months of therapy ,it should be biweekly.
C- Monitoring of IS trough level closely due to drug-drug interaction between IS and antiTB drugs specially rifambicin which is a strong enzyme inducer or replace with rifaximin
D- Monitoring of graft function. Would you manage differently if it was localized to one lung:
– The Spanish Society of Infectious Diseases and Clinical Microbiology recommend For treatment of localized , non severe TB infection and with out evidence of INR resistance to initiate treatment with (INH, ethambutol and pyrazinamide or levofloxacina and avoid the use of rifamycins to avoid their interaction with IS (AII).
– For maintainance : either 12-18months of two drugs (INH and ethambutol or pyrazinamide) orshorter duration of 12 months using three drugs (INH+ either ethambutol or pyrazinamide + levofloxacin (CIII).
Ref
1- Bednarova K, Slatinska J, Fabian O, Wohl P, Kopecka E, Viklicky O. Tuberculosis dissemination in kidney transplant recipient treated with anti-CD40 monoclonal antibody: a case report. BMC Nephrol. 2022 Aug 19;23(1):290.
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 Feb;102(2S Suppl 2):S60-S65.
3- Machuca I, Vidal E, de la Torre-Cisneros J, Rivero-Román A. Tuberculosis in immunosuppressed patients. Enferm Infecc Microbiol Clin (Engl Ed). 2018 Jun-Jul;36(6):366-374. English, Spanish.
-A case of Miliary TB after possible reactivation of LTBI
The patient need to be evaluated precisely taking medical history and clinically assessed regarding his oxygen saturation and his general status to decide if he will need ICU admission for close monitoring of his vitals and respiratory status as he can need oxygen supply as well as isolation in negative pressure room. Investigations
AFB smear testing from sputum samples as well as sputum and blood culture for TB
Xpert® MTB/RIF for Rifampicin resistance testing can be done soon too
Along with other basic labs CBC, LFT,KFT ,eGFR to evaluate the graft status
Pan CT is needed to detect the disseminated TB in different organs Treatment
Quadruple therapy need to be started soon in the forum of INH with pyridoxine ,Rifampicin, pyrazinamide and ethambutol for 2 months then INH with pyridoxine and rifampicin for 4 months in fact therapy can be extended with severe disseminated TB, to 9 month or longer duration of treatment may be preferred with response to AntiTB therapy ,Risk of recurrence is lower with extending therapy after 12 months
Bone and joint disease and severe disseminated disease are treated for a total of 6-9 months. Central nervous system disease involvement necessitate treatment duration of 9-12 months
With monitoring of liver function tests / 2weeks if stable very 6 weeks then on further bases Baseline and monthly visual acuity and red-green discrimination testing should be done with ethambutol use.
European guidelines recommend sputum smear and culture at least at two months and four months of treatment, at the end of therapy and on two further occasions until the end of 12 months. Extra-pulmonary TB is followed clinically.
Immunosuppressive drug levels need close monitoring as rifampicin is an enzyme inducer also drug interaction monitoring with other Anti TB has to be done
Also his brother the donor has to undergo investigation for LTBI as TST or IGRA and to start therapy if needed.
-Treatment regimens for milder cases is the same quadruple therapy but duration of therapy can be 6 months instead of longer durations indicated in severe diseases with extrapulmonary involvement.
Reference
-Bumbacea D, Arend SM, Eyuboglu F, Fishman JA, Goletti D, Ison MG, Jones CE, Kampmann B, Kotton CN, Lange C, et al. The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement. Eur Respir J. 2012;40:990–1013.
– Anand M, Nayyar E, Concepcion B, Salani M, Schaefer H. Tuberculosis in kidney transplant recipients: A case series. World J Transplant. 2017;7(3):213-221. doi:10.5500/wjt.v7.i3.213
GeneXpert is highly specific 100% and 84% sensitive
Reference Saeed M, Ahmad M, Iram S, Riaz S, Akhtar M, Aslam M. GeneXpert technology. A breakthrough for the diagnosis of tuberculous pericarditis and pleuritis in less than 2 hours. Saudi Med J. 2017;38(7):699-705.
Management of the case This a case of LTBI reactiation after kidney transplantation The picture show active pulmonary TB Investiigation should include;
Clinical suspicion should take place in diagnosing post-transplant TB as it presents with an atypical manifestation and extrapulmonary disease.
Diagnosis based on culture, clinical suspicion, and fever of unknown cause, fever persistent after a proper antibiotic protocol.
Rapid molecular test Xpert MTB/RIF is more sensitive and specific and helps in diagnosing rifampicin resistance.
The limitation of the test Xpert MTB/RIF is that of its false +ve result which can be detected in a treated TB.
According to the WHO 2018;
Treatment against active TB should be started immediately after diagnosis.
Period of traetment range from 6 to 24 months, but recommended to be at least 9-12 months.
American Society of Transplantation IDCOP; recommend 6 month for active uncomplicated pulmonary TB, and 9 month for cavity lesion or persistant culture positive after 2 month of therapy.
American Society of Transplantation-IDCOP recommend first line treatment should be 4 drugs regiment; intensive dose for 2 months (Rifampicin, Isoniazide, Pyrazinamide and ethambutol), and 4 month contiuation phaseof isoniazide and rifampicin.
ESCMID; standard regiment more than 6 months, and in localized non-sever TB, rifamocicn free regiment , so intensive phase should include (INH, Eth, Pyr, or levofloxacin , followed by a continuation phase of 12-18 months with Iso and Eth or Pyr.
Challenges with the treatment;
Rifampicin; potent cytochrome P450 inducer, so decrease the level of CNIs, mTORi, and affect glococorticoids, hence the risk of rejection, drug level monitoring is mandatory with optomising the immunosuppressants doses.
Rifabutin can be used instead of Rif. as it associated with less side effects.
INH, Rif, Pyr, and Eth. == hepatotoxicity, and cytopenia.
INH and Eth.== neurotoxicity.
Rif. and Eth. == visual disturbance.
Rif. == skin lesion.
Pyr. == hyperuricemia.
Rif. and Pyr. == interstitial nephritis
If the disease is mild and categoried as Latent infection reactivation with no active disease;
Considered after exclusion of active TB.
+ve TST, or IGRA test, a history of untreatd TB, history of recent contact, or donated kidney from donor with latent TB, untreated TB or recent exposure.
Isoniazide 5mg/kg/D, for 9 months with supplement vitB6.
Alternative regiment consist of ethambutol and levo or moxifloxacin.
Refferences;
Tonelli, M.; Wiebe, N.; Knoll, G.; Bello, A.; Browne, S.; Jadhav, D.; Klarenbach, S.; Gill, J. Systematic Review: Kidney Transplantation Compared with Dialysis in Clinically Relevant Outcomes. Am. J. Transplant. Off. J. Am. Soc. Transplant. Am. Soc. Transpl. Surg. 2011, 11, 2093–2109. [CrossRef] [PubMed] 2. Gill, J.S.; Abichandani, R.; Kausz, A.T.; Pereira, B.J.G. Mortality after Kidney Transplant Failure: The Impact of Non-Immunologic Factors. Kidney Int. 2002, 62, 1875–1883. [CrossRef] [PubMed] 3. Kim, J.; Watkins, A.; Aull, M.; Serur, D.; Hartono, C.; Kapur, S. Causes of Graft Loss After Kidney Transplantation Following Rabbit-Antithymocyte Gobulin Induction and Steroid-Sparing Maintenance. Abstract# 2922. Transplantation 2014, 98, 146. 4. Chan, S.; Pascoe, E.M.; Clayton, P.A.; McDonald, S.P.; Lim, W.H.; Sypek, M.P.; Palmer, S.C.; Isbel, N.M.; Francis, R.S.; Campbell, S.B.; et al. Infection-Related Mortality in Recipients of a Kidney Transplant in Australia and New Zealand. Clin. J. Am.
A 47-year-old CKD-5 patient receives a kidney transplant from his brother with a mismatch of 111 and no DSAs. Superior renal function. A year later, he arrived with a nighttime temperature of 39 degrees Celsius, a productive cough, and weight loss. Several shadows were detected in both lungs. This clinical situation and imaging findings are suggestive of active pulmonary tuberculosis, specifically miliary tuberculosis.
In the diagnosis of Tb, some factors make the diagnosis challenging, such as the IGRA and the tuberculin test, which are typically negative. Although you have active TB, sputum smear results are typically negative. Less than 5% of transplant recipients experience the typical cavitary changes seen in immunocompetent patients, whereas 40% of recipients experience focal infiltrates, 22% have miliary patterns, 15% have nodules, 13% have pleural effusions, and 5% have diffuse interstitial infiltrates. Before treatment, baseline laboratory studies should be taken, including liver function tests, renal function tests, and cultures.
Therapy for drug-susceptible tuberculosis includes Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol, which is administered for 2 months followed by Isoniazid and Rifampin for 4 months in all cases aside from osteoarticular and nervous system diseases. Osteoarticular and nervous system diseases necessitate prolonged maintenance therapy that lasts at least nine months. Treatment for milder diseases includes the same drug combination regimen, quadruple therapy.
Full assessment, sepsis work up, Bilateral lung infiltration sparing lung periperhy, lung TB is Differntial diagnosis, other DD can include CMV, interstitial lung disease.
Sputum MC&S or BAL for AFB, Molecular tests like (Xpert® MTB/RIF
Treatment for localized non severe disease consider following the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) for a regimen without rifampicin. Two month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide
Screen his brother for latent TB infection if it has not been done prior to Tx.
This is a presumptive case of pulmonary tuberculosis, likely miliary tuberculosis because of the widespread reticulonodular opacities of millet size.
Investigation Serum electrolytes – serum sodium may correlate with disease severity and may suggest syndrome of inappropriate ADH secretion or Addison disease. Baseline kidney function is essential before starting treatment. Liver Function Test – may be deranged in disseminated TB. Baseline is required before starting treatment. Full blood count – his may show leukocytosis of leukemoid reaction. ESR – This may be elevated in 50% of cases and tends to reduce as effective treatment commences.
Sputum GeneXpert – This is a fast method of diagnosis of tuberculosis for fast commencement of treatment. It can also detect resistance to rifampicin. Cultures – Sputum, blood and urine. This is necessary to isolate the organism and test for drug sensitivity. Culture generally takes time as MTB is slow growing, however, treatment with first line anti-TB medications can be commenced without delay.
Treatment
Rifampicin, Isoniazid, Pyrazinamide and Ethambutol (RHZE) – this is given for 2months intensive therapy and RH for 4 months in all forms of drug susceptible tuberculosis other than osteoarticular and nervous system disease. Osteoarticular and nervous system disease will require extended period of maintenance therapy for 0 months.
Rifampicin is a cytochrome p450 enzyme inducer, hence the dose of tacrolimus and cyclosporin should be adjusted. Rifabutin has less effect on enzyme induction and can be used instead.
My management will not change if it was milder or affecting one lung. However, other differential diagnosis has to be considered.
I love that reply.
Mild or severe disease, medication remains same. The regimen would change if there is suspicion (or proven) of drug-resistance.
Ajay
Based on the epidemiological risk, personal history, symptoms, and imagistic lesions, TB diagnosis requires a high index of suspicion.
CBC, CRP, chest x-rays, CT chest.
tuberculin skin test (TST) and
interferon-gamma release assay (IGRA
invasive procedures
(bronchoscopy with bronchoalveolar lavage, derangement of fluid samples assessed thereafter by smear, mycobacterium culture, and histological examination
Treatment.
Plane 1 with rifampicin
After a 2-drug treatment of Rifampicin + INH for 2 months, a 4-drug regimen of Rifampicin + INH is administered.
Plan without rifampicin
Following a 2-drug regimen of INH + either ethambutol or pyrazinamide for 12 to 18 months, a 3-drug regimen of INH+ ethambutol+pyrazinamide or levofloxacin is utilized for 2 months.
Plan 2
For 12 months, 3 medications (INH+ ethambutol+ pyrazinamide or levofloxacin) are administered.
Plan3
Rifabutiun can be used instead of rifampicin since it has less of an impact on cytochrome p450, resulting in fewer medication interactions, but there isn’t much experience with it being used in transplantation, even though HIV/TB patients seem to benefit from it.
Chanlange in this case is ;
Adjustment of immunosupression and with anti-TB drugs and keeping eye to their torget and dosage fopr the preventation of graft
Thankyou ,if you are dealing with this case as active TB with 4 drug start, then what is your plan for a milder case :
which drugs to use
for how long.
In the current scenario, after 1 year of transplantation patient is presented with night fever, weight loss and chest lesions , this raise the possibility of active tuberculosis
Other infections can cause the same picture including aspergillosis although it occur early in transplantation
Malignancy should be ruled out (PTLD)
Active TB after solid organ transplantation
The prevalence of active TB is significantly higher than general population, it differ according to geographic area, it ranges from 1.2-2.6% in developed countries and in 10-15% in endemic regions (1,2)
Mode of transmission (3,4)
Activation of latent TB (the most common)
Acquiring the disease from the graft (donor derived)
Acquiring new infection through air born transmission
Timing after transplantation
Around 95% of cases occur at 1 mouth to 1 year after transplantation (5). Donor-derived TB usually occur earlier compared to activation of latent TB
Clinical presentation
Fever occur in 91% of disseminated TB, and in 64% of localized TB cases
Night sweats and weight loss are commonly seen
The presentation differ from immunocompetent patients in the following
Atypical presentation is more common (pyomyositis, , tenosynovitis , skin ulcers or abscess)
Around 30-50% of cases presents with extra pulmonary or disseminated TB (much higher than immunocompetent hosts) (6).
Diagnosis
The diagnosis is challenging due to the following
Tuberculin test and IGRA are usually negative
Sputum smear smear for TB is usually negative despite active TB (7).
Less than 5% of transplant patients have the classic cavitary changes seen in immunocompetent patients , on the other hand focal infiltrate is seen in 40%, military pattern in 22%, nodules in 15%, pleural effusion in 13%, and diffuse interstitial infiltrates in 5%
So …
High index of suspicion is needed in all SOT patients presenting with any skin or pulmonary lesions, unexplained fevers, night sweats, and weight loss
Any specimen collected (sputum, abscess fluid, lung tissue) should be stained and cultured for AFP, tested for PCR (rapid diagnosis) together with with histopathological examination of tissue taken if available
To reach diagnosis invasive procedure is usually required including bronchoscopy and BAL or lung biopsy
Treatment
The treatment of TB in SOT is challenging due to the following
Drug-drug interaction between rifampicin (the cornstone of TB treatment) and immunosuppressive medications used in transplantation
Loss of host immune response to TB due to the use of immunosuppressive drugs
Nephrotoxicity and other side effects related to the use of anti –TB medications
Protocols used in treatment of TB
I- Rifampicin containing regimen
Regimen A– 4-drug regimen of Rifampicin+ INH+ ethambutol + pyrazinamide for 2 months, followed by a 2-drug regimen of Rifampicin + INH for 4 months
It is recommended to increase the duration of treatment to at least 9 months if one of the following is present
Disseminated disease
Cavitary disease with positive sputum culture after 2 months of treatment
Bone and joint disease
CNS disease.
Some recommends extending the duration of treatment to 9 months in all SOT recipients since there is improvement in the mortality when using extended duration (8)
II- Rifampicin free regimen
Regimen A – 3-drug regimen of INH+ ethambutol + pyrazinamide or levofloxacin are used for 2 months, followed by a 2-drug regimen of INH + either ethambutol or pyrazinamide for 12 to 18 months
Regimen B – 3 drugs (INH+ ethambutol + pyrazinamide or levofloxacin are used for 12 months
Regimen C – Rifabutiun can be used instead of rifampicin due to its lesser effect on cytochrome p450, so minimal drug-drug interactions but experience is little when using this drug in transplantation, although it seems effective in HIV TB patients.(9)
It is strongly recommended to use Rifampicin containing regimen especially in patients with severe (cavitary or multilobar) or disseminated disease or if there is an evidence of INH resistance.(9)
In non-severe cases with no evidence of INH resistance, Rifampicin is sometimes avoided due to its intense drug-drug interactions with immunosuppressive drug with subsequent increase in the risk of rejections (9), so it is better to use rifampicin free protocols
Induction of CYP3A4 with rifampicin takes several days to occur and peak at 1 week after initiating the drug. Once rifampin is used, it is recommended to increase the dose of CNI or rapamycin 3-5 folds, with close follow up of serum level (9)
In SOT it is recommended to save Rifampicin for severe and resistant cases , and avoid streptomycin due to its nephrotoxicity (9)
Avoid extreme reduction of the immunosuppressive agents to decrease the possibility of anti tuberculous therapy – induced immune reconstitution inflammatory syndrome (IRIS). IRIS occur due to flare of immunity after the start of anti-TB drugs , manifested as worsening of fever, pulmonary infiltrates, lymphadenopathy, pleural and pericardial effusions (10). In one study evaluating transplant recipient s with TB, IRIS occur after 1.5 month of initiating anti-TB drugs in 14% of cases.(10) risk factors associated with IRIS includes liver transplantation, CMV infection and use of Rifampicin.
TB in SOT is associated with around 20% graft and patient loss, poor prognostic factors includes the use of ATG, OKT3, previous rejection and disseminated disease.
How do you manage this case?
I will do full laboratory investigations including CBC, renal functions, liver functions, LDH, CRP, ESR, urine analysis, ACR
Tuberculin skin test and IGRA can be done although the probability of being positive in immunosuppressed patients is low
Sputum sample should be obtained using Induction of cough by hypertonic saline or better by BAL and the sample is stained and cultured for AFP, adding PCR may increase accuracy
Pan CT with contrast to assess the extent of the disease
Drug level (CNI or rabamycin ) according to which drug is used
Once TB is diagnosed I will start Rifampicin containing regimen for 9 months
Once treatment is started I will increase the dose of CNI or rabamycin buy 3 folds
I will monitor drug level frequently every 3 days keeping trough at lower target ( trough around 5 for tacrolimus), I will keep lower Therabiotic dose of MMF and steroid
Would your management differ if the disease was mild and affected one lung?
Yes at this time I will avoid Rifampicin and use one of the Rifampicin free regimens
References
1. Lopez de Castilla D, Schluger NW. Tuberculosis following solid organ transplantation. Transpl Infect Dis 2010; 12:106.
2. Abad CLR, Razonable RR. Mycobacterium tuberculosis after solid organ transplantation: A review of more than 2000 cases. Clin Transplant 2018; 32:e13259.
3. Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clin Infect Dis 1998; 27:1266.
4. Muñoz P, Rodríguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clin Infect Dis 2005; 40:581.
5. Torre-Cisneros J, Doblas A, Aguado JM, et al. Tuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort. Clin Infect Dis 2009; 48:1657.
6. Fiske CT, Griffin MR, Erin H, et al. Black race, sex, and extrapulmonary tuberculosis risk: an observational study. BMC Infect Dis 2010; 10:16.
7. 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; 33:e13513.
8. Aguado JM, Herrero JA, Gavaldá J, et al. Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Spanish Transplantation Infection Study Group, GESITRA. Transplantation 1997; 63:1278.
9. Aguado JM, Torre-Cisneros J, Fortún J, et al. Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clin Infect Dis 2009; 48:1276.
10. Sun HY, Munoz P, Torre-Cisneros J, et al. Mycobacterium tuberculosis-associated immune reconstitution syndrome in solid-organ transplant recipients. Transplantation 2013; 95:1173.
Thankyou Sherif for your well organaised review and good choice decision.
It will be complete if you included information of LATENT cases ,diagnosis and prophylactic treatment in SOT as they constitute the major cause of activation post TX.
Well done.
Recipients with latent TB are at high risk of conversion to active TB after transplantation, on the other hand, if the donor has latent TB and did not receive treatment it carry a risk of transmission to the recipient
So all recipients and donors should both be undergo careful evaluation of the risk, history, examination and CXR, together with test for latent TB
In general, all transplant recipients and donors should be evaluated for the presence of latent TB and once detected treatment should be received
2 test are used to detect latent TB, tuberculin skin test (TST) and IGRA, both are usually negative in immunosuppressed patients due to their dependence on the host immune response which is impaired in these sets of patients
Patient and donor should have no symptoms, CXR should be normal and no evidence of exra-pulmonary TB in order to settle the diagnosis of latent TB
Which test to use?
In low risk transplant recipients, it is it is preferred to use IGRA over TST due to its higher sensitivity in these sets of patients
In low risk donor, either of both tests can be used, with the preference of IGRA in patients with previous vaccination
In high risk transplant recipients and donor (patient who are living in country with high TB prevalence , contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), it is better to do both tests to maximize sensitivity, at that time IGRA should be done either at the same time of before TST to avoid TST-mediated IGRA response.
All transplant recipients and donors should have thorough history taking and CXR
Interpretation of the result
If TST is negative the test should be repeated after 7-10 days to detect posted effect
If IGRA is negative treatment is considered only in high risk transplant recipients
If the TST is positive (Induration ≥5 mm in recipient or > 10 mm in donor), there is a history of positive TST, or IGRA is positive, the patients is considered to have latent TB provided that the CXR is normal and the patient is asymptomatic
If radiology is suspicious for TB (apical fibronodular lesions, calcified solitary nodule, calcified lymph nodes, or pleural thickening) thorough evaluation including microbiological assessment is indicated to exclude TB as a cause
If TB diagnosed in the recipient transplantation should be delayed till complete treatment of TB
If TB is diagnosed in the donor donation should be postboned till successful treatment is given for at least 6 months
Indications of treatment of latent TB in transplant recipient and donor
Positive TST (> 5mm in recipient, > 10 mm in donor) or a positive IGRA
History of positive TST or pervious history of TB
Negative TST and/or IGRA in a patient with close contact to an active TB case
If the donor has latent TB and did not receive treatment (treat the recipient), but if the donor received treatment there is no need to treat the recipient
Protocol for treatment of latent TB
The preferred regimen in renal transplant candidate is the use of INH in a dose of 5 mg/kg (maximum dose 300 mg) together with oral pyridoxine 50 mg daily for 6-9 months (9 months is preferred).
Rifampin in a dose of 600 mg for 4 months
INH+ weekly rifapentine for 3 months
Ideally, regimen should be started before transplantation, but if it started after transplantation, Rifampicin containing regimen should be avoided
Patient should be monitored for liver enzymes and bilirubin at baseline, every 2 weeks for 6 weeks then monthly, if there is 3 fold rise of liver enzymes with symptoms or 5 fold rise without symptoms , INH should be stopped
Case of cough, weight loss and fever in immunosuppressed patient with changes on chest xray and CT scan of bilateral reticulonodular changes and cavitatory lesions. These finding are high suggestive of pulmonary TB.
Other possible causes:
Bacterial Pneumonia
Viral pneumonia like CMV
Fungal pneumonia like PCP
Firstly, we need to confirm the diagnosis by careful, history and investigations.
After initial routine basic investigation, CBC, Chemistry, CRP, ESR.
Specific confirmatory tests include sputum for AFB, Sputum culture, TB PCR from sputum, TB culture, and if needed BAL.
If confirmed to be pulmonary TB, then we need to start treatment and manage the immunosuppressive medications and monitor for side effects and drug interaction.
Regarding treatment regimen, American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) guidelines recommends that in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months.
2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin. Rifamycin is recommended for its sterilization capacity and efficiency but also to reduce the risk of resistance. Monitoring for side effects and CNI level is essential, especially liver function tests and graft function. CNI dose needs to be increased 3-5folds when using this regimen.
Would your management differ if the disease was mild and affected one lung?
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) suggests a standard regimen used for a period longer than 6 months, and, in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present. If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide. Additionally, if second-line drugs are used, a longer period of treatment is recommended.
References.
1-Sorohan, B.M.; Ismail, G.; Tacu, D.; Obris, c ˘a, B.; Ciolan, G.; Gîngu, C.; Sinescu, I.; Baston, C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens 2022, 11, 1041. https://doi.org/10.3390/ pathogens11091041
Thanks prof Ajay..
the longer period is preferred for localized disease when less medications are used, ie without rifamycin and when second-line medications are used. I’ve quoted the American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) sentence. But for others, I’ve mentioned in the answer to the 1st question the duration 6 months.
A 47-year-old CKD 5 has kidney transplantation from his brother, 111 mismatch, and no DSAs. Excellent kidney function. One year later, he presented with a night fever of 39 C, productive cough, and weight loss. Imaging showed multiple shadows in both lungs.
Tuberculosis is a common bacterial infection with high prevalence in developing countries, causing significant morbidity and economic burden.
This article reviews existing knowledge on post renal transplant TB, the difficulties in diagnosis, changes in the protocols of treatment, prognosis, risk factors for acquiring the disease, and current advances.
The median period for onset was assessed to be nine months after transplantation in a global assessment on TB.
Differential Diagnosis Bacterial pneumonia
Sudden onset of symptoms, such as high fever, cough, purulent sputum, chest pain, leukocytosis, chest X-ray shows consolidation.
Bronchogenic carcinoma
May be asymptomatic, usually at older ages (> 50 years old), cough, hemoptysis, weight loss
Brucellosis
Fever, anorexia, night sweats, malaise,back pain , headache, and depression. History of exposure to infected animal
Hodgkin lymphoma
Fever, night sweats, pruritus, painless adenopathy, mediastinal mass
Mycoplasmal pneumonia
Gradual onset of dry cough, headache, malaise, sore throat. Diffuse bilateral infiltrates on chest X-ray.
Miliary TB
Miliary TB occurs when tubercle bacilli enter the bloodstream and disseminate to all parts of the body, where they grow and cause disease in multiple sites.
This condition is rare but serious. “Miliary” refers to the radiograph appearance of millet seeds scattered throughout the lung . It is most common in infants and children younger than 5 years of age and in severely immunocompromised pateint .
Acid-fast staining is the most commonly used method for pulmonary tuberculosis, but gastric juice aspiration may be used if expectoration is scanty.
Auramine-rhodamine or auramine O fluorescence staining is more sensitive than Ziehl-Nielsen.
Culture and sensitivity can help diagnose drug resistance, but it may take up to six weeks for positive reports.
Radiolabelled nutrient substrate utilization, gas pressure monitoring and fluorescence emission are used to detect growth earlier.
High-resolution computerized tomography and Positron emission tomography can improve diagnosis.
Polymerase chain reaction can amplify genetic material, but sensitivity is variable.
Interferon gamma response is specific to Mycobacterium tuberculosis and ELISA and immunospot assays are used to detect infection in immunosuppressed patients.
Plan manegement
Treatment of TB requires a multidrug regimen with antituberculous drugs, first-line essential drugs, supplemental agents, and second-line agents.
Isoniazid, ethambutol, pyrazinamide are safe agents.
Rifampicin should be avoided in solid organ due to unpredictable interaction with CYP450 microsomal enzyme system.
The WHO Consolidated Guidelines on Tuberculosis, Module 4: Treatment – Drug-Susceptible Tuberculosis Treatment recommends a 4-month regimen composed of rifapentine, isoniazid, pyrazinamide, and moxifloxacin.
The dose of calcineurin inhibitors may have to be increased two- to fivefold to overcome this effect with decrease dose of Mycophenolate Mofetil (CellCept) and Mycophenolate Sodium (Myfortic)
Randomized studies are needed to validate the four-drug regimens used in different centers.pyrazinamide (three months); ofloxacin (nine months); INH and ethambutol (18 months). Regimens vary in dose and duration, based on individual preferences and response.
The dose of INH and ethambutol has to be adjusted for the degree of renal function. If rifampicin has to be used for those who are not on cyclosporine, prednisolone dose has to be doubled.
Module 4: treatment: drug-susceptible tuberculosis treatment 24 May 2022 Guideline
Moon, Myung-Sang (2014). “Tuberculosis of Spine: Current Views in Diagnosis and Management”. Asian Spine Journal. 8 (1): 97.
Sundaram M, Adhikary SD, John GT, Kekre NS. Tuberculosis in renal transplant recipients. Indian J Urol. 2008;24(3):396-400. doi:10.4103/0970-1591.42625
Torre-Cisneros J, Doblas A, Aguado JM, et al. Tuberculosis after solid organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort. Clin Infect Dis 2009; 48: 1657–1665
Mycophenolate is an immunosuppressant widely prescribed in renal transplantation, which is metabolized to its main metabolites MPA 7-O-glucuronide and AcMPAG.
Therapeutic drug monitoring (TDM) is advocated due to the large inter-individual variability in pharmacokinetic profiles and intra-individual variability between early and stable transplant periods.
Rifampicin is known to increase the metabolism and decrease enterohepatic recirculation of mycophenolic acid, but the time required for the MPA area under the curve to return is unknown.
Rifampicin significantly reduces MPA-AUC, requiring more than three weeks for concentrations to be restored.
MPA-AUC0-12corr increased 2.5 fold after discontinuation of rifampicin, serum creatinine improved to 1.7 mg%.
Annapandian VM, Fleming DH, Mathew BS, John GT. Mycophenolic acid area under the curve recovery time following rifampicin withdrawal. Indian J Nephrol. 2010;20(1):51-53. doi:10.4103/0971-4065.62091
One year after living donor kidney transplant, night high grade fever , weight loss, and productive cough Chest X ray= diffuse bilateral nodular pattern with hilar lymphadenopathy. Chest CT = diffuse nodular pattern with peri-hilar lymphadenopathy. Differential diagnosis: Military TB. Lymphangitic spread of lung cancers. Bronchiolitis Sarcoidosis Atypical bacterial/fungal/viral infections How do you manage this case? The patient history and symptoms with radiological findings put high on the list of differential diagnosis Tuberculosis. From the history – vaccination history, history of contact with TB patient, is he in and endemic area are important. Review of his previous chest X ray. Laboratory tests: CBC, BUN , creatinine , Na,K , Calcium, total serum protein and albumin, liver function test (ALT,AST, Alkaline phosphatase, bilirubin, PT, PTT,INR), early morning sputum for AFB, gram stain, an culture. Blood culture, urinalysis and culture. Broncho-alveolar lavage, for analysis, culture, and PCR testing for CMV, PCP, TB…. etc Multidisciplinary team approach= Radiologist, Pulmonologist, Infectious disease and transplant physician. Thorough clinical examination is a must including signs of meningism, if present consider lumbar puncture, hepatosplenomegaly. Admission to medical ward IV antibiotics with broad spectrum coverage.
After reaching the diagnosis which most probably Miliary Tuberculosis, start 6 months treatment with traditional isoniazide, rifampicin, pyrazinamide, and ethambutol. Or 4months treatment with rifapentine- moxifloxscin.
Rifampin should be used with caution due to significant interactions between this class of drug and the calcineurin inhibitors and rapamycin (sirolimus). The rifamycins (especially rifampin) Reduce serum concentration of tacrolim, cyclosporine, rapamycin (sirolimus), and everolimus via induction of the cytochrome p450 isoenzyme CYP3A4, and the combination of a rifamycin with these drugs has been associated with the development of rejection.
Although streptomycin is often used as part of the initial treatment regimen in nontransplant patients with a contraindication to the rifamycins, this agent is generally avoided in SOT recipients because of the risk of nephrotoxicity.
The major concern is the immune reconstitution inflammatory syndrome (IRIS), I might decrease the dose of MMF, but keeping the patient in stress dose steroid and 3-5 times higher dose of CNI.
Would your management differ if the disease was mild and affected one lung? Yes, start him on antibiotics checking the BAL, and lung biopsy while keeping him on IV broad spectrum antibiotics References: (1) Wang W, Wang AS, Wang ZY, Wang JH, Lin MG, Zhang T, Li J, An HR, Li YF. [Tuberculosis after organ transplantation: clinical analysis and literature review]. Zhonghua Jie He He Hu Xi Za Zhi. 2007 Feb;30(2):124-6. Chinese. PMID: 17445475. (2) Rattazzi LC, Simmons RL, Spanos PK, Bradford DS, Najarian JS. Successful management of miliary tuberculosis after renal transplantation. Am J Surg. 1975 Sep;130(3):359-61. doi: 10.1016/0002-9610(75)90402-x. PMID: 1101720. (3) UpToDate-tuberculosis in solid organ transplantation candidate and recipient.
Thank you Prof. caseating granuloma, suggestive of TB in lung biopsy.
the reduction is by 25-50% with continuous blood testing for drug toxicity and levels
This patient is a post kidney transplant patient from his brother 111 mismatch present one year after transplantation with fever ,night sweat,productive cough and weight loss which is highly suggestive of pulmonary TBImaging showed bilateral diffuse lung infiltrates . Management :
-MDT includes (pulmonologist ,ID ,clinical pharmacist and nephrologist) first assessment regarding respiratory and hemodynamic support then proper full detailed history and examination .
-Full blood count ,baseline graft function and liver function test . .
Sputum smears and culture must be performed if not possible bronchoscopy and culture of the bronchoalveolar aspirate and/or lavage fluid specimen should be performed.
Molecular tests based on rapid nucleic acid amplification techniques, (Xpert® MTB/RIF )a new test that is revolutionizing tuberculosis (TB) control by contributing to the rapid diagnosis of TB disease and drug resistance ..
According to AST-IDCOP, recommendation the treatments is :
2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin .
– If cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months.
Drug interaction : -Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein, it decrease the levels of CNI (cyclosporine, tacrolimus), and the (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection . – Calcineurin and mTOR inhibitors levels should be closely monitored if rifampicin-based regimen is used, the dose of calcineurin and mTOR inhibitor should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target. – After the rifampicin is stopped, the immunosuppressive doses should be reduced to the value before the start of rifampicin and then adjusted to obtain the therapeutic target .
An alternative to rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy . Likewise, even in rifabutin-based regimens, immunosuppression doses could be modified, and levels should be closely monitored . Another safe and effective alternative to rifampicin in KT recipients is treatment with fluoroquinolones.
Isolation :
Patients should be isolated until it has been shown that the patient does not have TB ; if the patient is improving clinically after clinically , and has 3 consecutive negative sputum smear results. .
Would your management differ if the disease was mild and affected one lung?
-Since it is proven to be active TB but localized and mild I will provide rifampicin free regimen using fluoroquinolone or rifabutin instead to minimize the risk of rejection . REFERRENCE :
I like your pragmatic and scientific clinical approach well supported by relevant references.
Half-hearted treatment without rifabutin in transplant patients (or without rifampicin in non-transplant patients) may be responsible for drug resistance. What is your basis for this recommendation?
According to AST-IDCOP, the first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases .
Rifamycin is recommended for its sterilization capacity and efficiency but also to reduce the risk of resistance .
Rifabutin is an alternative to rifampicin , which is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy if the risk of rejection is challenging.
Fluoroquinolones are also good alternatives in high risk of rejection in SOT patients but indiscriminate use in the general population has been associated with an increase in resistance of M. tuberculosis to these drugs in recent years.
The decision to use a determinate number of drugs for treatment of TB in SOT recipients is driven by the rate of drug resistance in each country and is based on the epidemiology in individual cases.
👉 The current case presented with night fever, weight loss and bilateral diffuse infiltration in CT chest is highly suggestive of miliary pulmonary TB. Onset after 1 year suggests that it is mostly activation of latent TB in the recipient or may be exposure to open TB case after transplantation.
👉 Management is to confirm diagnosis of TB by:
_Sputum analysis and smear staining with ZN stain for acid fast bacilli and culture on BACTEC system.
_Culture is more sensitive but takes 4-6 weeks to give results which is too long and the patient will deteriorate through this long waiting time. _Molecualr analysis (Gene Xpert from the blood, sputum or urine).and DNA amplification will be reasonable and fast diagnosis. _No role of tuberculin skin test (TST) or IGRA (Interferon gama release assay) on diagnosis of active TB as they represent immunological reaction to TB antigen which is already impaired in such immunocompromised individual under the effect of IS medications.
👉 Treatment of active TB in KT is the same or derived from treatment in immunocompetent hosts as 2 months initial therapy of 4 anti tuberculous therapy (INH, rifampin , ethambutol and pyrazinamide ) followed by 10 months of dual therapy (INH and rifampin).
⭐ Rifampin is mandatory here in such severe case with multi-lobar affection.
⭐ Rifampin is cyt 3A4 inducer, so it will reduce the plasma concentration of CNI , sirolimus and even steroids , so close monitoring of trough level and increase dose of CNI 3-5 times guided by trough level is warranted also increasing dose of steroids to avoid allograft rejection and loss.
⭐ Rifabutin is an alternative with less drug drug interaction but not well studied as effective alternative to rifampin.
⭐ Follow up of liver enzymes to avoid hepatotoxicity of INH and graft function as rifampin is nephrotoxic.
⭐ IRIS (immune reconstitution inflammatory syndrome) is well described complication of rifampin use in treatment of active TB (due to relief of immunosupression state by anti tuberculous therapy leading to worsening of pulmonary symptoms, intense fever and pleurisy together with possible graft dysfunction.
👉 Treatment in case of unilateral affection:. _Avoiding rifampin and saving it to severe cases.
_use of INH ,ethambutol and pyrazinamide (tripple therapy) for 12 months or use initial (INH, pyrazinamide plus ethambutol or levofloxacin for 2 months ) followed by dual therapy (INH plus either pyrazinamide or ethambutol for 12-18 months).
Findings on chest xray and CT scan:
Bilateral pulmonary reticulo-nodular shadow diffuse and involving both lungs with no pleural effusion, on a background of a febrile illness associated with productive cough night sweating and weight loss in a middle-aged kidney transplant recipient. primary impression, Differential diagnosis:
Bronchopneumonia.
Miliary tuberculosis.
pulmonary fungal infection, Histoplasmosis
malignant infiltration. either secondary, commonly from thyroid , breast, colonic , and renal cell carcinoma
Hemosiderosis
viral pneumonia , Varicella pneumonia. Work up :
Blood tests: CBC, CRP, blood culture.Results of blood tests are nonspecific and varies from leukopenia, to leukocytosis and lymphocytosis. Leukemoid reaction might be prominent as well. Fundal examination revealing choroid tubercles is diagnostic of milliary TB
sputum for AFB and fungi, with ZN stain, or using auramine-rhodamine dye. Culture in the solid LJ media or the liquid Bactec media which is usually yielding the result within 1-2 weeks.
PCR can be utilized for diagnosing TB.
CT scan and PET scan are advised to screen for involvement of other organs .
Bronchoscpy and lung biopsy might be indicated to prove the diagnosis.
Tuberculine skin test is usually negative. Bone marrow biopsy, echocardiography
Treatment:
6 months of induction with Rifampicin, INH, Pyerazinamide and Ethambutol and maintenance INH and Rifamipicin for 4 months.
Unilateral involvement denotes pulomonary TB. management would be varied from Miliary TB management in the term of duration of therapy and co-therapy with Corticosteroid.
References:
1]Kamila Bednarova et al. Tuberculosis dissemination in kidney transplant recipient treated with anti-CD40 monoclonal antibody: a case report.BMC Nephrologyvolume 23, Article number: 290 (2022)
Patients with relevant clinical signs (cough, lymphadenopathy, fevers, night sweats, weight loss) and epidemiologic variables (such as a history of past TB infection or illness, known or probable TB exposure) should be suspected of pulmonary TB.
investigations:
CBC, ESR, CRP, drug level and RFT, serum sodium level, and serum calcium level are some of the tests that will be performed at the laboratory.
Smear and culture investigation of sputum that has been either spontaneously or artificially produced.
Tuberculin test
Assays for the release of interferon-gamma
Chest computed tomography (CT) are more sensitive than plain chest radiography.
BACTEC liquid media help to detect the organism within 2 weeks.
NAA testing should be used for rapid diagnosis (usually within 24 to 48 hours) of organisms belonging to the M. tuberculosis complex in patients with suspected TB.
Treatment:
Rifampicin is commonly given to SOT patients, particularly kidney recipients, although its use is contentious.
European kidney transplantation guidelines propose 2 months of isoniazid, rifampicin, and pyrazinamide (with ethambutol for 14% isoniazid resistance), followed by 4 months of isoniazid and rifampicin.
Rifampicin lowers tacrolimus, cyclosporine, rapamycin, everolimus, and corticosteroids (although there is less information about corticosteroids). Binding rifampicin and CNI increases the likelihood of graft rejection, graft loss, and overall TB-related mortality. Hence, the dosage of calcineurin inhibitors should be raised 3–5-fold, and levels should be monitored
Rifabutin induces cytochrome P450 less than rifampicin. Despite proper supervision. supplementing pyridoxine.
Would your management differ if the disease was mild and affected one lung?
The radiological presentation does not affect the treatment. Our patient is immunocompromised. even with a mild form of TB. As long as the culture is positive, he will start treatment on 4 drugs for 2 months and maintain it for a total of 6–9 months. depend on the culture and radiological response.
References: Aguado, José María, et al. “Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology.” Clinical infectious diseases 48.9 (2009): 1276-1284.
TBNET and ESCMID recommend a non-rifamycin regimen for localized ( pulmonary) nonsevere TB in the absence of isoniazid (INH) resistance.
In patients without rifamycin, a three-drug combination of INH, ethambutol, and either pyrazinamide or levofloxacin for two months is followed by a two-drug regimen for 12 to 18 months. A three-drug regimen may be completed in 12 months.
Half-hearted treatment without rifabutin in transplant patients (or without rifampicin in non-transplant patients) may be responsible for drug resistance.
A 47-year-old CKD 5 has kidney transplantation from his brother, 111 mismatch, and no DSAs. Excellent kidney function. One year later, he presented with a night fever of 39 C, productive cough, and weight loss. Imaging showed multiple shadows in both longs. How do you manage this case?
TB should be considered in all transplant recipients with unexplained fevers, night sweats, and weight loss . History:-
Contact with patient with active pulmonary TB.
Past history of TB. Full clinical examination . Investigations:
(CBC, RFT, LFT, CRP, and Staining and culture for acid-fast bacilli should be performed on all induced sputum and bronchoscopy specimens in such patients.
Nucleic acid amplification methods can increase the rapidity of diagnosis). Radiological:
CXRY showing military pattern of TB.
Renal USG and may or may not PET scan to exclude and collection of TB abscess in other systems or lymph nodes. Treatments:
Treatment of active drug susceptible TB usually involves two months of INH, rifampin/rifabutin, pyrazinamide, +/- ethambutol, followed by a continuation phase therapy of four months of INH and rifampin, with a total duration for six months.
We should bear in mind the drug-drug interaction as Rifampin is a strong inducer of CYTP3A4 leading to increased metabolism of calcineurin inhibitors, mammalian target of rapamycin (mTOR) inhibitors, Mycophenolate mofetil and corticosteroids, so we should closely monitoring the drug level.
Will follow up ATT side effects . Would your management differ if the disease was mild and affected one lung?
Once, our patient diagnosed as active TB case should be treated as mentioned above also if any recipient diagnosed as Latent TB case should be treated with isoniazid (300 mg/day), supplemented with vitamin B6 for 9 months. References:
1-Anand M, Nayyar E, Concepcion B, Salani M, Schaefer H. Tuberculosis in kidney transplant recipients: A case series. World J Transplant. 2017;7(3):213-221. doi:10.5500/wjt.v7.i3.213.
2-José María Aguado, Julián Torre-Cisneros, Jesús Fortún, Natividad Benito, Yolanda Meije, Antonio Doblas, Patricia Muñoz, David R. Snydman, Tuberculosis in Solid-Organ Transplant Recipients: Consensus Statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology, Clinical Infectious Diseases, Volume 48, Issue 9, 1 May 2009, Pages 1276–1284, https://doi.org/10.1086/597590.
You prefer 6 months of therapy (including 4 drugs for 2 months) for those without INH resistance, while other colleague such as Dr Abiola, as below, prefers 9 months of ATT.
Half-hearted treatment without rifabutin in transplant patients (or without rifampicin in non-transplant patients) may be responsible for drug resistance.
The above radiological images show fine granular diffuse military infiltrates that are widely scattered throughout both lung fields.
Also with clinical symptoms of fever, productive cough, and weight loss post-KTP
The most likely diagnosis is military pulmonary Tuberculosis
Differential Diagnosis
Histoplasmosis
Pneumoconiosis
Bronchopneumonia
CMV infection
Investigations
Sputum for AFB, Culture, and gene Xpert
BAL may be required to obtain more bacteria load for the above tests
ESR, CRP
Liver function test
Kidney function test
Urinalysis
FBC + differentials
Eye check for retinal
HIV 1 &11
CMV PCR DNA
Treatment
For the intensive phase: INH, Rifabutin, Ethambutol, and Pyrazinamide x 2 months
For the maintenance phase: Rifabutin + INH X 7 months because of wide-spread cavitary lesions and involvement of a major organ of the body
Tab Pyridoxine 25mg daily
Ensure family-assisted DOT for drug adherence, particularly in the first 2 months
LFT check every 2 weeks during the intensive phase, then monthly
Regular CNI inhibitor or mTORi trough level to avoid graft rejection, there may be a need to increase the dose by 3 -5 fold
Double the dose of glucocorticoid, since its metabolism can be increased by CNIs
Regular serum creatinine level check
Check CXR after completing the intensive phase
Check weight gain, and sputum AFB after the intensive phase
Advice to avoid exposure and ensure cough hygiene
How will you manage if is mild and affects one lung?
This may be a primary pulmonary Tuberculosis with the presence of likely Ghon focus in the lung
I will still manage as above with the exception of the duration of treatment for six months
References
Bogdan Marian Sorohan, Gener Ismail, Dorina Tacu, Bogdan Obris, C, et al. Mycobacteria Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens. 2022; 11: 1041
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: 13513
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
De Castilla, D.L.; Rakita, R.M.; Spitters, C.E.; Narita, M.; Jain, R.; Limaye, A.P. Short-Course Isoniazid Plus Rifapentine Directly Observed Therapy for Latent Tuberculosis in Solid-Organ Transplant Candidates. Transplantation 2014, 97, 206–211
TB in kidney Transplantation Lecture by Prof. Ahmed Skoker
Half-hearted treatment without rifabutin in transplant patients (or without rifampicin in non-transplant patients) may be responsible for drug resistance.
What is your comment on this statement of mine. You may or may not agree with me.
The American Society of Transplantation recommends that rifamycin containing regimen is strongly preferred for both severe and localized nonsevere TB due to its potent sterilizing activity and more importantly it prevents the emergence of drug resistance.
I completely agree with you prof.
Unfortunately this guy developed symptoms of infections one year after transplantation informs of fever, productive cough & high lost. He had CXR/CT which showed bilateral diffuse pulmonary infiltrates and small cavities. TB need to be excluded in this case.
Sputum microspcopy for Acid fast bacilli & sputum culture
Sputum/urine/ for gene Xpert
Bronchoscopy & BAL may be needed, gene Xpert can be done on the biopsy sample
Inflammatory markers; e.g. CRP
Routine test: FBC, UECs, LFTs
Other differential diagnosis of respiratory infections after 6 months posttransplantation
Community acquired pneumonia
Aspergillosis & other fungi
Nocardiasis
CMV
As soon as TB is confirmed
Counsel the patient about the long treatment, side effects, risk of rejection, morbidity, mortality and increased cost because of increasing dosages and more frequent monitoring.
Start anti-TB per local protocol; in our set up initiation phase consist of INH, Rifampicin, Pyrizinamide, & Ethambutol and the continuation phase is made of INH + Rifampicin for at at least 6 months
Rifampicin can be substituted with Rifabutin if available to reduce interactions with tacroliumus
Consider B6 25 to 50 mg daily
Monitor FBC, UECs, LFTs at least bi-weekly then monthly
Visula assessment and monitoring
Increased tacrolimus by 3 to 5 folds
Monitory frequently tacrolimus level
Double the steroids dose
Sometimes there is an option of therapeutic trial in difficults cases in endemic areas i.e., diagnosis after treatment.
Q2.
Yes, one may save rifampicin specially in absence of INH resistant to reduce the risk of drug-drug interactions & the nephrotoxicity associated with rifampicin. The alternative here can be fluoroquinolones.
Source, Nephrology secret fourth edition, TB infection after kidney transplantation (Bogdan Marian Sorohan et al.)
This chest X ray shows diffuse bilateral reticulonodular infiltration consisting of miliary TB
Laboratory studies for CBC, ESR, CRP, Drug level and DSA level
RFT and serum sodium level and serum calcium level.
Smear and culture examination of spontaneously expectorated or induced sputum.
Tuberculin test
Interferon-gamma release assays
CT chest
Ultrasound to role out disseminated of disease to internal organ like liver and spleen.
Trans bronchial lung biopsy to confirm miliary TB.
Treatment reduce immunosuppressive therapy to half and keep steroid dose
Anti tuberculosis regime for 6 to 9 months depend on recommended protocols.
TB guidelines suggest 6 months of treatment (2-month intensive phase with isoniazid, rifampicin, pyrazinamide, and ethambutol or streptomycin, followed by a 4-month maintenance phase with isoniazid and rifampicin).
Would your management differ if the disease was mild and affected one lung?
No need to reduce immunosuppressive dose in mild form.
How do you manage this case?
It is a patient with a disseminated nodular pulmonary condition, very suggestive of pulmonary tuberculosis. Histoplasmosis can present a similar picture, even if immunosuppression is more pronounced and if there is an epidemiological context (caves, chicken coops, rural areas with old houses).
The positivity of blood tests is low in this context. The ideal would be a bronchoalveolar lavage with a collection of genetic material for Tuberculosis (Gene Xpert), bacilloscopy, and transbronchial biopsy). Histoplasmosis in an immunosuppressed patient has been diagnosed with urinary or serum antigen with more than 90% sensitivity.
1. Measure serum levels of CNI and other immunosuppressants. As it appears in more immunosuppressed patients, we should reduce the dose of these drugs.
2. Avoid rifampicin in the scheme or adequately monitor serum levels of immunosuppressants if it is part of the scheme
3. Start the classic scheme. In Brazil, we use four drugs in combination. Rifampicin+Isoniazid+Pirazimanid+Ethambutol depending on weight for two months and four more months of Rifampicin+Isoniazid.
Would your management differ if the disease was mild and affected one lung?
If the disease was localized, it is suggestive of recent exposure and the people closest to you should be investigated. There would be no need to decrease immunosuppression unless there were serum levels to suggest it.
As the treatment has a high drug interaction, after starting the antituberculostatic regimen there is a need for serum monitoring, mainly CNI and mTor.
Rifampicin is the best drug for treating tuberculosis. In cases of disseminated disease, it should be the priority in the scheme. In localized diseases, we can switch more safely to Rifapentine, which is less toxic, fewer drug interactions with immunosuppressants and other drugs.
For disseminated disease I would prioritize Rifampicin
There are bilateral diffuse nodular infiltrates, highly suggestive of miliary TB, given the clinical scenario in this case.
A miliary pattern on chest imaging may be due to many conditions, including Histoplasmosis and Sarcoidosis.
Diagnosis: respiratory culture for Acid-fast smear and culture, lymph node biopsy if possible and molecular tests in regions where available. Molecular tests can be useful rapid diagnostic tools.
TREATMENT In general, the approach to antimicrobial therapy for the treatment of miliary TB consists of the traditional regimen (≥6 months) for the treatment of pulmonary TB.
Modifications to the standard drug regimen may be justified in the setting of drug-resistant TB.
Thanks, Fakhriya You missed many points, looks like you are in a hurry. Your patient will become sensitised and lose the graft because of AMR. You treated TB, but you patient landed successfully on dialysis.
The constellation of symptoms, signs, and radiological features in this post-kidney transplantation patient are highly suggestive of pulmonary tuberculosis.
M. tuberculosis bacilli must be found by direct observation, culture, & nucleic acid testing to the diagnosis.
A quick molecular test, like the Xpert MTB/RIF assay, is very specific and has an estimated sensitivity of 98% in smear positive respiratory samples and 67% in smear negative respiratory samples.
Moreover, it enables the simultaneous identification of as rifampicin resistance.
Treatment
Treatment for LTBI is a successful technique to prevent transplant recipients from developing active TB infection.
For TX candidates who have not been previously treated & have positive TST or IGRA, LTBI therapy is advised.
Treatment of active TB is with a combination of 4 anti-tuberculous drugs (rifampicin, isoniazid, pyrazinamide & ethambutol).
It is unknown how long TX recipients should receive TB medication.
Based on the findings of a few studies that revealed a link between shorter regimens & higher recurrence & death, several physicians advise that treatment last for at least 9 months.
Close monitoring is important because of the increased risk of A/Es & possible drug interactions, particularly during the 1st 2 months of treatment when it should be done biweekly.
INH, rifampicin, & pyrazinamide use concurrently is linked to a higher risk of hepatotoxicity, particularly in liver recipients.
During the 1st 2 months of treatment, low-grade elevation of aminotransferases can be seen, but treatment must be stopped if it increases threefold with any symptom or fivefold without any symptomatology.
Drug interactions
Induction of cytochrome P450 system by rifamycin, results in a decrease in the blood levels of the majority of IS medications (tacrolimus, cyclosporine, sirolimus, everolimus, & corticosteroids).
A higher risk of graft rejection is linked to a lower blood level of IS medications. Thus, careful observation & dose adjustment are strongly advised.
To keep the drug’s trough levels in the therapeutic range, daily doses of cyclosporine, tacrolimus, & mTOR inhibitors typically need to be increased by 2 to 5 times.
Second-line drugs (quinolones, aminoglycoside and clarithromycin) are indicated because of first-line drug resistance or side effect, severe clinical condition or co-infection with atypical mycobacteria.
==========================
·Would your management differ if the disease was mild and affected one lung?
In any case, it needs to receive a thorough course of treatment.
In SOT recipients, rifampicin is not contraindicated, & it has a higher sterilizing effect when used in regimens. Furthermore, treatment with rifampicin-based regimens has no impact on rejection or mortality rates, given that sufficient monitoring is in place.
References
Emmanuel Canet, Jacques Dantal, Gilles Blancho, Maryvonne Hourmant, Stéphanie Coupel, Tuberculosis following kidney transplantation: clinical features and outcome. A French multicentre experience in the last 20 years, Nephrology Dialysis Transplantation, Volume 26, Issue 11, November 2011, Pages 3773–3778,https://doi.org/10.1093/ndt/gfr156
Santoro-Lopes, Guilherme; Subramanian, Aruna K.; Molina, Israel; Aguado, José María ; Rabagliatti, Ricardo; Len, Oscar. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation 102(2S):p S60-S65, February 2018. | DOI: 10.1097/TP.0000000000002014
Honestly, I am not sure of any differences in medical treatment of TB depending on whether one or both lungs are involved.
It may be relevant if surgical treatment is considered.
Lung transplantation may be indicated if a destructive disease affected both lungs.
night fever 39 C, productive cough, and weight loss in immunocompromised patient together with bilateral pulmonary infiltration can raise suspicion of pulmonary TB.
management:
1- sputum sample for AFB smear
2-PCR for TB
3-start antiTB medications four-drug regimen: pyrazinamide (three months); ofloxacin (nine months); INH and ethambutol (18 months). The dose of INH and ethambutol has to be adjusted for the degree of renal function. If rifampicin has to be used for those who are not on cyclosporine, prednisolone dose has to be doubled. secondary prophylaxis should be considered after successful treatment.
non responding means atypical infection or multi drug resistance
no, the management will not differ if diagnosis of TB confirmed
of course the tacrolimus is the cornerstone immunosuppressive medications in the renal transplant recipient and rifampicin is the cornerstone of anti TB medications , both interact with each others ; rifampicin decreases the trough level of tacrolimus expose the patient to risk of allograft rejection, so the dose of tacrolimus should be increased to adjust the trough level which should be monitored closely.
Rifampicin is a strong inducer of CYP3A4 and can lead to increase or enhance metabolism of CNI, mTOR, MMF and steroid maximize the dose of CNI will be associated with more adverse effects and more cost
some add ketoconazole to decrease the dose of tacrolimus hence adjust trough level and decrease adverse effect and cost but this may decrease efficacy of antiTB medication
rifabutin is alternative drug to rifampicin but less interaction with CNI but mostly it is unavailable
close and frequent monitoring of trough level of CNI is very important to decrease the risk of graft rejection
The presented radiological images show bilateral diffuse pulmonary infiltrates with perihilar basifications (mostly representing enlarged perihilar lymph nodes).
These findings, with the history of night fever, productive cough and loss of weight in an immunocompromised patient as in the presented case scenario, should raise the suspicion of pulmonary TB (miliary TB) (1).
How do you manage this case?
– The first step will be to confirm the diagnosis:
The diagnosis of pulmonary TB is definitively established by isolation of Mycobacterium tuberculosis from a bodily secretion (eg, a culture of sputum, bronchoalveolar lavage, or pleural fluid) or tissue (pleural biopsy or lung biopsy) (2).
Sputum acid-fast bacilli (AFB) smear and nucleic acid amplification (NAA) testing are considered additional diagnostic tools for active TB infection. positive NAA test (with or without AFB smear positivity) is considered sufficient for the diagnosis of TB (2). An approach for the interpretation of the NAA test in suspicious case scenarios is illustrated in the attached algorithm (2).
Additionally, a tuberculin skin test (TST) or interferon-gamma release assay (IGRA) can be performed. A positive result supports (but cannot be used to establish) a diagnosis of active TB disease, and a negative result does not rule out active TB disease (2).
– The second step in management will be the initiation of the appropriate therapy:
1) Reduction of immune suppression will be a logical approach in the face of severe and potentially fatal infection. We will start by reduction of antimetabolite by 50%, with possible total withdrawal if the infection becomes progressive and not responding to treatment (3).
2) Because of the increase in multidrug-resistant (MDR) strains, appropriate therapy should include four agents: isoniazid (INH), rifampin or rifabutin, pyrazinamide, and ethambutol for at least two months or until susceptibility test results are available followed by up to 10 months of INH and rifampin (3).
3) Rifampin (and rifabutin to a lesser extent) markedly reduces cyclosporine and tacrolimus levels, and it may be difficult to achieve therapeutic levels for patients taking rifampin, the use of which should be avoided if at all possible. Pyrazinamide and ethambutol may reduce drug levels, and their use requires monitoring (3).
Would your management differ if the disease was mild and affected one lung?
The American Society of Transplantation (AST) states that a rifamycin-containing regimen is strongly preferred for both severe and localized non-severe TB due to the potent sterilizing activity of such regimens and the importance of preventing the emergence of resistance (4).
Experts agree that rifamycins are indicated in patients with severe (eg, cavitary or multilobar disease) or disseminated TB or when there is suspicion or documentation of INH resistance (4).
Therefore, if the disease is mild and resistant strains of TB are unlikely (based on the patient history and discussion with the local microbiologist), I will recommend Rifamycin-free anti-tuberculous protocols with close monitoring of the patient’s condition and allograft function.
In our local practice, 5 years ago, we faced a challenging case with an open pulmonary TB (resistance could not be excluded). He was admitted in the isolation room and received quadrable therapy formed of isoniazid (INH), rifampicin, pyrazinamide, and ethambutol for three months till he had 2 sequential negative sputum samples. The patient maintenance immune suppression before infection was everolimus, MMF and steroid 5 mg daily. During the course of treatment, the everolimus was persistently undetectable despite multiplying the dose four times. We reduced the MMF dose by 75%, and the dose of prednisolone was increased to 15 mg daily (as a part of the management of stress resulting from generalized sepsis after a discussion with our infection control team).
The patient had a stable allograft function throughout the whole treatment course (possibly secondary to immune paresis), and he was discharged home with normal allograft functions. The patient is still following up in our transplantation clinic with the latest serum Cr around 90 umol/L. TB reactivation never occurred, and the anti-TB drugs were stopped completely after 12 months from the initiation of treatment.
4) 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;33(9):e13513.
The medications used in the treatment of active TB are illustrated in the attached table (1).
References:
1) Subramanian AK, Morris MI, AST Infectious Diseases Community of Practice. Mycobacterium tuberculosis infections in solid organ transplantation. Am J Transplant. 2013;13 Suppl 4:68-76.
The medications used in the treatment of active TB are illustrated in the attached table (1).
(( I am sorry for the duplication, but the table failed to be attached to the previous contribution)) References:
1) Subramanian AK, Morris MI, AST Infectious Diseases Community of Practice. Mycobacterium tuberculosis infections in solid organ transplantation. Am J Transplant. 2013;13 Suppl 4:68-76.
“A tuberculin skin test (TST) or interferon-gamma release assay (IGRA) can be performed. A positive result supports (but cannot be used to establish) a diagnosis of active TB disease, and a negative result does not rule out active TB disease”.
I would be very grateful if you explain this paragraph quoted from your excellent answer.
Also, It is not clear to me how would you treat it if it is affecting a single lung.
Tuberculin skin test and IGRA represent immunological reaction of the body immune system to TB, so they are mostly negative in case of active TB, as actually reactivation of latent TB to active disease occurs in immunosupression state like kidney transplant recipients.
I agree with the contribution of Dr Mai Shawky Korkor as both tuberculin skin test (TST), and interferon-gamma release assay (IGRA) are immunological assays which depend on the immune response of the patient’s immune system. Therefore, their results should be interpreted with great caution in immune-compromised patients like HIV-infected persons and Solid organ transplant recipients.
Additionally, false positive results of TST can occur secondary to effective BCG vaccination.
The attached table illustrates a comparison between TST and IGRA. It also mentions special situations with false negative results (1). Therefore, we can not rely on these tests alone for diagnosis or exclusion of active TB disease.
Also, It is not clear to me how would you treat it if it is affecting a single lung.
Expert opinion suggests using rifabutin in place of rifampin due to the less potent enzyme inducer effect (2). Additionally, some studies showed non-inferior outcomes of a four-month rifapentine-moxifloxacin regimen in the management of drug-susceptible pulmonary tuberculosis (3).
The aim is to minimize the drug interaction of traditional rifampin whenever possible.
3) Dorman SE, Nahid P, Kurbatova EV, et al. Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis. N Engl J Med. 2021;384(18):1705.
How do you manage this case? D/D
Miliary TB
disseminated fungal infections like blastomycosis, cryptococcosis, histoplasmosis or coccidioidomycosis.
primary lung malignancy like adenocarcinoma can mimic mottling
metastasis from highly vascular tumour like renal cell carcinoma and melanoma or from breast, thyroid and prostate neoplasms.
Sarcoidosis
pneumoconiosis (silicosis)
hypersensivity pneumonitis
rarely pulmonary alveolar microlithiasis.
Investigations
Routine blood labs
Chest xray
CT scan chest
tuberculin skin test
sputum for gram and acid-fast stain.
Sputum culture for bacterial and fungal infections
erythrocytic sedimentation rate
PCR tests on sputum
if still diagnosis not certain then Bronchial wash and transbronchial biopsy
if needed Computed tomography-guided needle biopsy
treatment
for military TB
INH x 18 months
Ethambutol x 18 months
Pyrazinamide x 3 months
Ofloxacin 9 months
Tuberculosis in renal transplant recipients
Madhivanan Sundaram et al
Polka dot lung: classical miliary mottling in an adult
Satish Swain et al
Would your management differ if the disease was mild and affected one lung?
No ,treatment remains same in military TB.
The patient is a 47-year-old recipient of a kidney transplant from a living donor with a mismatch of 111, no DSAs, and stable graft function who presents one year post-transplant with a fever of 39 degrees Celsius, weight loss, and a productive cough.
The X-ray of the chest reveals reticulonodular shadows in the hilar regions of the bilateral lung fields. Multiple miliary nodular lesions (arrows) were detected throughout the lung parenchyma on the HRCT thorax section imaged.
Based on the presented clinico-radiological picture, miliary tuberculosis is the most likely diagnosis. Nonetheless, the diagnosis must be confirmed, and because the patient is a renal transplant recipient, other differential diagnoses, including pneumonia causes, must be kept in mind.
Differential diagnosis:
1) Viral: Respiratory viruses (Influenza, parainfluenza etc), Herpesviruses (like cytomegalovirus, CMV)
2) Fungal: Pneumocystis jirovecii (PCP), histoplasma, Cryptococcus
3) Bacterial: community acquired like streptococci, tuberculosis etc.
4) Parasitic
5) Non-infectious: mTOR inhibitor associated pneumonitis
A thorough medical history and physical examination. The history of prior tuberculosis, the use of induction therapy, and the immunosuppressive regimen employed are particularly significant. Inquire about any recent contact with a patient with tuberculosis, as well as the donor’s own tuberculosis history.
2. Laboratory testing consisting of a complete blood count, renal function tests, liver function tests, C reactive protein, blood culture, chest X-ray, influenza testing (if in influenza season) and other respiratory viral testing (biofire), serum beta-D glucan, serum LDH, and calcineurin inhibitor (CNI) trough levels (if on CNIs).
3. Examination of induced sputum for cytology, Gram stain, acid-fast bacilli (AFB) stain, and culture
high-resolution computed tomography (HRCT) scan of the thorax.
5. CMV PCR testing: to exclude the possibility of CMV infection (although it is unlikely in this context).
Bronchoscopy with bronchoalveolar lavage (BAL) with or without transbronchial lung biopsy: for stain and culture (fungal, AFB) as well as PCR for respiratory viruses, CMV, pneumocystis, and histopathology evaluation.
If the diagnosis of active tuberculosis is confirmed, the treatment consists of a 4-drug regimen of Isoniazid, Rifampicin (or rifabutin), Pyrazinamide, and Ethambutol for the initial 2 months (intensive phase), followed by Isoniazid and Rifampicin (or rifabutin) for an additional 4 months (continuation phase) in immunocompetent patients (2). Ethambutol can be discontinued if the organism’s susceptibility to the other three medications is confirmed (3).
Rifampicin is an inducer of the enzyme CYP3A4, which increases the metabolism of immunosuppressive drugs (cyclosporin, tacrolimus, sirolimus, everolimus, and steroids), necessitating a dose increase (up to 2–5 times for cyclosporine/tacrolimus and 2 times for steroids) and close monitoring of drug levels (4). Rifabutin can be substituted for rifampicin, resulting in a smaller increase in immunosuppressant drug dose than when rifampicin is used (5). Ethambutol and isoniazid appear to have no interaction with immunosuppressive drugs (4).
The optimal duration of treatment has not been determined; however, many specialists recommend 9 months (5). Uncomplicated pulmonary tuberculosis with a negative sputum test after 2 months of treatment requires only 6 months of treatment, whereas a positive sputum test after 2 months of treatment requires 9 months of treatment (2). It is also recommended that patients with bone and joint involvement, central nervous system involvement, or disseminated disease receive treatment for a longer duration (2).
Due to the prevalence of miliary pulmonary nodules in the index patient, there is a high probability of multisystem involvement; therefore, the patient may require 9 months of treatment.
In addition to monitoring drug levels and graft function, liver function tests must also be monitored due to the risk of hepatotoxicity associated with anti-tubercular drugs. Pyridoxine must be administered with isoniazid.
If the patient’s clinical condition deteriorates, the antimetabolite (MMF or azathioprine) dose may need to be decreased or discontinued.
Would your management differ if the disease was mild and affected only one lung?
No, the treatment would remain the same (4-drug regimen) for a duration of 6 months (localized tuberculosis).
This is a case of miliary tuberculosis after renal transplant..Patient has fever, night sweats and cough with weight loss…there is evidence of miliary tuberculosis in CT scan with hilar lymphadenopathy….
the other differential diagnosis for miliary mottling in the lung fields are langerhans histiocytosis, viral pneumonumonia, sarcoidosis, histoplasmosis, cryptococcidiomycosis, histoplasmosis and metastasis….
For definitive diagnosis we need to prove TB in the sputum by AFB stain or Gene Xpert MTB…We may need bronchoscopy and BAL for better yield…Bronchoscopy and Transbronchial lymph node biopsy is also needed to establish tissue diagnosis….
According to the American Society of Transplantation, the goal is to eradicate TB completely….The treatment protocol does not vary if there is localized miliary mottling of one lung
the treatment is standard 4 TB drugs namely Tab Isoniazid 10mg/kg, T. Rifampicin 15mg/Kg, combutol 25-30mg/Kg and Pyrazinamide 1000mg/day with addition of pyridoxine 40mg/day
The interaction of rifampicin with immunosuppressive agents require them to change to second line agent like levofloxacin which has less interaction with CNI
In this case, a renal transplant recipient presented with symptoms of fever, productive cough, and weight loss, along with bilateral lung infiltrates and hilar lymphadenopathy on imaging. The differential diagnosis for diffuse nodular opacities in the lung includes conditions such as pulmonary TB, Langerhans cell histiocytosis, diffuse pneumonia (bacterial or viral), silicosis, hypersensitivity pneumonitis, sarcoidosis, and metastatic lung cancer. To definitively diagnose TB, further workup and investigations are necessary, including isolating Mycobacterium TB via culture or acid-fast bacilli in sputum smear, or using nucleic acid amplification testing like the Gene-Xpert test.
Tests like Tuberculin skin test (TST) and Interferon Gamma Release Assay (IGRAs) can support the diagnosis of TB but are less reliable in immune-compromised patients. Other causes of the differential diagnosis should also be ruled out through tests such as urinary or serum antigen for histoplasmosis, CMV PCR, sputum or BAL culture for bacteria and fungi, and B D-glucan.
If TB is confirmed as the diagnosis, a 4-drug regimen is recommended initially for at least 2 months (INH + Rifampin + Pyrazinamide + Ethambutol), followed by a 2-drug regimen for 6-9 months (INH + Rifampin). Management of immunosuppressive medications involves reducing anti-metabolites, increasing the dose of steroids, monitoring therapeutic levels of calcineurin inhibitors (CNI), and adjusting CNI doses due to drug interactions with anti-TB medications. Regular monitoring of renal and liver function tests, medication side effects, and vision changes (in the case of ethambutol) is necessary. Treatment can be stopped after two negative sequential sputum samples by GeneXpert.
Consultation with the infection control team and microbiology team is crucial for appropriate management of the patient. Regular follow-up is important to monitor for TB reactivation and ensure successful treatment.
According to the guidelines provided by the American Society of Transplantation, the treatment approach for both severe and localized non-severe tuberculosis (TB) is the same. The goal is to administer a regimen that ensures complete and thorough treatment, aiming to eliminate the infection and prevent the development of treatment resistance.
Before treatment of LTBI, active TB needs to be excluded. Medications will need to be discontinued or dose adjusted if liver function tests are more than three times the upper limit of normal with symptoms/signs, or more than five times the upper limit of normal without symptoms
Treatment of active drug susceptible TB usually involves two months of an initial phase therapy with INH, rifampin/rifabutin, pyrazinamide, +/- ethambutol, followed by a continuation phase therapy of four months of INH and rifampin, with a total duration for six months.
Reference
. Subramanian AK, Morris MI. Mycobacterium tuberculosis infections in solid organ transplantation. Am J Transplant. 2013;13 Suppl 4:68–76. [PubMed] [Google Scholar]
12. Bumbacea D, Arend SM, Eyuboglu F, Fishman JA, Goletti D, Ison MG, Jones CE, Kampmann B, Kotton CN, Lange C, et al. The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement. Eur Respir J. 2012;40:990–1013. [PubMed] [Google Scholar]
● An Immunocompromised recipient with intense immunosuppression due to ABOi presented 1 year after transplantation with weight loss, night fever, and productive cough .
● Radiographic imaging shows perihilar reticulonodular infiltrates that consists with military TB
● Other concomitant infections as fungal, PJP, and viral infections must be rule out .
● For diagnosis we need:
** Staining acid-fast bacilli in the sputum
** Sputum calture
** PCR mycobacterium tuberculosis in blood
** Broncosopy with BAL and lung biopsy
** General teste: CBC,CRP,ESR,liver tests, renal function tests, LDH, and PCR ( CMV,EBV).
● Treatment:
** Duration should be at least 6–9 M
The first-line treatment should be a four-drug regimen containing rifamycin and consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin
** Second-line regimen without rifamycin the 2-month contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a phase of 12–18 months with isoniazid and ethambutol or pyrazinamide. Here a longer period of treatment is recommended
** One challenge is the drug interaction between rifampicin and IS drugs
☆ Rifampicin decrease the levels of CNi , mTORi and affects steroid metabolization,
which increases the risk of rejection
☆ Therefore calcineurin and mTOR inhibitors levels should be monitored and increased three- and five-fold and the glucocorticoid dose should be doubled
☆ An alternative to rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 or fluoroquinolones
● In cases of localized mild condition regimen without rifambicin could be used for 6 months
How do you manage this case?
This index case presented with night fever, productive cough and weight loss.
CXR and CT lungs showed bilateral lung infiltrates without sub-pleural spare.
The clinical picture and radiographic findings points to a pulmonary TB infection.
DD:
· · Atypical pneumonia.
· · CMV pneumonitis.
· · PJP Pneumonia
Management plan:
· Detailed history including history of previous TB exposure and treatment with anti-TB treatment. Beside, recent contact or travel to an endemic area. Also, the history of induction therapy used, and the maintenance immunosuppressive regimen used is of great importance.
· MDT approach involving a pulmonologist and ID team
· Supportive measures: adequate hydration and antipyretics, nutritional support. CMV
Screening for TB:
· Sputum microscopy and culture for AFB.
· Rapid molecular test (the Xpert MTB/RIF assay) is highly specific. The sensitivity in a smear positive sample is 98% and in smear negative sample is 67%
· Exclude other possible causes: CMV PCR, PJP and atypical pneumonia
· The treatment is according to the cause.
Treatment of active TB infection:
· Duration: at least 9–12 months (like our index case with military TB). Longer duration treatment is recommended in patients with disseminated disease, bone, joint and CNS involvement.
· First-line treatment is a four-drug regimen containing Rapamycin used in both severe and non-severe cases.
· Standard regimen: 2-month using 4 drugs (intensive phase) including isoniazid, rifampicin (Rifabutin), pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and Rifampicin (Rifabutin can be used instead as it has a lesser effect on cytochrome p450). Pyridoxine should be given with isoniazid.
Adjustment of immunosuppression dose:
· Rifampicin is a CYP 450 enzyme inducer increasing the metabolism of immunosuppressive drugs. Therefore, we need to increase the dose of cyclosporine or tacrolimus by2-5 times and steroids by 2 times. This should be coupled with close monitoring of the drug levels. If the clinical status of the patient worsens, antimetabolites (MMF or azathioprine) might require reduction or cessation.
· Rifampicin free regimens can be used in non-severe disease or if there is interaction between Rifampicin and other immunosuppressive drugs.
Rifampicin free Regimens include:
· Regimen A: INH + ethambutol + pyrazinamide or levofloxacin are used for 2 months, followed by INH + either ethambutol or pyrazinamide for 12 to 18 months.
· Regimen B : INH + ethambutol + pyrazinamide or levofloxacin are used for 12 months
Would your management differ if the disease was mild and affected one lung?
· The treatment is the same (4-drug regime). However, a 6 month duration of anti-TB treatment may be given (localized tuberculosis).
References:
1. Sparkes T, Lemonovich TL; AST Infectious Diseases Community of Practice. Interactions between anti-infective agents and immunosuppressant-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13510
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 Feb; 102(2S Suppl 2):S60-S65.
Clinical features and Radiological features are suggestive of Milliary Tuberculosis.
How do you manage this case?
CBC with ESR should be sent.In miliary TB, haematological abnormalities may include anaemia, leukopenia, leukocytosis, monocytosis, agranulocytosis, thrombocytopenia and pancytopenia . Also, ESR is typically high.Sputum test for AFB should be sent.Also if available PCR testing can be done on sputum.If Diagnosis is not confirmed ,BAl fluid examination can be done. Transbronchial lung biopsy can be performed if any doubt exists .
Treatment for TB was initiated with rifampicin (10 mg/kg/day), isoniazid (5 mg/kg/ day), ethambutol (25 mg/kg/day), pyrazinamide (15 mg/ kg/day) and pyridoxine (10 mg/day. Treatment duration should be at least 9 months, based on the results of a few studies that have suggested an association between shorter regimens and greater recurrence and mortality.Cyclosporine /tacrolimus and mycophenolate dose may have to increase by 2 to 5 folds due to drug interaction between rifampicin and Tacrolimus/mycophenolate.
Would your management differ if the disease was mild and affected one lung?
No,same managment
How do you manage this case?
the finding and the history making miliary TB is the diagnosis but other causes as CMV, PJP, and atypical pneumonia
diagnosis:
TB PCR
TB culture
CMV PCR
Treatment
duration 9-12 months as it is disseminated
standard regimen:
4drugs for 2months ( INH, Rifampicin, pyrazinamide and ethambutol)
2drugs ( INH, Rifampicin)
Rifabutin can be used instead of Rifampicin as it has lesser effect on cytochrome p450.
Would your management differ if the disease was mild and affected one lung?
the treatment is the same but the duration 6 months
Q1: CXR shows bilateral small nodular shadows indicating miliary TB (probably MDR) and tracheostomy.
History of previous exposure or treatment of active TB and reactivation post-TX and originally or travel to endemic areas of TB should be taken.
Other opportunistic infections such as pulmonary CMV aspergillus, histoplasmosis, PJP and fungal infections should be considered. PCR to detect genetic mutation and smear and staining or culture for acid fast bacilli from induced sputum or BAL fluid should be done.
Imaging studies like bone abdominal and pelvic or brain CT scan or even CSF analysis are necessary for treatment. Start with a four-drug regimen for at least 2 months and continue with at least four months with rifampicin and isoniazid.
The optimal treatment duration varies from 6 to 24 months and at least 9 to 12 months. As rifampicin reduces CNI and mTORi levels, the dose of CNIs, mTORi should be increased by three to five times and the glucocorticoid dose should be doubled.
Q2: according to AST, the first-time treatment is a
four-drug regimen for both severe and non-severe cases. Close monitoring for
CNI and mTORi levels is necessary.
Rifampicin-free regimens include INH and ethambutol for 18
months, levofloxacin for 6, and pyrazinamide for three months. (if no
resistance to INH)
Rifabutin is an alternative drug with fewer effects on
cytochrome p450, cyp3A4, and p-glycoprotein.
Reference:
Subramanian, A. K., & Theodoropoulos, N. M. (2019). Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious diseases community of practice of the American Society of Transplantation. Clinical Transplantation, 33(9). https://doi.org/10.1111/ctr.13513
How do you manage this case?
The diagnosis is Tuberculosis and other diagnosis is PCP or CMV pneumonia. The mainstay treatment is anti-TB medications. Treatment is with Rifampicin, Isonaizid, Ethambutol and Pyrazinamide for 2-4 months.
Would your management differ if the disease was mild and affected one lung?
Treatment will remain same.
I would perform with a boncoscopy with bronchoalveolar lavage:
– PCR for Tuberculosis and BAAR
– Cultures of mycobacterium and fungis
– Galactomana
– Citologic study
In this case, I would choose to associate the BAL with the performance of a biopsy for histopathological and staining analysis, considering the possibility of malignancy.
Hx base diagnosis; Miliary tuberculosis most probably
D/D
PCP
Viral pneumonia
CMV pneumonia
Fungal pneumonia
Investigation; Peripheral smear, CRP Sputum for AFB, Gene Xpert & culture, PCR in sputum
CSF examination if CNS involment study if neurological finding present
Lymph node biopsy if palpable esp neck lymph node
Treatment.
First two month 4 anti tuberculous drugs and next 4 month 2 antituberculous drugs with monitoring of mTOR and CNI level
No difference in treatment
From the given history & radiological findings (multiple miliary mottling shadow affecting both lung field), this patient is suffering from miliary TB.
– Detail history & clinical examination to find out dessiminated TB
Investigations:
-CBC, CRP
– RFT, LFT
– Sputum for AFB, Gene Xpert & culture
– CSF study if neurological finding present
– FNAC of lymp node in case of lymphadenopathy.
Treatment
– Anti TB – 6 month
(Intensive phase – INZ, Rifampicin, ehambutol, PZA for 2 month then continuation phase with INZ & rifampicin for 4 month)
– Monitoring CNI & m TORi level.
– Increase dose of CNI / mTORi to maintain therapeutic range.
– Double the dose of steroid.
– Monitoring liver function 2 weekly for first 2 month then monthly thereafter.
– After completion of Anti TB dose reduction of CNI/mTORi & steroid to previous dose.
No difference. Similar treatment
How do you manage this case?
Chest X-ray showed diffuse bilateral reticulonodular opacities and HRCT chest showed miliary mottling with multiple small nodules involving both lungs
1 year post transplant, having fever, productive cough and weight loss – provisional diagnosis is Miliary Tuberculosis should be made.
Other Differential Diagnosis:
– PCP
– Viral / Bacterial (atypical) / Fungal pneumonia
– Hypersensitivity pneumonitis
– Histiocytosis X (Langerhans cell histiocytosis)
– Lymphangitis carcinomatosa
Ø Diagnosis can be confirmed by
o Sputum AFB (ZN stain), Sputum Culture (BACTEC) and drug sensitivity;
o TB PCR in sputum (Gene X pert / TB-Gold) test
· To rule out PJP in sputum
Ø Treatment:
1. Minimize immunosuppression and starting ATT
Miliary TB being a life-threatening condition, stopping all IS except steroids which can be given in preferably higher dose.
Alternately, graded approach of stopping MMF, continuing Tacrolimus and steroid at higher dose –> if symptoms does not improve by 3-4 weeks, stopping Tacrolimus also is imperative.
2. ATT – intensive phase with 4-drugs regimen (INH, Rifampicin, Pyrazinamide, Ethambutol + Pyridoxine) in standard dose.
– Intensive phase to continue for minimum of 2-3 months, or till 2 sequential sputum samples become negative.
Continuation phase 9-10 months with (INH + Rifampicin + pyridoxine)
– Total duration 12 months – can be extended up to 24 months, depending on response and side effects.
– Rifampicin interaction with CNI – needs Tacrolimus dose increase (2-5 folds) to maintain desired trough level.
– If initial response to intensive phase (4 drugs regimen) is encouraging, Rifa-sparing regimen (INH + Ethambutol + Moxifloxacin / Levofloxacin) can be tried for 12-24months, with better graft survival.
– Rifabutin has less potential for P450 enzyme induction, may be tried in place of Rifampicin.
– Regular monitoring RFT (for rejection), CNI drug level, LFT, ATT related side effects.
3. Sputum AFB / culture / Gene X-pert tests to be repeated to monitor treatment response
4. Nutrition – high protein diet
Would your management differ if the disease was mild and affected one lung?
– Yes, the management, outcome and complications would differ
– IS reduction would have been graded (MMF by 50%) or not required.
– ATT regimen: 2months intensive phase with 3-4 drugs, then Rifa sparing regimen for 9-12 months.
– Rifa-sparing regimen, al together also may be tried.
REFERENCE:
1. Infectious Disease Society of Clinical Practice Guidelines; Tx of drug susceptible TB; Clin infectious diseases 2016 Oct; 63 (7): 147-195.
2. Subramanian AK, Theodor Opoulos NM. Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious disease community of practice of the American Society of Transplantation. Clinical transplantation. 2019 Sep; 33(9): e13513. PubMed PMID: 30817030. Epub 2019/03/01.
3. Sun HY, Munoz P, Torre-Cisneros J, Aguado JM, Lattes R, Montejo M, et al. Mycobacterium tuberculosis-associated immune reconstitution syndrome in solid-organ transplant recipients. Transplantation. 2013 May 15;95(9):1173-81. PubMed PMID: 23435454. Epub 2013/02/26.
4. Abad CLR, Razonable RR. Mycobacterium tuberculosis after solid organ transplantation: A review of more than 2000 cases. Clinical transplantation. 2018 Jun;32(6):e13259. PubMed PMID: 29656530. Epub 2018/04/16.
5. Anand M, Nayyar E, Concepcion B, Salani M, Schaefer H. Tuberculosis in kidney transplant recipients: a case series. World journal of transplantation. 2017;7(3):213.
Diagnosis:
Millary TB
INVESTIGATION:
CBC, ESR, LFT, CRP, RFT
QUANTIFERON TB test
Sputum for C/S
Isoniazid, ethambutol, pyrazinamide are safe in post transplant patients.
Rifampicin reduces the levels of CNI and preferably should be avoided.
Ofloxacin, is often added to four-drug regimens.
Four-drug regimen:
INH and ethambutol (18 months)
ofloxacin (nine months)
pyrazinamide (three months)
The dose of isoniazid and ethambutol should be adjusted according to the degree of renal function.
Would your management differ if the disease was mild and affected one lung?
The management is the same for one lung or both lungs involvement.
References;
1. https://pubmed.ncbi.nlm.nih.gov/36145473/.
2. https://ann-clinmicrob.biomedcentral.com/articles/10.1186/1476-0711-5-3.
How do you manage this case?
fever 1 year after RTX
weight loss
CXR ( bilateral diffuse reticular nodular infoltration )
==> active TB (military TB)
●History and clinical examination
History of previous exposure to TB or previous treated TB infection
othe differential diagnosis still
bacterial pneumonia
viral pneumonia (herpes virus- Covid19)
CMV pneumonia
Fungal pneumonia
●this patient needs to be admitted in the hospital
●monitoring vital signs (RR- saturation– )
●depending on saturation he may need O2
●laboratory tests (CBC- CRP- ESR – LFT- Crea- )
● tracheal aspirate and staining for Acid fast bacilli ( the sensitivity low,)
●Culture needs to wait for long time
● bronchoscopy, and BAL assay, and it may need to exclude CMV (PCR) and other bacterial and viral infections
●PCR techniques of tracheal aspiration samples to identify the genetic mutations of MDR-TB
●This case is a severe TB rifamycins are recommended
●Rifampin should be used with caution
●The rifamycins (especially rifampin) reduce serum concentrations of tacrolimus cyclosporine rapamycin everolimus
●Patients receiving a rifamycin-containing regimen should be treated for a minimum of six to nine months.
●non-rifamycin-based regimen in cases of localized (eg, pulmonary) nonsevere TB when there is no suspicion or evidence of isoniazid resistance .
●In patients not receiving a rifamycin, treatment options include a three-drug regimen of INH + ETHAMBUTOL + either pyrazinamide or levofloxacin for 2 months, followed by a two-drug regimen of INH plus ethambutol or pyrazinamide for 12 to 18 months.
● In those receiving a three-drug regimen for the entirety, the duration of treatment can be shortened to 12 months
● if any suspection, of bacterial or CMV infection; empirical antibiotics treatment and starting IV ganciclovir treatment is necessary until the results appear
●HIV test should be performed
-1-How do you manage this case?
Imaging (X-Ray Chest and HRCT chest )in the above case showed bilateral reticulo-nodular opacities with perihilar shadowing. Fever in the renal transplant case with night sweats and above findings suggest miliary tuberculosis. Other differentials which need to be considered include viral and fungal pneumonias.
After detailed history and examination, tests which need to be carried out include CBC, ESR, RFT, LFTs Sputum for AFB by stain ,AFB C/S and Genexpert-RIF resistance and if no sputum production then BAL for AFB,AFB C/S and Genexpert-RIF. Viral pneumonias test include PCR for CMV DNA and HZV virus .Tac level to be monitored closely and frequently.
Once the diagnosis is confirmed, patient will be started on weight based standard four drug regimen (rifampicin,Pyrazinamide,INH, myambutol) during the intensive phase but with close monitoring of drug level and side effects .Tacrolimus dose to be increased few days before ATT commencement and MMF to be withheld for few weeks. After 02 months, patient will be started on continuation phase with two drugs and hat to be continued for six months. Duration of ATT also depends on the extent of involvement of the disease. For extensive and cavitatory disease-duration is for 9 months however, for disseminated disease, it is for 12 months.
Would your management differ if the disease was mild and affected one lung?
Treatment will remain the same i.e., standard four drug for mild case for six months and will be different for resistant and extensive disease.IF rifampicin not to be used ,then 02 month regimen , isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by isoniazid and ethambutol or pyrazinamide for 12–18 months.
REFERENCE:
1-Sorohan, B.M.; Ismail, G.; Tacu, D.; et al. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens 2022, 11, 1041.
The patient is a post renal transplant within one year who presented with fever cough and night sweats…. He has received kidney transplant from his brother with haplomatch and no DSA…..
CXR shows miliary mottling of both the lungs…. CT scan also shows Miliary mottling with few small nodulo cavitatory lesions….
The most likely diagnosis is Tuberculosis post renal transplant…
The patient management includes investigations and treatment…Investigations include CBC, Renal function test and Liver function test….Procalcitonin and Blood cultures should be done.. Empirical antibiotics should be given… Patient should be asked about the hisotry of LTBI in the donor and recipient if any before transplant…. sputum for AFB, Gene Xpert MTB should be asked for..In this Gene Xpert MTB rifampicin resistance is also detected… So this will help in the treatment also….if the sputum is not sufficient we should encourage them to give induced sputum after 3% saline nebulization…. ideally 3 sputum AFB samples in the morning is recommended as per RNTCP program in our country… but in transplant patients even one sample of AFB positivity is enough…. sometimes adequate sputum sample is needed and may not be able to procure….We have to start treatment empirically given the clinical scenario in this patient…. We need to look into tacrolimus level as a baseline…
The treatment of the above include 4 drug regimen ….Namely Rifampicin, Isoniazid, Combutol and Pyrazinamide with pyridoxine…. The treatment duration is generally continued for 9 to 12 months depending on the severity of the disease..6 months of treatment is sufficient of extra pulmonary TB but not for miliary TB treatment .. Every country has a different protocol for the treatment of TB…In our country, We need to start the 4 medicines and continue them for 9 months… the treatment for miliary TB is minimum 9 to 12 months in immunocompromised patient….The first 2 months include the intensive phase namely all the 4 drugs followed by remaining months of INH and Rifampicin
Rifampicin is an enzyme inducer and it can reduce the levels of Tacrolimus and steroids….Hence another alternative is to give non rifampicin based regimen, which include Isoniazid, PZA, ethambutol and Levofloxacin….
Another alternative is to use Rifabutin which is a less powerful enzyme inducer, but there are hardly any trials or enough data to support the use in renal transplants….
The liver functions need to be monitored for the hepatotoxicity of the medicines
The management should not differ if the disease is localized or mild and affecting one lung as the recommendations from Infectious disease society of America and WHO guidelines suggest disease treatment for 9 months or as far as possible in order to avoid disease treatment and eradication
Diagnosis:
Millary TB
INVESTIGATION:
CBC, ESR, LFT, CRP, RFT
QUANTIFERON TB test
Sputum for C/S
Isoniazid, ethambutol, pyrazinamide are safe in post transplant patients.
Rifampicin reduces the levels of CNI and preferably should be avoided.
Ofloxacin, is often added to four-drug regimens.
Four-drug regimen:
INH and ethambutol (18 months)
ofloxacin (nine months)
pyrazinamide (three months)
The dose of isoniazid and ethambutol should be adjusted according to the degree of renal function.
· How do you manage this case?
· This is a case of immunocompromissed patient with history of solid organ transplantation. He is around (20-74)18.5% more at risk of developing opportunistic infection then normal population.
· If latent disease there is 80-100% risk of developing reactivation.
· According to the history post-transplant, immunocompromissed, no history of prophylaxes, history fever, productive cough of some infection, X-ray chest looks like miliary mottling.
· Further to confirm the diagnosis. Baseline investigation including ESR, CRP, procalcitonine, blood culture, sputum culture, and for AFB,
· May need BAL,
· HRCT,
· Gene Xpert,
Management;
General management,
Treat as pulmonary tuberculosis and also look for dissemination.
First line therapy for Tb is same as general population, initially full dose with four drugs for two months, with frequent monitoring of CNI drugs level, keep CNIs in 2 folds higher level,
The standard dose is four month continuation of two drugs, but it varies according to organ involvement up-to 18 months.
If difficulty in drug level achievement can switch to mTORi , or quinolones.
· Would your management differ if the disease was mild and affected one lung?
· The management is the same for one lung or both lungs involvement.
References;
1. https://pubmed.ncbi.nlm.nih.gov/36145473/.
2. https://ann-clinmicrob.biomedcentral.com/articles/10.1186/1476-0711-5-3.
History: Contact tracing.
Investigations: Sputum AFB. Gene Xpert. ESR. Liver function tests for baseline values. Eye examination for baseline evaluation.
Treatment:
-Counselling [disease, duration of taking medications; need for adherende; possible side effects to expect; regular checks to get blood levels of the immunosuppresants]
-Isolation if smear positive till patient has three negative smear sputums
-Medicines: The recommendation for treatment of tubeculosis infection in transplant recipients, who are on immunisuppression, is the same as the recomendation for the general population, except that the regimen will change, and the duration. Regimen change is because the Rifamycin family [Rifampicin, Rifabutin or Rifapentine] do interact with the immunosuppresants [the CNIs, MTORi’s, and costicosteroids].
Treatment is with Rifampicin, Isonaizid, Ethambutol and Pyrazinamide for twomonths, and then continue with Rifampicin and Isonaizid for four more months. With the use of Rifampicin, the dose of the CNIs should be increased 3-5 fold, and the levels closely monitored.
Rifabutin can be used in place of Rifampicin, as it is a weker inducer of CytochromeP450, but levels of the immunosuppresants should still be monitored.
No it wont. MAnagement is the same whether its a mild disease or affects one lung only
References
José María Aguado, Julián Torre-Cisneros, Jesús Fortún, Natividad Benito, Yolanda Meije, Antonio Doblas, Patricia Muñoz, David R. Snydman, Tuberculosis in Solid-Organ Transplant Recipients: Consensus Statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology, Clinical Infectious Diseases, Volume 48, Issue 9, 1 May 2009, Pages 1276–1284, https://doi.org/10.1086/597590
Guidelines for the prevention and management of Mycobacterium tuberculosis infection and disease in adult patients with chronic kidney disease
This immunocompromised below 50-year-old recipient with high suspension to have miliary TB, as the CT is not suggestive of viral or fungal infection.
Investigations required:
· Blood and urine cultures.
· sputum culture, stain, AFB. If sputum not obtained bronchoscope for BAL should be done.
· Mycobacterial culture: Conventional and Rapid culture techniques
· Xpert MTB/RIF assay.
Treatment of active TB:
The treatment of active TB should be started immediately once the diagnosis has been established.
the duration of treatment is recommended to be at least 9–12 months
Traditional regimen (≥6 months):
· intensive phase of two months and continuation phase of at least four months, includes the drugs isoniazid, rifampin, pyrazinamide, and ethambutol
· If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.
· when a rifampicin-based regimen is used, CNI and mTORi levels should be closely monitored, the dose of CNI and mTORi should be increased between 3-5-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
· after the rifampicin is stopped, the immunosuppression doses should be reduced to the value before the start of rifampicin and then adjusted to obtain the therapeutic target
· Reduction of immunosuppression in this case of severe TB should be considered.
Would your management differ if the disease was mild and affected one lung?
in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present
this case scenario findings (both clinical and radiological ) make a high suspicious of military TB , at the same time should think about other differential diagnosis such such viral, fungal infections, and extensive micro metastasis….
workup : sputum or BAL for AFB & culture
require a co-ordination between nephrologist, pulmonologist and microbiologist
Rx.:
Radiological picture is classical of disseminated miliary TB involving both lungs.
There must be milliary lesions all over the body
differential diagnosis could be viral or fungal pneumonia , ARDS,diffuse pulmonary haemorrhage
diagnosis
Even the CXR is pathognomic of TB in endemic area like India
sputum- AFB smear or Gene xpert test
treatment
reduction in immunosuppression is must
considering the gravity of disease all drugs can be stopped except steroid
involvement of respiratory and infectious disease specialist is done early after the suspicion of TB
AKT- anti koch treatment of 4 drugs( INH REFAMPICIN ETHAMBUTOL PYRIZINAMIDE ) for 2 months and 2 drugs for 6-8 months as per guideline of national TB programme
CNI serum level is monitored closely if at all it is on due to interaction with refampicin
involvement of one lung only make respiratory management easy but TB protocol will remain same in line of miliary TB
· With above scenario with Chest X-ray and CT showed miliary mottling involved bilaterally. My provisional diagnosis is Miliary TB
· Differentials are pneumonia caused by virus, bacteria and fungus or lymphangitis carcinomatosa.
· Diagnosis should be confirmed prior treatment by sending sputum for AFB, Sputum for Gene X pert TB test
· Once confirmed that it is Miliary TB, first step should be to minimize immunosupression.
· From chest x-ray patient expected to be in life threatening condition, I will go either stopping all IS except giving higher dose of steroids or stopping MMF and continue Tacrolimus and steroid at higher dose.
· 2 months of intensive treatment with the combination of 4 dru; isoniazid (INH), rifampicin, pyrazinamide, and ethambutol till 2 sequential negative sputum samples then followed by 7-9 months of continuation phase with INH and rifampicin.
· Treatment duration can be extended up to 24 months
· Rifampicin interaction with CNI s should be kept in mind and if used dose of Tacrolimus should be increased 3-5 fold and similarly decreased once drug is stopped.
· For minor disease or single lung involvement RIF sparing protocol can be considered.
REFERENCE:
(i) UpToDate
(ii)Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
can be considered
The radiological findings of milletlike Numerous small, nodular lesions combined with clinical manifestation of night fever, productive cough and weight loss strongly suggest military TB
The differential diagnosis includes the following:
Pneumocystis carinii pneumonia
Bacterial pneumonia
Community-acquired pneumonia
Fungal pneumonia
Viral pneumonia
Other problems to be considered include the following:
Histiocytosis X (Langerhans cell histiocytosis)
HIV-related pulmonary opportunistic infections
Lymphangitic spread of cancer (eg, thyroid carcinoma, malignant melanoma)
Acute respiratory distress syndrome
Blastomycosis
Hypersensitivity pneumonitis
Investigation
CBC, LFT, KFT, UEC, CNI level
Sputum for acid fast bacilli
BAL for cytology, culture and geneXpert
Treatment: quadruple anti-TB therapy for 2 months with Rifampicin, isoniazid, pyrazinamide and ethambutol, followed by 4 months of isoniazid and rifampicin.with increasing steroid and CNI doses up to 2 and 3-5 fold respectively with careful monitoring of liver enzymes
Rifabuntin is a less enzyme inducer and can be used as an alternative to rifampicin
the same regimen would be applied for unilateral affection
HOW DO YOU MANAGE THIS CASE;
OUR CASE;
MANAGEMENT
;Continuation phase ;2 drugs INH,RIF
MILD DX AFFECTING ONE LUNG.
REF
The CXR and CT show widespread, random, bilateral micro nodular infiltrates.
The Differential Diagnosis includes Miliary TB, Fungal infections such as Histoplasmosis, Metastatic lung disease, Sarcoidosis. Given this patients risk factors and presentation, Miliary TB is most likely.
Management:
I would mange this patient with a thorough clinical and laboratory evaluation while starting appropriate treatment early.
History of contact with a TB positive patient, history of TB on the donor if not evaluated pre-transplant. I would check if the patient had evidence of Latent TB pre transplant and if they got prophylaxis. Other symptoms such as chills, rigours, night sweats are worth noting. I would check for Lymphadenopathy, ascites and hepatosplenomegaly.
I would evaluate with basic labs including FBC, U&E/Creat, LFT, ESR, CRP. Sputum to be sent for MCS, AFB and Gene Xpert analysis. If the sputum tests are negative, as they may be in immunocompromised patients, I would consider Bronchoscopy with BALF and transbronchial biopsy.
I would treat with ATT as per our national TB treatment protocol. In Botswana we use a weight based four drug regimen (RHZE) for two months of the intensive phase, followed by a four month two drug (RH) consolidation phase.
Special consideration when transplant patient is on ATT:
I would manage the patient in the same way for mild disease
Miliary TB usually presents with bilateral lung findings as it is from haematogenous spread. I would question the diagnosis if unilateral and seek definitive answer from sputum, BAL or transbronchial biopsy
References
Andreu J, Mauleón S, Pallisa E, Majó J, Martinez-Rodriguez M, Cáceres J. Miliary lung disease revisited. Curr Probl Diagn Radiol 2002;31:189–197.
Munoz PRodriguez CBouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants.Clin Infect Dis. 2005; 40: 581-587
How would you manage this case?
One year post-kidney transplant presented with fever, productive cough and weight loss. CXR showed diffuse bilateral reticular-nodular opacities and CT scan showed mottling with multiple nodules.
Most likely diagnosis: miliary TB.
Differential diagnosis: Bacterial pneumonia
Fungal pneumonia
Viral pneumonia
Metastatic malignancy.
Investigation
CBC, RFTs SE LFTs and Tac trough level
AFB on sputum.
BAL Cytology and culture (MDR AND XDR)
Treatment
Four drug combination of Isoniazid, Rifampicin, pyrazinamide and ethambutol for 2 months along with pyridoxine and monitoring LFTs fortnightly. Followed by 4-6 months of two agents’ combination isoniazid and rifampicin. Total duration of treatment 6-9months.
CNI during ATT should be closely monitored and usually be scale up upto 4 folds and increasing Steroids from 5mg to 10mg/day.
Rifabuntin can be used as an alternative for rifampicin because of less potent inducer of P450 than rifampicin.
Monitoring ; close monitoring of Tac level, monthly liver function and Renal function.
Would your management differ if the disease was mild and affected one lung?
I will treat the same way.
The above image on left is cxr and on right is coronal slice of CT scan. Correlating both the images with the patient’s history, the most likely diagnosis is Miliary tuberculosis.
Other DDs like pneumonia, viral infection, fungal infection can be kept but is very unlikely. This appears to be classical book picture of miliary TB.
When we compare the pathogenesis of two forms of pulmonary tuberculosis viz, Miliary TB and Ghon focus (PPC), then it is well established that miliary TB is seen in immunocompromised patients and undernourished children.
Investigations:
Treatment:
Each country has somewhat different treatment protocols.
India is an endemic country for tuberculosis. So we use CB-NAAT as gold standard for diagnosis which also detects rifampin resistance.
We have a national program governed by GOVT which is RNTCP (revised national tuberculosis program).
Our treatment recommendations:
American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP):
Specifically, rifampicin usage decrease the levels of CNI, mTORi and affects glucocorticoids metabolization, which increases the risk of rejection. Therefore, when a rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin and mTOR inhibitor should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
REF:
Clinical scenario with radiological evidence is suggestive of active tuberculosis (Miliary) while other differential are;
· Viral infection
· Fungal infection
· PTLD
Active tuberculosis in SOT;
Active TB in SOT is well described particularly beyond first year mainly due to reactivation of latent TB. Median incidence is 2.37% and up to 15% in endemic areas. [1]
Investigation
CBC, RFTs SE LFTs and Tac trough level
AFB and geneXpert on sputum.
BAL Cytology, geneXpert and culture (MDR AND XDR)
Treatment
Four drug combination of Isoniazid, Rifampicin, pyrazinamide and ethambutol for 2 months along with pyridoxine and monitoring LFTs fortnightly. Followed by 4-6 months of two agents’ combination isoniazid and rifampicin. Total duration of treatment 6-9months.
CNI during ATT should be closely monitored and usually be scale up upto 5 folds and increasing Steroids from 5mg to 10mg/day.
Rifabuntin can be used as an alternative for rifampicin because of less potent inducer of P450 than rifampicin.
Monitoring ; close monitoring of tac level, monthly liver function and Renal function.
Would your management differ if the disease was mild and affected one lung? I will treat the same way.
References
1. Abad CLR, Razonable RR. Mycobacterium tuberculosis after solid organ transplantation: A review of more than 2000 cases. Clin Transplant. 2018 Jun;32(6):e13259. doi: 10.1111/ctr.13259. Epub 2018 May 7. PMID: 29656530.
2. UpToDate
How would you manage this case?
One year post-kidney transplant presented with fever, productive cough and weight loss. CXR showed diffuse bilateral reticular-nodular opacities and CT scan showed mottling with multiple nodules.
Most likely diagnosis: miliary TB.
Differential diagnosis: Bacterial pneumonia
Fungal pneumonia
Viral pneumonia
Metastatic malignancy.
Management should be multidisciplinary including chest physicians, transplant physicians and infectious disease specialist.
Workups:Sputum for AAFB and Gene Xpert
Treatment: 4 drug regimen with Rifampicin, isoniazid, pyrazinamide and ethambutol for 2 months intensive phase, followed by 4 months of isoniazid and rifampicin. Total duration of 6-9 months.
Increment of the CNI 3-5 fold and doubling steroids.
Monitoring of the liver enzymes bi weekly in the intensive phase then monthly there after.
Rifabuntin is a less potent cytochrome P450 thus can be used as an alternative for rifampicin due to drug interactions.
Would you manage this case differently if this was mild and affected one lung?
No, the regimen would be the same only difference would be a short duration of 6 months.
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
I appreciate clarity of your thought process in managing this clinical problem and I quote your comment in italics:
No, the regimen would be the same only difference would be a short duration of 6 months.
I appreciate clarity of your thought process in managing this clinical problem.
However, I suggest you to 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.
Scenario 1
47-year-old CKD 5 has kidney transplantation after One year, he presented with a night fever of 39 C, productive cough, and weight loss. Imaging showed diffuse bilateral infiltrate suggestive of military TB
Probably the most challenging situation lies on the clinical suspicion of active infection.
TB should be considered in the differential diagnosis of patients presenting with fever of unknown origin.
Diagnosis
The definitive diagnosis of pulmonary TB is established by isolation of M. tuberculosis .
It can be done from
>>> body secretion or fluid through
>>> tissue through pleural biopsy or lung biopsy
>>> Additional diagnostic tools include
>>> Radiographic studies are important supportive diagnostic tools.
Note that Neither TST nor IGRAs are recommended for diagnosing active infection.
Treatment
Many specialists recommend that treatment of active TB duration should be at least 9 months.
A 4-drug regimen is recommended. INH and rifampicin are the most powerful first-line drugs against TB. 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin .In the context of SOT, many factors should be carefully considered and must be well educated to the patient especially the risk of hepatotoxicity related to the antituberculous treatment and drug interactions of rifampicin and CNIs.
Two-to 5-fold increments in the daily dose of cyclosporine, tacrolimus, and mammalian target of rapamycin inhibitors are generally necessary to maintain trough levels of the drug in the therapeutic range.
Although enzyme induction start within hours after the first dose of rifampin, maximum effect is reached in about 1 to 2 weeks and slowly declines over 2 weeks after stopping its use. Thus, therapeutic drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption, all to reduce of graft rejection or even loss.
Would your management differ if the disease was mild and affected one lung?
According to AST-IDCOP, the first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases.
Compared to AST-IDCOP, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) suggests a standard regimen used for a period longer than 6 months, and, in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present .
If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide. Additionally, if second-line drugs are used, a longer period of treatment is recommended.
Reference
Bogdan Marian Sorohan 1,2, * , Gener Ismail 2,3 , Dorina Tacu 1 , Bogdan Obriscă2,3 , Costin Gîngu 1,2, Ioanel Sinescu 1,2and Cătălin Baston1,2
Guilherme Santoro-Lopes, MD, PhD, 1,2 Aruna K. Subramanian, MD, 3 Israel Molina, MD,4,5 José María Aguado, MD, PhD, 6Ricardo Rabagliatti, MD, PhD, 7and Oscar Len, MD, PhD
Uptodate
I appreciate your debate regarding the uncertainty on optimal duration of therapy
one year
post kidney transplant
Night Fever
weight loss
Productive cough
CXR and CT suggestive of miliary mottling
The first diagnosis is Miliary TB
The possibility of other pneumonia s like viral , bacterial and fungal should also be kept in mind.
Diagnosis should be confirmed by sending sputum for AFB
Sputum for Gene X pert /RIF assay
Once confirmed that it is Miliary TB, first step should be to minimize immunosupression.
The radiological pic looks very scary and one can think of stopping all immunosuppressants and pump steroids a bit
A four drug regimen should be introduced and kept for two months followed by RIF and INH for another 7 months.Pyridoxine should be given alongside.
Rifampicin interaction with CNI s should be kept in mind and if used dose of Tac should be increased four fold and similarly decreased once drug is stopped
For minor disease or single lung involvement RIF sparing protocol can be considered
Thankyou
any suggested protocols!
How do you manage this case?
This 47 years male
Post transplant
On immune suppression
Have excellent kidney function
Presented with chronic productive cough for 1 year
Also presented with night fever
Loss of weight
From the above history the diagnosis is most probably
Miliary tuberculosis .
other differential :
malignancy (metastatic lung disease)
viral pneumonitis(cmv.covid 19)
bacterial pneumonia.
Fungal pneumonia
We need to share this case with pulmonologist and infectious disease team
Then we need to take history of any past diagnosis of TB,history of contact ,or even travelling to endemic area.
Then examination of any extra pulmonary TB.
Investigation :
Sputum for detect AAFB(acid alchol fast bacilii) by culture on ZN stain.
Sputum culture for gram staining for bacterial.
Gene expert test of sputum or BAL.
CMV PCR.
Treatment
The first-line treatment should be a four-drug regimen. Standard regimen consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed bya4-month continuation phase of isoniazid and rifampicin as in general.
With this regimen included rifampcin , must be monitoring the CNI,also monitoring for hepatotoxicity ,neurotoxicity ,cytopenia ,visual disturbances ,skin lesions,hyperuricaemia,and interstitial nephritis.
If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.
In this case which is sever symptoms and signs reducing immune supressions is mandatory .
Would your management differ if the disease was mild and affected one lung?
No ,treatment same.
references
1.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. [CrossRef]
2. 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.
3.Bolt, H.M. Rifampicin, a Keystone Inducer of Drug Metabolism: From Herbert Remmer’s Pioneering Ideas to Modern Concepts. Drug Metab. Rev. 2004, 36, 497–509. [CrossRef
Thank you very much for your reply
1. A 47-year-old CKD 5 has kidney transplantation from his brother, 111 mismatch, and no DSAs. Excellent kidney function. One year later, he presented with a night fever of 39 C, productive cough, and weight loss. Imaging showed multiple shadows in both lungs.
Issues/ concerns
– 47yo, CKD 5, kidney transplant, excellent kidney function
– donor – brother, 111 mismatch, no DSAs
– 1yr later fever 39, productive cough, weight loss
– CXR revealed bilateral reticulonodular pattern, perihilar adenopathy
– Chest CT scan revealed small multiple shadows/ nodules ?miliary pattern
How do you manage this case?
– differential diagnosis
– multidisciplinary approach: – pulmonologist, microbiologist, infectious disease specialist
– detailed history: – drenching night sweats, TB contact, INH prophylaxis, induction therapy, maintenance immunosuppressive therapy, previous TB infection, history of LTBI in both the donor and the recipient
– thorough physical examination
– baseline investigations: – CBC, ESR, CRP, Procalcitonin, blood culture, urine m/c/s, BGA, UECs, LFTs, HIV Ab, CNI trough level
– sputum smear, gene xpert, sputum m/c/s or BAL fluid gene xpert
– gene xpert MTB/ RIF assay is highly specific and sensitive, it allows for detection of rifampicin resistance
– screen for routine bacterial, fungal (PCP, aspergillosis), CMV, Covid, VZV, and other respiratory viral infections
– IGRA and TST do not distinguish between active and latent TB; can be falsely negative in immunocompromised patients
– Treatment: –
– incidence of TB among transplant recipients is higher than in the general population (6)
– active TB usually occurs in the 1st year post -transplantation
– reactivation of latent TB within the first year is a common occurrence (7)
– 30-50% of the cases of TB in post-transplant patients are extrapulmonary/ disseminated. This is a much higher rate than that seen among immunocompetent individuals (8)
– TB in transplant recipients remains a diagnostic and therapeutic challenge
– Transmission – TB occurs as a result of: – (9)
– the diagnosis is often delayed due to atypical symptoms in some patients
– possible radiographic findings include: – focal infiltrates, miliary pattern, nodules, pleural effusions, diffuse interstitial infiltrates, cavities (10)
– the treatment is challenging given the drug interactions and side effects
– hence screening for LTBI (using IGRA and TST) prior to transplantation and consequent INH prophylaxis is essential
– false negative TST and IGRA is common in patients with an impaired immune system (11)
– Risk factors for LTBI: – older age, lack of BCG vaccination, immunosuppression, positive DSAs
– TB-related mortality is higher among transplant recipients compared to immunocompetent persons
– screening methods: –
-if a potential kidney transplant recipient tests positive for TB, they should complete TB treatment unless there is an urgent underlying need for transplant
Would your management differ if the disease was mild and affected one lung?
– no, management would remain the same i.e., for SOT patients with non-severe and localized TB without suspicion/ evidence of INH resistance use of a rifamycin-based regimen similar to what is used in immunocompetent patients is recommended (4)
References
1. Aguado JM, Herrero JA, Gavaldá J, Torre-Cisneros J, Blanes M, Rufí G, et al. Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Spanish Transplantation Infection Study Group, GESITRA. Transplantation. 1997 May 15;63(9):1278-86. PubMed PMID: 9158022. Epub 1997/05/15. eng.
2. Aguado JM, Torre-Cisneros J, Fortún J, Benito N, Meije Y, Doblas A, et al. Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2009 May 1;48(9):1276-84. PubMed PMID: 19320593. Epub 2009/03/27. eng.
3. Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivistö KT. Pharmacokinetic interactions with rifampicin : clinical relevance. Clinical pharmacokinetics. 2003;42(9):819-50. PubMed PMID: 12882588. Epub 2003/07/29. 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. Sun HY, Munoz P, Torre-Cisneros J, Aguado JM, Lattes R, Montejo M, et al. Mycobacterium tuberculosis-associated immune reconstitution syndrome in solid-organ transplant recipients. Transplantation. 2013 May 15;95(9):1173-81. PubMed PMID: 23435454. Epub 2013/02/26. eng.
6. Abad CLR, Razonable RR. Mycobacterium tuberculosis after solid organ transplantation: A review of more than 2000 cases. Clinical transplantation. 2018 Jun;32(6):e13259. PubMed PMID: 29656530. Epub 2018/04/16. eng.
7. Anand M, Nayyar E, Concepcion B, Salani M, Schaefer H. Tuberculosis in kidney transplant recipients: a case series. World journal of transplantation. 2017;7(3):213.
8. Fiske CT, Griffin MR, Erin H, Warkentin J, Lisa K, Arbogast PG, et al. Black race, sex, and extrapulmonary tuberculosis risk: an observational study. BMC Infect Dis. 2010 Jan 22;10:16. PubMed PMID: 20096113. Pubmed Central PMCID: PMC2823615. Epub 2010/01/26. eng.
9. Muñoz P, Rodríguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2005 Feb 15;40(4):581-7. PubMed PMID: 15712081. Epub 2005/02/16. eng.
10. Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1998 Nov;27(5):1266-77. PubMed PMID: 9827281. Epub 1998/11/25. eng.
11. Diel R, Loddenkemper R, Niemann S, Meywald-Walter K, Nienhaus A. Negative and positive predictive value of a whole-blood interferon-γ release assay for developing active tuberculosis: an update. American journal of respiratory and critical care medicine. 2011;183(1):88-95.
12. Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K. Updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection – United States, 2010. MMWR Recommendations and reports : Morbidity and mortality weekly report Recommendations and reports. 2010 Jun 25;59(RR-5):1-25. PubMed PMID: 20577159. Epub 2010/06/26. eng.
Thank you very much for your reply
This is a case of bilateral small nodular infiltration for differential diagnosis
–Viral, bacterial and fungal panel should be send from day 1 and because of high clinical suspicious of TB sputum and BAL test for AFB and culture using molecular testing and NAA.
–Tuberculin skin test and IGRA can be done with cautious interpretation of the previous tests because of expected false negative results.
–AFB and NAA depend on bacterial load in the sample that’s repeated negative tests one from sputum and confirmation from BAL and good explanation of the condition based on requested labs.
–TST and IGRA positivity depend on immunological response so if results positive it will support diagnosis but negative results don’t exclude disease.
-From chest x-ray patient expected to be in life threatening condition that’s why I will go either stopping all immunosuppression except giving stress dose of steroids or stopping MMF and continue only on tacrolimus and steroids stress dose.
-From chest x-ray and based on recommendations of American society of transplantation treatment should include rifampicine to avoid resistance and for clearance achievement
–2 months of treatment including 4 medications isoniazid (INH), rifampicin, pyrazinamide, and ethambutol till 2 sequential negative sputum samples then followed by 7-9 months of INH and rifampicin.
-If rifampicin protocol was decided and also tacrolimus decided to continue so empirically dose of tacrolimus will be multiplied by 4 and frequent monitoring of tac level targeting level around 5.
How would you treat it if it is affecting a single lung?
I would go for rifampicin free protocol to avoid drug-drug interaction with CNI especially that this is new transplant since only one year.
REFERENCE
1) Jay A Fishman. Approach to the immunocompromised patient with fever and pulmonary infiltrates. © 2023 UpToDate (accessed on 25 February 2023).
2) John Bernardo. Diagnosis of pulmonary tuberculosis in adults. © 2023 UpToDate (accessed on 25 February 2023).
3) Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
Excellent Ramy
How do you manage this case?
Clinical Scenario: Renal transplant recipient (Living donor, no DSAs, 1-1-1 Mismatch) presented one-year post transplantation with: night Fever, productive cough, loss of weight. He had a chest x-ray done showing: Bilateral lung infiltrates with bilateral hilar lymph adenopathy.
CT chest showed: bilateral small nodular infiltrates.
DD of diffuse nodular opacities in the lung:
1- Pulmonary TB (Miliary TB) —à fits with the index clinical scenario.
2- Langerhans cell Histoplasmosis.
3- Diffuse pneumonia (Bacteria or viral like CMV)
4- Silicosis.
5- Hypersensitivity pneumonitis.
6- Sarcoidosis.
7- Metastatic lung cancer.
A- Definitive diagnosis of TB needs further work up and investigations that include:
· Any positive test from the following is sufficient for diagnosis of active TB infection:
1- Isolation of Mycobacterium TB via culture of sputum or Broncho-alveolar swab, or pleural fluid.
2- Isolation of acid-fast bacilli in sputum smear.
3- Nucleic acid amplification testing, like Gene-Xpert test which is 98% sensitive, and results will available within 2-4 hours.
· The following 2 tests are used to support diagnosis in suspicious cases:
Tuberculin skin test (TST) and Interferon Gamma Release Assay (IGRAs) depend on patient’s immune response which makes their interpretation in immune-compromised patients (HIV infected or SOT recipients on IS) less reliable and can’t be used for diagnosis of active TB.
TST:
Advantages: 1- less expensive. 2- doesn’t need laboratory analysis.
Disadvantages: 1-Requires ID injection, follow up in the clinic to be reviewed by well-trained staff within 48-72 hours.
2- False positive results can happen following BCG vaccination or non-tuberculous mycobacteria.
3-False negative results can happen because of immune-suppression state.
4- Serial TST interpretation can be complicated by potential boosting.
5- TST can lead to adverse reactions like blistering and ulceration.
IGRAs:
Advantages: 1- doesn’t require follow up visits for interpretation. 2- doesn’t give false positive results because of previous BCG vaccination.
Disadvantages: 1- Costlier than TST because of Lab, sampling, reagents.
2- Results would be available after 24hours at least.
3-False negative results can happen because of IS.
4-Serial IGRAs interpretation is complicated by frequent conversions and spontaneous reversions and lack of consensus about the optimum threshold.
B- Work up to rule other causes of DD:
· Urinary or serum antigen for histoplasmosis with >90% sensitivity.
· CMV PCR.
· Sputum, BAL Culture for bacteria, fungi.
· B D-glucan.
Treatment if TB is the diagnosis:
1- 4-drug regimen is the appropriate therapy: (INH + (Rifampin or Rifaputin) + Pyrazinamide + Ethambutol) for at least 2-months then 6-9months of 2-drug regimen (INH + Rifampin).
2- Rifaputin has less enzyme inducing effect than Rifampin.
3- Add B6 50mg po od.
4- Rifamycins are recommended for severe (cavitary or multi-lobar disease) or disseminated TB or with suspected or documented INH resistance.
5- Second-line drugs (quinolones, aminoglycoside and clarithromycin) can be used in case of resistance or side effects to first line medications or poor clinical condition or infection with atypical mycobacteria.
Management of IS medications:
1- Reduction of IS maintenance medications: at least 50% reduction of anti-metabolites (MMF or Azathioprine) with potential withdrawal if progressive infection not responding to treatment.
2- Increase the dose of steroids.
3- Monitoring the therapeutic level of CNI because of drug interaction with anti-TB medications which tend to reduce the level of CNI exposing the patient to the risk of rejection.
4- Anti-TB are enzyme inducers, so CNI or m-TOR inhibitors level will be low and dose usually increase by 2-5 folds while being on anti-TB.
Monitoring of treatment:
1- Monitor renal and liver function tests.
2- Monitor for side effects of medications.
3- Monitor vision before and after starting ethambutol.
4- Regular follow up for reactivation of TB.
5- Anti-TB treatment can be stopped after having 2 negative sequential sputum samples by GeneXpert (NAAT).
6- Consult infection control team and microbiology team.
Would your management differ if the disease was mild and affected one lung?
The treatment will be the same according the American society of transplantation, both severe and localized non-severe TB should be treated with the same regimen to ensure radical treatment and prevent resistance to treatment.
References:
1- Dick Menzies. Lab Interpretation: Positive or uninterpretable interferon-gamma release assay in adults. © 2023 UpToDate (accessed on 26 February 2023).
2- Jay A Fishman. Approach to the immunocompromised patient with fever and pulmonary infiltrates.
3- 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;33(9):e13513.
4- Emmanuel Canet, Jacques Dantal, Gilles Blancho, Maryvonne Hourmant, Stéphanie Coupel, Tuberculosis following kidney transplantation: clinical features and outcome. A French multicentre experience in the last 20 years, Nephrology Dialysis Transplantation, Volume 26, Issue 11, November 2011, Pages 3773–3778.
5- 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
6- Lopez de Castilla D, Schluger NW. Tuberculosis following solid organ transplantation. Transpl Infect Dis 2010; 12:106.
Thank you Hamdy very much for your reply
How do you manage this case?
After 1 year of renal transplant, he presented with fever, wt loss, and productive cough and chest X-ray showing reticulonodular opacities in both lung field and HRCT shows multiple scattered modular lesions, so this picture is pointing to miliary TB while other Differential diagnosis:
viral infection : CMV , influenza
Bacterial
Fungal : pneumocystis jirovecii
The management:
Proper history taking , full examination
Lab test: CBC, RFT , LFT, ESR, CRP, blood cultures , CMV PCR , serum B D Glucan, drug level
Sputum culture , cytology , gram staining , TB PCR ,
Bronchoalveolar lavage
Radiology: chest X-ray , HRCT
Treatment:
Anti TB drugs as :
First line INH, , Rifampicin or rifabutin , Pyrazinamide and Ethambutol are used for 2 months then INH and Rifabutin for 4 months may total duration up to 9 months
Rifampicin is more enzyme inducer than rifabutin , so drug level must be carefully monitored and the dose may be increased up to 2-5 folds
B6 must be given with INH
2. Would your management differ if the disease was mild and affected one lung?
No, the treatment will be the same
References:
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.
Anand M, Nayyar E, Concepcion B, Salani M, Schaefer H. Tuberculosis in kidney transplant recipients: a case series. World journal of transplantation. 2017;7(3):213.
This 47-year-old post-RTX for 1 year presented with typical features and high suspicious of pulmonary TB , HE IS HAVING FEVEER WITH SWEATING and wt loss
his chest x-ray showed bilateral chest mottling and HRCT of bilateral scaTTERED LUNG NODULE.
In such cases, we need to di fukk routine tests like CBC, CMP, LFT and ESR, which is giving us a good clue to pulmonary TB as usually > 3 figures in favour of pulmonary TP.
we need to know from the history if he has HX of TP or contact with TP patients.
The donor status and if he has latent TB.
We need to know the area of the patients and the donor if ist is endemic in TB .
Once the diagnosis is made the patient should start the treatment to prevent complications.
the treatment of pulmonary TB is for 6 months in case not complicated but may extend to 9 months in case of a cavitary lung lesion or disseminated disease.
The first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases.
Bone and CNS TB may need a longer course of treatment up to 9 to 12 months.
Monitoring of LVT and RFT during treatment adding close observation for CNI level as it will be affected by anti TB treatment and may increase the risk of rejection to 30%
references
uptodate
Thank you very much for your reply, there are typos, please read-proof before submission.
1. How do you manage this case?
The clinicoradiological features of this patient goes with the diagnosis of miliary TB , although other differential diagnosis must be considered.
DDX include:
Bacterial infection , viral like CMV , fungal , pneumocystis.
The management plan start from detailed history of endemic area, history of TB , history of treatment of latent TB , close contact to index case, details about the donors , any history of TB , details about IS .any history of travel to highly endemic areas.
Physical examination and investigation like : CBC, ESR, CRP, LFT ,RFT
CXR , HRCT, induced sputum for cytology and gram stain and Z-N stain for AFB , or BAL and bronchoscopical examination, PCR for CMV and pneumocystis.
The treatment of active TB should be started immediately after the diagnosis has been established.
The epidemiological features from the area of patient’s origin and drug resistance patterns should be assessed .
The optimal period of treatment could vary from 6 to 24 months and, in some cases, the duration of treatment is recommended to be at least 9–12 months .
in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months .In case of severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months .Patients with central nervous system involvement should be treated for at least 9–12 months.
the first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases.
Rifamycin is recommended for its effectiveness and also to reduce the risk of resistance .
2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin .
a regimen without rifampicin could be used if no resistance to isoniazid is present .
If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide. Additionally, if second-line drugs are used, a longer period of treatment is recommended .
One challenge in the treatment of KT recipients with active TB is the drug interaction between rifampicin and transplant-associated immunosuppression .Rifampicin, a potent inducer of cytochrome P450 3A4 interferes with immunosuppression metabolization .
Specifically, rifampicin usage decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection .Therefore, when a rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin and mTOR inhibitor should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target. Additionally, after the rifampicin is stopped, the immunosuppression doses should be reduced to the value before the start of rifampicin and then adjusted to obtain the therapeutic target .
An alternative to rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy .Likewise, even in rifabutin-based regimens, immunosuppression doses could be modified, and levels should be closely monitored .Another safe and effective alternative to rifampicin in KT recipients is treatment with fluoroquinolones .
Another challenge is linked to the adverse effects of TB therapy, which are more frequent than in the general population. Therefore, some first-line drugs could not be used, and consequently, the treatment period will be increased .Patients treated with anti-TB drugs should be closely monitored for hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol), neurotoxicity (isoniazid, ethambutol), cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol), visual disturbances (rifabutin, ethambutol), skin lesions (rifampicin), hyperuricemia (pyrazinamide) or interstitial nephritis (rifampicin, pyrazinamide) .The most common adverse event associated with anti-TB therapy is hepatotoxicity; therefore, liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter .
Treatment adherence could also be an issue in KT recipients.
An additional caveat is that patients with KT could have different degrees of graft function and therefore is very important to evaluate creatinine clearance and adjust the doses for pyrazinamide and ethambutol .
Reduction of immunosuppression in the case of severe TB or when a vital organ is involved should be considered.
2-Would your management differ if the disease was mild and affected one lung?
No, but the duration for 6 months .
Reference:
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
Bogdan Marian Sorohan 1,2,* , Gener Ismail 2,3, Dorina Tacu 1, Bogdan Obris, că 2,3 , Gina Ciolan 4, Costin Gîngu 1,2, Ioanel Sinescu 1,2 and Cătălin Baston
Thank you very much for your reply Asmaa
How do you manage this case?
This patient has night fever of 39 C, productive cough, and weight loss. The chest X ray shows diffuse nodular shadowing with tracheostomy tube in situ. On X ray it is difficult to comment on mediastinal lymphadenopathy. CT scan axial view shows wide spread scattered nodules indicating miliary tuberculosis.
A detailed history of any previous Tuberculosis, exposure or use of ATT should be taken. A thorough physical examination is mandatory to rule out any lymphadenopathy.
Investigations
Blood CP/ESR. Renal and liver functions , CRP,
Diagnostic tests for tuberculosis will include –
Sputum for AFB smear and AFB culture
Molecular tests based on NAA
FNAC of any palpable lymph node
Treatment
As there is clinical suspicion , Anti tuberculosis treatment should be started.
AST- IDCOP guidelines recommends 4 drug regimen
Initial two months of 4 drugs- Rifampicin, ethambutol, INH and pyrazinamide
Next 4 months with INH and Rifamicin
AST- IDCOP guidelines recommends 6 months treatment in case of uncomplicated tuberculosis
AST- IDCOP guidelines recommends 9 months treatment if there are cavitating lesions or persistently positive sputum 2 months post initiation of drug therapy.
CNS involvement 9-12 months
In the index case there is suspicion of miliary tuberculosis, so 9 months treatmnet should be considered.
Regular monitoring of liver functions, graft functions
Pyridoxine should be use to prevent neuropathy
If situation worsens then antimetabolites can be reduced
Would your management differ if the disease was mild and affected one lung?
Treatment will be same with four drugs . Total duration 6 months
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
Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: treatment of drug-susceptible tuberculosis. Clin Infect Dis. 2016;63(7):e147-e95.
Thank you very much for your reply
The scenario of fever and night sweats, cough, and weight loss combined with transplantation (immunosuppression), in addition to somehow typical military pattern that seems consistent with TB. Control of CBC, CRP, ESR, LDH, acid-fast staining, sputum culture, TBC staining, and culture is needed.
Treatment is the same as immunocompetent patients except for special considerations regarding drug interaction.
** AST states that Rifamycine containing regimen used for severe and nonsevere localized infections because of potency of treatment and prevention of resistance. rifamycines are good option especially in cavitary infection. Tretemenof our case needs to be as long as 12 months.
Management should be in cooperation with pulmonologist and or infectious diseases.
**If the lesions were localized or in one side , I prefer the same potent treatment.
Paying attention to drug interaction or Rifampicin and CNIs is essential
…
Interms of immunosuppression we should balance the severity and life threting situation. In case of localized infection we can sustain IS but with severe infection like our case , we should minimize and monitor RFTs.
Thank you very much for your reply
I would be very grateful if you could add references. I would treat unilateral lesions the same.
Based on thoracic society paper (https://www.thoracic.org/statements/resources/tb-opi/treatment-of-drug-susceptible-tuberculosis.pdf )there is no local treatment. Whether unilateral or bilateral, drugs are the same. sever disease may extend auto 12 months
1- The onset, clinical picture and chest imaging are highly suggestive of miliary TB.
Management include:
-The first-line treatment should be a four-drug regimen c
– Consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and
ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin
-Duration of treatment can be extended up to 24 months till clinical improvement
and negative smear.
2- In mild cases: there is no need to reduce IS treatment.
Thank you very much for your reply
I would be very grateful if you could add references.
How do you manage this case?
Non TB infection.
Histoplasmosis.
Cryptococcosis.
Blastomycosis.
Coccidioidomycosis.
Bronchiolitis obliterans.
Metastatic lung diseases.
Treatment of active drug susceptible TB:
Two months of an initial phase therapy with INH, rifampin/rifabutin, pyrazinamide, +/-
ethambutol.
Continuation phase therapy of four months of INH and rifampin, with a total duration for
six months.
Cavitary TB, with positive sputum culture after two months of intensive phase therapy, is
treated for nine months’ duration with prolongation of continuation phase therapy.
Sputum cultures obtained monthly until two consecutive cultures are negative.
· Would your management differ if the disease was mild and affected one lung?
· TBNET and ESCMID suggest a non-rifamycin-based regimen in cases of localized
(e g, pulmonary) non severe TB when there is no suspicion or evidence
of isoniazid resistance.
· In patients not receiving a rifamycin, treatment options include a three-drug
regimen of INH plus ethambutol plus either pyrazinamide or levofloxacin for 2 months,
followed by a two-drug regimen of INH plus ethambutol or pyrazinamide for 12 to 18
months. (1)
· In those receiving a three-drug regimen for the entirety, the duration of treatment
can be shortened to 12 month.
References:
1-Aguado JM, Torre-Cisneros J, Fortún J, Benito N, Meije Y, Doblas A, Muñoz P
.Tuberculosis in solid-organ transplant recipients: consensus statement of the group for
the study of infection in transplant recipients (GESITRA) of the Spanish Society of
Infectious Diseases and Clinical Microbiology. Clin Infect Dis. 2009;48(9):1276.
Thank you very much for your reply
This patient presented with symptoms suggestive of TB .
Needs detailed history of contact with the patient diagnosed as case of TB or Contact with patient has chronic cough
Past medical history of TB .
Ask about donor screening from TB at the time of transplant .
Full clinical examination
Investigations:
CBC
ESR
CRP
LFT
RFT
Sputum for culture and sensitivity.
Gene xpert MTB /rif assay .Histology for biopsy or aspirate acid fast bacilli
Test for latent TB infection :
TST and IGRA
Renal US
Treatment of active TB::
Commonly used anti-tuberculosis drugs are are isoniazid, rifampicin, pyrazinamide and ethambutol and one of the quinolones.
.The first three are called essential first-line drugs and are the mainstay of short-term treatment. The latter two are first-line adjuvants. Second-line drugs are highly toxic and are only used when resistance to first-line drugs develops.
Isoniazid, ethambutol, pyrazinamide are safe drugs. Rifampicin, an essential drug in the ATT regimen, induces the cytochrome-c P450 microsomal enzyme system responsible for the metabolism of cyclosporine, sirolimus and prednisolone. This unpredictable interaction has been associated with acute rejection in 30% of cases and graft loss in 20% of cases and should therefore be avoided in solid organ transplantation.
Doses of calcineurin inhibitors may need to be increased two to five times to overcome this effect.
Ofloxacin, a quinolone withantimycobacterial properties, is often added to four-drug regimens. It is considered as effective as ethambutol and has fewer side effects.
.
Duration of therapy:
Four-drug regimen: pyrazinamide (three months); ofloxacin (nine months); INH and ethambutol (18 months).
The dose of isoniazid and ethambutol should be adjusted according to the degree of renal function. The dose of prednisolone should be doubled if rifampicin is given to patients not taking ciclosporin
References :
1. John GT. Infections after renal transplantation in India. Indian J Nephrol. 2003;13:14. [Google Scholar]
2. Sakhuja V, Jha V, Varma PP, Joshi K, Chugh KS. The high incidence of tuberculosis amongrenaltransplantrecipients in India. Transplantation. 1996;61:211. [PubMed] [Google Scholar]
3. Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid organ transplantation recipients: Impact and implications for management. Clin Infect Dis. 1998;27:1266. [PubMed] [Google Scholar]
4. John GT, Date A, Mathew CM, Jeyaseelan L, Jacob CK, Shastry JC. A timetable of infectionsaftertransplantation in the tropics. Transplantation. 1996;61:970. [PubMed] [Google Scholar]
5. John GT, Shankar V. Mycobacterial infections in organ transplant recipients. Seminar Res Infect. 2002;17:274. [PubMed] [Google Scholar]
Thank you very much for your reply
How do you manage this case?
Would your management differ if the disease was mild and affected one lung?
Thank you very much for your reply
How would you manage immunosuppression while on anti-tuberculous treatment?
1. How do you manage this case?
The index patient is a 47-year-old living donor renal transplant recipient, with 111 mismatch, no DSAs and stable graft function, now presenting 1 year post-transplant with fever of 39 degree Celsius, weight loss, and productive cough.
Chest X ray shows reticulonodular shadows in bilateral lung fields with hilar prominence. HRCT chest section shown revealed multiple miliary nodular lesions (arrows) throughout the lung parenchyma.
In view of the clinico-radiological picture presented, the first possibility is miliary tuberculosis. Nevertheless, the diagnosis need to be confirmed, and the patient being a renal transplant recipient, other differential diagnosis, including causes of pneumonia should be kept in the differential diagnosis (1).
Differential diagnosis:
1) Viral: Respiratory viruses (Influenza, parainfluenza etc), Herpesviruses (like cytomegalovirus, CMV)
2) Fungal: Pneumocystis jirovecii (PCP), histoplasma, Cryptococcus
3) Bacterial: community acquired like streptococcus, tuberculosis etc.
4) Parasitic
5) Non-infectious: mTOR inhibitor associated
The management of the index case involves:
1. A detailed history and clinical examination. History regarding prior tuberculosis, induction therapy use, and the immunosuppressive regime being used is especially important. History of recent contact with any patient with tuberculosis, and history of tuberculosis in the donor should also be elicited.
2. Laboratory testing including complete blood count, renal function tests, liver function tests, C reactive protein, blood culture, chest X ray, influenza testing (if in influenza season) and other respiratory viral testing (biofire), serum beta D Glucan, Serum LDH, Calcineurin inhibitor (CNI) trough levels (if on CNIs).
3. Induced sputum examination for cytology, gram stain and acid-fast bacilli (AFB) stain, and culture.
4. High resolution computed tomogram (HRCT) of chest.
5. CMV PCR testing: To rule out CMV infection (although unlikely in this setting).
6. Bronchoscopy with bronchoalveolar lavage (BAL) with or without transbronchial lung biopsy: For stain and culture (fungal, AFB), as well as PCR for respiratory viruses, CMV, pneumocystis, and histopathological analysis.
Treatment: If the diagnosis of active tuberculosis is confirmed, the treatment involves 4-drug regimen of Isoniazid, Rifampicin (or rifabutin), Pyrazinamide, and Ethambutol for first 2 months (intensive phase) followed by Isoniazid and Rifampicin (or rifabutin) for 4 more months (continuation phase), as advised in immunocompetent patients (2). Ethambutol can be stopped if it is confirmed that the organism is susceptible to the other 3 drugs (3).
Rifampicin is an enzyme CYP3A4 inducer, leading to increased metabolism of immunosuppressives drugs (cyclosporin, tacrolimus, sirolimus, everolimus, and steroids) thereby requiring an increase in the doses (upto 2-5 times for cyclosporine/ tacrolimus, and 2 times for steroids) and close monitoring of the drug levels (4). Rifabutin can be used in place of Rifampicin, with the resultant required immunosuppressant drug dose increase being less than that with use of rifampicin (5). Ethambutol and isoniazid do not appear to interact with the immunosuppressive medications (4).
The optimal duration of treatment has not been defined, with many specialists recommending a duration of 9 months (5). Uncomplicated pulmonary tuberculosis showing sputum negativity after 2 months of treatment can be given treatment for 6 months only, while a positive sputum test for tuberculosis after 2 month treatment warrants treatment for 9 months (2). Longer duration treatment is also recommended in patients with bone and joint involvement, central nervous system involvement, or a disseminated disease (2).
Considering the presence of miliary pulmonary nodules in the index patient, there is high probability of multisystem involvement in the patient, hence patient may require treatment for 9 months.
In addition of monitoring of drug levels and graft function, liver function tests are also required to be monitored in view of risks of hepatotoxicity with the anti-tubercular medications. Pyridoxine should be given with isoniazid.
If the clinical status of the patient worsens, dose of antimetabolite (MMF or azathioprine) might require reduction or cessation.
2. Would your management differ if the disease was mild and affected one lung?
No. The treatment would remain same (4-drug regime) with 6 month duration of antitubercular treatment (localized tuberculosis).
References:
1. Dulek DE, Mueller NJ; AST Infectious Diseases Community of Practice. Pneumonia in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13545. doi: 10.1111/ctr.13545. Epub 2019 Apr 23. PMID: 30900275; PMCID: PMC7162188.
2. 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.
3. 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.
4. Sparkes T, Lemonovich TL; AST Infectious Diseases Community of Practice. Interactions between anti-infective agents and immunosuppressants-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13510. doi: 10.1111/ctr.13510. Epub 2019 Apr 23. PMID: 30817021.
5. 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 Amit .
What are the accurate diagnostic, rapid tests (sure) for TB
What then are the Rifampicin free regimens and when are they indicated.
Thank you Professor.
Rapid nucleic acid amplification technique (NAAT) test like Xpert MTB/RIF (Cepheid Inc) can be used to increase the sensitivity and rapidity to diagnose tuberculosis, in addition to finding resistance to rifampicin (1).
Rifampicin free regimens can be used in following conditions:
1) Localized, non-severe TB with no resistance to isoniazid (2). Patients can be given 3 drugs (Isoniazid, Ethambutol and pyrazinamide or levofloxacin) for 2 months followed by 2 drugs (isoniazid with ethambutol or pyrazinamide) for 12-18 months. Another regimen used includes use of 3 drug regimen (Isoniazid, Ethambutol and pyrazinamide or levofloxacin) for 12 months.
2) Use of rifabutin in place of rifampicin in transplant recipient on CNI .
3) Patient with latent tuberculous infection (LTBI): Isoniazid monotherapy for 9 months (3).
References:
A 47-year-old CKD 5 has kidney transplantation from his brother, 111 mismatch, and no DSAs. Excellent kidney function. One year later, he presented with a night fever of 39 C, productive cough, and weight loss. Imaging showed multiple shadows in both lungs.
How would you manage this case?
The CXR => showed bilateral reticulo-nodular shadows with peri-hilar infiltrate and opacities represent mediastinal LNs.
The CT Thorax => showed numerous small sized nodules distributed throughout both lungs, (most likely military TB).
(Active pulmonary TB ; most probably 2ry to reactivation of LTBI in recipient).
DD:
– PJP pneumonia
– Aspergillosis
– PTLD
– CMV pneumonitis
– Drug induced pneumonitis if he was treated with m TOR.
– Other bacterial and opportunistic pneumonia.
Prevalence of TB after solid organ transplantation:
It significantly higher than general population, it differs according to geographic area, it ranges from 1.2-2.6% in developed countries and in 10-15% in endemic regions, around 95% of cases occur at 1 mouth to 1 year after transplantation, Donor-derived TB usually occur earlier compared to activation of latent TB.
Mode of transmission:
– Activation of latent TB (the most common)
– Acquiring the disease from the graft (donor derived)
– Acquiring new infection through air born transmission
C/P:
– Fever occurs in 91% of disseminated TB, and in 64% of localized TB cases.
– Night sweats and weight loss are commonly seen.
– The presentation differs from immunocompetent patients in the following.
– Atypical presentation is more common (pyomyositis, tenosynovitis, skin ulcers or abscess)
– Around 30-50% of cases present with extra pulmonary or disseminated TB (much higher than immunocompetent hosts).
Investigations:
The diagnosis of TB requires a high index of suspicion based on the epidemiological risk, personal history, manifestations, and imagistic lesions,
-Rapid Molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test (Xpert® MTB/RIF) could provide false negative results when mycobacterial load is low, which is highly predictive of MDR-TB.
-Tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not useful in the diagnosis of active TB.
-Probability of association with other co-infections, so further investigations r/o other fungal or viral infections (CMV-EBV-HIV).
-Sputum for AFB smear, Culture and drug sensitivity (it will take long time and decision need to be taken rapidly).
-BAL Fungal infection cultures, staining and PCR.
Screening for donor:
-His brother should be screened for latent TB infection if it has not been done prior to KT using (TST/IGRA).
-Recognizing latent infection or undiagnosed active TB in the kidney donors is critical in preventing post-transplant infection.
–A careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors.
–Current guidelines provide recommendations for latent TB screening in all KT candidates and donors before transplantation.
-Patients should be isolated until he is improving clinically, or after 3 consecutive negative sputum smear results (guided by I.C. recommendation)
-The treatment of active TB should be promptly started immediately after the diagnosis has been established.
-The epidemiological features from the area of patient’s origin and drug resistance patterns should be assessed.
-The optimal period of treatment could vary from 6 to 24 months and, in some cases, based on experts’ opinion, the duration of treatment is recommended to be at least 9–12 months.
Other work up:
– CBC, ESR, CRP, CBC, renal functions, liver functions, LDH, CRP, ESR, urine analysis, ACR.
– Viral screening; EBV, CMV, VZV and HIV.
-Drug level (CNIs, mTORs), monitor drug level frequently every 3 days keeping trough at lower target (trough around 5 for tacrolimus), I will keep lower Therapeutic dose of MMF and steroid.
-Pan CT with contrast to assess the extent of the disease.
Treatment:
The treatment of TB in SOT is challenging due to the following.
Drug-drug interaction between rifampicin (the corn stone of TB treatment) and immunosuppressive medications used in transplantation.
Loss of host immune response to TB due to the use of immunosuppressive drugs
Nephrotoxicity and other side effects related to the use of anti –TB medications.
Protocols used in treatment of TB:
I- Rifampicin containing regimen:
Regimen A– 4-drug regimen of Rifampicin+ INH+ ethambutol + pyrazinamide for 2 months, followed by a 2-drug regimen of Rifampicin + INH for 4 months.
It is recommended to increase the duration of treatment to at least 9 months if one of the following is present.
II- Rifampicin free regimen:
Regimen A – 3-drug regimen of INH+ ethambutol + pyrazinamide or levofloxacin are used for 2 months, followed by a 2-drug regimen of INH + either ethambutol or pyrazinamide for 12 to 18 months.
Regimen B – 3 drugs (INH+ ethambutol + pyrazinamide or levofloxacin are used for 12 months
Regimen C – Rifabutiun can be used instead of rifampicin due to its lesser effect on cytochrome p450, so minimal drug-drug interactions but experience is little when using this drug in transplantation, although it seems effective in HIV TB patients.(9)
Would your management differ if the disease was mild and affected one lung?
Yes, at this time I will avoid Rifampicin and use one of the Rifampicin free regimens.
Diagnosis of latent TB:
-Recipients with latent TB are at high risk of conversion to active TB after transplantation, on the other hand, if the donor has latent TB and did not receive treatment it carry a risk of transmission to the recipient.
-So, all recipients and donors should both be undergo careful evaluation of the risk, history, examination and CXR, together with test for latent TB
-In general, all transplant recipients and donors should be evaluated for the presence of latent TB and once detected treatment should be received.
-2 tests are used to detect latent TB, tuberculin skin test (TST) and IGRA, both are usually negative in immunosuppressed patients due to their dependence on the host immune response which is impaired in these sets of patients.
-Patient and donor should have no symptoms, CXR should be normal and no evidence of exra-pulmonary TB to settle the diagnosis of latent TB.
Which test to use?
-In low-risk transplant recipients, it is it is preferred to use IGRA over TST due to its higher sensitivity in these sets of patients.
-In low-risk donor, either of both tests can be used, with the preference of IGRA in patients with previous vaccination.
-In high-risk transplant recipients and donor (patient who are living in country with high TB prevalence, contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), it is better to do both tests to maximize sensitivity, at that time IGRA should be done either at the same time of before TST to avoid TST-mediated IGRA response.
-All transplant recipients and donors should have thorough history taking and CXR.
Interpretation of the result:
If TST is negative the test should be repeated after 7-10 days to detect posted effect
If IGRA is negative treatment is considered only in high-risk transplant recipients
If the TST is positive (Induration ≥5 mm in recipient or > 10 mm in donor), there is a history of positive TST, or IGRA is positive, the patients is considered to have latent TB provided that the CXR is normal and the patient is asymptomatic
If radiology is suspicious for TB (apical fibronodular lesions, calcified solitary nodule, calcified lymph nodes, or pleural thickening) thorough evaluation including microbiological assessment is indicated to exclude TB as a cause.
If TB diagnosed in the recipient transplantation should be delayed till complete treatment of TB
If TB is diagnosed in the donor donation should be postboned till successful treatment is given for at least 6 months.
Indications of treatment of latent TB in transplant recipient and donor:
Positive TST (> 5mm in recipient, > 10 mm in donor) or a positive IGRA
History of positive TST or pervious history of TB
Negative TST and/or IGRA in a patient with close contact to an active TB case
If the donor has latent TB and did not receive treatment (treat the recipient), but if the donor received treatment there is no need to treat the recipient.
Protocol for treatment of latent TB:
The preferred regimen in renal transplant candidate is the use of INH in a dose of 5 mg/kg (maximum dose 300 mg) together with oral pyridoxine 50 mg daily for 6-9 months (9 months is preferred).
Rifampin in a dose of 600 mg for 4 months
INH+ weekly Rifampin for 3 months
Regimen should be started before transplantation, but if it started after transplantation, Rifampicin containing regimen should be avoided.
Patient should be monitored for liver enzymes and bilirubin at baseline, every 2 weeks for 6 weeks then monthly, if there is 3 fold rise of liver enzymes with symptoms or 5 fold rise without symptoms, INH should be stopped
References:
* Lopez de Castilla D, Schluger NW. Tuberculosis following solid organ transplantation. Transpl Infect Dis 2010; 12:106.
* Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clin Infect Dis 1998; 27:1266.
*Aguado JM, Torre-Cisneros J, Fortún J, et al. Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clin Infect Dis 2009; 48:1276.
*Abad CLR, Razonable RR. Mycobacterium tuberculosis after solid organ transplantation: A review of more than 2000 cases. Clin Transplant 2018; 32: e13259.
* Muñoz P, Rodríguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clin Infect Dis 2005; 40:581.
*Torre-Cisneros J, Doblas A, Aguado JM, et al. Tuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort. Clin Infect Dis 2009; 48:1657.
Long, but well done.
DD could be: miliary TB,CMV pnemonitis, pneumocystis pneumonia, PTLD and other bacterial, fungul, and opportunistic pneumonia.
To confirm TB:
History of TB disease, contact with TB patient or travel to endemic area. Clinical examination to look for extrapulmonary TB.
Sputum C&S with Z-N stain to detect acid fast bacilli ,BACTEC.
Sputum C&S for Bacterial, fungal, PCP
Gene Xpert of sputum or BAL.
Bronchoscopy, BAL and PCR for PCP
CMV PCR.
Drug treatment:
Start anti TB protocol with Rifampicin, INH& Ethionamide ( all for 9 months) and Pyrazinamide for 2 months
Several protocols are available including treatment from 9 months up to 18 months.
Rifampicin is P450 cytochrome inducer causing reduction in CNI levels, so we need to monitor CNI levels and increasing of CNI dose.
Alternative to Rifampicin, we can use: INH for18 months, Ethambutol for 18 months, Pyrazinamide for 3 months and Levofloxacin for 6 months.
Monitoring of graft function is warranted..
If the disease is mild and affecting one lung:
According to ESCMID guidelines: in cases of localized mild TB, a rifampicin free regimen could be used if no resistance to isoniazid. Rifabutin; rifamycin having weaker inducer of cytochrome P450 3A4, is an alternative for rifampicin or fluoroquinolones. Immunosuppression drugs doses could be modified, and levels closely monitored.
What are suggested Rifampicin free regimens.?
This image most probably suggests tubercular infection post-transplant.
Mangement:
Monitor side effects of the drugs:
if the disease was mild and affected one lung?
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.
Well done.
How do you manage this case?
rifamycin-containing regimen- treatment should be continued for at least nine months
In general, the approach to antimicrobial therapy for treatment of miliary TB consists of the traditional regimen (≥6 months) for treatment of pulmonary TB .
MANAGEMENT OF ACTIVE TUBERCULOSIS
the 2019 guidelines of the American Society of Transplantation (AST) , and the 2014 guidelines of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID)
The AST, ESCMID, and TBNET have all recommended that the approach to the treatment of TB in SOT recipients be similar to immunocompetent hosts However, the following important issues specific to SOT recipients should be noted:
●The AST states that a rifamycin-containing regimen is strongly preferred for both severe and localized nonsevere TB due to the potent sterilizing activity of such regimens and the importance of preventing the emergence of resistance
●TBNET and ESCMID suggest a non-rifamycin-based regimen in cases of localized (eg, pulmonary) nonsevere TB when there is no suspicion or evidence of isoniazid (INH) resistance . In patients not receiving a rifamycin, treatment options include a three-drug regimen of INH plus ethambutol plus either pyrazinamide or levofloxacin for 2 months, followed by a two-drug regimen of INH plus ethambutol or pyrazinamide for 12 to 18 months. In those receiving a three-drug regimen for the entirety, the duration of treatment can be shortened to 12 months.
●Experts agree that rifamycins are indicated in patients with severe (eg, cavitary or multilobar disease) or disseminated TB or when there is suspicion or documentation of INH resistance
●Rifampin should be used with caution due to significant interactions between this class of drug and the calcineurin inhibitors and rapamycin (sirolimus). The rifamycins (especially rifampin) reduce serum concentrations of tacrolimus, cyclosporine, rapamycin (sirolimus), and everolimus via induction of the cytochrome p450 isoenzyme CYP3A4, and the combination of a rifamycin with these drugs has been associated with the development of rejection . Rifamycins also reduce levels of glucocorticoids, although this has been less well characterized
●If rifampin is used, the dose of the calcineurin inhibitor or rapamycin should be increased approximately three- to fivefold, and serum concentrations should be monitored . Rifabutin has similar activity against M. tuberculosis but is a weaker inducer of cytochrome p450
●Patients receiving a rifamycin-containing regimen should be treated for a minimum of six months. However, duration should be extended in patients with severe disseminated disease, treatment should be continued for at least nine months in all SOT recipients, since a shorter duration may be associated with increased mortality in this population
●Caution is advised against the overzealous reduction in immunosuppression while treating post-transplant TB given the challenge of immune reconstitution inflammatory syndrome (IRIS).
Antituberculous therapy reverses the immunosuppressive effects associated with TB infection, and IRIS may manifest with a paradoxical worsening of pulmonary infiltrates, fever, pleural or pericardial effusion, or lymphadenopathy
Would your management differ if the disease was mild and affected one lung?
YES
TBNET and ESCMID suggest a non-rifamycin-based regimen in cases of localized (eg, pulmonary) nonsevere TB when there is no suspicion or evidence of isoniazid (INH) resistance . In patients not receiving a rifamycin, treatment options include a three-drug regimen of INH plus ethambutol plus either pyrazinamide or levofloxacin for 2 months, followed by a two-drug regimen of INH plus ethambutol or pyrazinamide for 12 to 18 months. In those receiving a three-drug regimen for the entirety, the duration of treatment can be shortened to 12 months
REFERENCES UpToDate
Thankyou well done,
When does IRIS occur and what is the level of IS at that time?
How do you manage this case?
The diagnosis of the current scenario most probably is disseminated TB with imaging showed pulmonary TB with general manifestations of wight loss, night fever and sweat.
In renal transplant patients on immunosuppression and history of induction with lymphocyte depleting agents, these patients represent a high-risk to develop TB infection either localized or disseminated. The source of infection either reactivation of latent infection or TB transmission from the donor allograft to the recipient (The reactivation of latent tuberculosis in organ transplant recipients within the first twelve months is the most common manifestation).
In addition to imaging findings of disseminated TB, blood Mycobacterium tuberculosis PCR test must be done to confirm TB infection. bronchoscopy with bronchoalveolar lavage or lung biopsy may be needed for diagnosis. Sputum should be sent for acid-fast bacilli staining and culture and histopathology.
Treatment with antituberculosis treatment consisting of rifampicin, isoniazid, pyrazinamide, and ethambutol to be started immediately for 2 months, followed by a two-drug regimen of INH plus ethambutol or pyrazinamide for 12 to 18 months. .In addition to hold MMF and target tacrolimus level of 5-7 (rifampin reduce serum concentrations of tacrolimus, cyclosporine, rapamycin , and everolimus via induction of the cytochrome p450 isoenzyme CYP3A4). the dose of the calcineurin inhibitor or rapamycin should be increased approximately three- to fivefold, and serum concentrations should be monitored.
screening for latent tuberculosis infection prior to transplantation and consequent prophylaxis with isoniazid is essential. Available screening tests for latent tuberculosis, including interferon gamma-release assays (IGRA) and tuberculin skin tests (TST), are limited in patients with chronic kidney disease, as the tests rely on an intact immune response.
Would your management differ if the disease was mild and affected one lung?
suggested a non-rifamycin-based regimen in cases of localized (eg, pulmonary) nonsevere TB when there is no suspicion or evidence of isoniazid (INH) resistance.
Thankyou
How is Rifapentine better ,what other conditions is it more convenient.
The index scenario is a KTR with night fever, productive cough and weight loss. CXR and CT lungs showed bilateral lung infiltrates without subpleural spare. Symptoms and radiographic findings are highly suggestive of TB infection.
The differentials for this scenario:
· Pulmonary TB.
· Atypical pneumonia.
· CMV pneumonitis.
· Pneumonia due to PJP.
Management plan:
1. Supportive measures; full hydration, good nutrition and anti-pyretic.
2. General investigations: CBC, RFT, LFT, CRP, RBG, Urinalysis and LDH.
3. Screening for TB:
· sputum microscopy and culture for AAFB.
· Rapid molecular test(the Xpert MTB/RIF assay) is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively(1).
4. Screening tests for CMV(CMV IgG & IgM) and PJP.
5. Treatment of the causative agent; in case of active TB infection(2):
a) The optimal period of treatment could vary from 6 to 24 months. Recommended to be at least 9–12 months.
b) According to AST-IDCOP, the first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases.
c) The standard regimen is similar to that used for the general population and consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin.
d) Adjustment of immunosuppression as Rifampicin reduces the level of CNIs and mTORi:
· the dose of CNIs and mTORi should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
Would your management differ if the disease was mild and affected one lung?
· The treatment will differ only in the duration of therapy from 6 -24 months. In case of mild disease 6-9 months may be adequate. Not less than 6 months.
· According to AST-IDCOP, the first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases(2).
References
1. 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.
2. 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.
Well done
How do you manage this case?
the indexed case of an immunocompromised patient after kidney transplantation from his brother with a history of fever around 1 year after transplantation with wt loss, night sweat, and CXR on the RT side showed bilateral diffuse reticular nodular shadows with an endotracheal tube( tracheostomized patient ), which indicate the possibility of active TB and probably MDR – resistant MBT complicated by miliary TB as the radiological images including CT chest highly suggestive of miliary TB, we need to ask more history about the previous exposure or previously treated on the line of active pulmonary TB or LTBI and reactivation after transplantation which is the commonest source of infection, also need to ask about recent contact or travel to an endemic area or his originally might be from an endemic area. Did he receive anti-TB treatment and now with complications my concern about MDR – MBT with superadded invasive infections like fungal infection, CMV, aspergillosis
histoplasmosis
Diagnosis of MDR -MBT
Genotypic (or molecular) methods have revolutionized the diagnosis of MDR-TB. These methods generally use polymerase chain reaction techniques to detect the genetic mutations that are known to confer resistance to drugs in his case will get tracheal aspiration for gene expert, molecular methods will be better than culture, as will get the results faster, and cultures need to wait for weeks, also direct staining for from tracheal aspirate for Acid fast bacilli but the sensitivity low, bronchoscopy, and BAL assay, a positive molecular test for rifampicin resistance can be considered diagnostic for MDR-TB because, in most countries, greater than 90% of rifampicin-resistant strains are also resistant to isoniazid.
This patient should be in negative pressure room isolation, get ID consultation and consider second-line anti-TB to cover for possible MDR – resistant TB Patients who are infected with strains resistant to isoniazid and rifampicin, called multidrug-resistant (MDR) TB, are practically incurable by standard first-line treatment. And carry a high mortality rate, with increased frequency in endemic areas of up to 20% and even more in those with a previous history of TB of up to 50%.
Would your management differ if the disease was mild and affected one lung?
For patients with drug-susceptible TB, standard treatment based on isoniazid and rifampicin, the two most powerful drugs, results in excellent cure rates but need frequent monitoring for hepatotoxicity and drug interaction with CNI including, cyclosporine, tacrolimus everolimus, sirolimus, rifampicin is an enzyme inducer induction of cytochrome 450, cyp3A4, and can significantly reduce the level even to undetectable level and need dose adjustment by 3-5 folds and frequent drug monitoring to avoid the risk of rejection vs drug toxicity
References
1.Seung KJ, Keshavjee S, Rich ML. Multidrug-Resistant Tuberculosis and Extensively Drug-Resistant Tuberculosis. Cold Spring Harb Perspect Med. 2015 Apr 27;5(9):a017863.
the main challenge in post-transplantation TB is the late diagnosis due to atypical and nonspecific findings, I have two cases of laryngeal TB after kidney transplantation one in Iraq just a few months after transplantation with hoarseness of the voice, and another Omani female patient two years back presented to us with 8 months history of fever of unknown origin with wt loss and also hoarseness of the voice later on complicated by stridor ( 12 years after commercial TX in Pakistan ), she underwent extensive work up in the regional hospital then referred for expert opinion during her admission she had a respiratory arrest, intubated and again tracheal aspirate was positive for MBT and improved with anti-TB medications.
also, I missed adding further imaging including CT Brain, and CSF analysis for the abdominal images, to rule out disseminated TB
Thankyou for the exellent answer.
Thankyou for sharing your cases, the Omani lady after 12 years this is probably a new infection as it is too late for activation of a latent one.
Post transplant patient with night fever, cough, and dyspnea having Ct chest finding of bilateral reticulonodular lesions is consistent with miliary TB. But other DD could be
For confirmation of Milliary TB
Previous history of TB disease, contact with TB patient or travel to endemic area would be important but not necessary. Detail examination to look for sign and symptoms of extrapulmonary TB.
Sputum C&S with Z-N stain to detect acid fast bacilli.
Sputum C&S for Bacterial, fungal, PCP
Gene Xpert of sputum or BAL for TB
Bronchoscopy, BAL and PCR for PCP
CMV PCR.
CBC, LDH, ESR, CRP
Treament options
Start anti TB protocol with
– Rifampicin for 9 months
– INH for 9 months
– Ethunamide for 9 months
– Pyrazinamide for 2 months
Duration of treatment: Several protocols are available including treatment from 9 months up to 18 months.
As Rifampicin is P450 cytochrome inducer leading to reduction in CNI levels therefore if 4 drugs mentioned above are to be used, we have to closely monitor CNI levels and upscaling of CNI would be required.
If Rifampicin is to be avoided to maintain the CNI in study stat, we have to give.
Close Monitoring of graft function during this therapy is recommended.
Adverse effects of TB therapy:
1. Hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol)
2. Neurotoxicity (isoniazid, ethambutol)
3. Cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol)
4. Visual disturbances (rifabutin, ethambutol)
5. Skin lesions (rifampicin)
6. Hyperuricemia (pyrazinamide)
7. Interstitial nephritis (rifampicin, pyrazinamide)
Would your management differ if the disease was mild and affected one lung?
o ESCMID guidelines treatment: in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid (the 2-month intensive phase contains isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide)
o Rifabutin, a rifamycin with weaker inducer of cytochrome P450 3A4 and P-glycoprotein, is an alternative for rifampin (as effective as rifampin for the treatment of TB in trials conducted in non-transplant patients). Immunosuppression doses could be modified, and levels should be closely monitored.
o Another safe and effective alternative to rifampicin is treatment with fluoroquinolones
References
1- Bednarova K, Slatinska J, Fabian O, Wohl P, Kopecka E, Viklicky O. Tuberculosis dissemination in kidney transplant recipient treated with anti-CD40 monoclonal antibody: a case report. BMC Nephrol. 2022 Aug 19;23(1):290.
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 Feb;102(2S Suppl 2):S60-S65.
3- Machuca I, Vidal E, de la Torre-Cisneros J, Rivero-Román A. Tuberculosis in immunosuppressed patients. Enferm Infecc Microbiol Clin (Engl Ed). 2018 Jun-Jul;36(6):366-374. English, Spanish.
Thankyou but localized milder cases to treat for 12 to 18 months!!!!
Well done ,
What about drug resistant TB! what is the recommendation to diagnose and treat.
How do you manage this case?
Symptoms of night fever, productive cough, and weight loss and radiological features in a post-transplant period is highly suggestive of pulmonary TB (other co-infection should be considered)
Chest x ray showed: bilateral hilar shadows and bilateral reticulnodular shadows of both lungs
CT chest showed: bilateral reticulonodular shadows with well-defined scattered small nodules (military TB) with possible cavitatory lesions
Active Tuberculosis: usually occurs in the first year after KT (a median time of 11.5 months) in the case of reactivation (the most common cause) and earlier in the case of donor-derived infection (in the first 3 months). Diagnosis is by detection of M. tuberculosis bacilli by direct observation, culture, and NAT
Screening of active TB and other extra-pulmonary TB
History of previous TB infection, contact with active TB patient, travel to area with high endemic of TB, prophylaxis and vaccination, and donor LTBI
Symptoms: Chronic cough, weight loss, night sweats, and anorexia. Symptoms of extrapulmonry involvement (urinary, neurological and others)
Clinical examination: full examination of the chest, examine for lymph nodes, and exclude other extra pulmonary TB
Investigations: CBC, CRP, RFT, LFT, sputum microscopy for AFB and culture, molecular tests based on rapid nucleic acid amplification techniques, lymph nodes aspiration and urinary tract where indicated
Imaging: Chest x ray/CT chest, renal ultrasound, spinal MRI and CT/MRI brain where indicated
TST and IGRA are not useful in the diagnosis of active TB
Treatment of pulmonary TB (at least 9–12 months)
AST-IDCOP guidelines recommend:
1. Active uncomplicated pulmonary TB (treatment duration should be at least 6 months)
2. if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy (9 months)
3. Severe disseminated disease or bone and joint disease (at least 6–9 months)
4. CNS involvement (at least 9–12 months)
AST-IDCOP guidelines treatment:
First-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases (2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by isoniazid and rifampicin)
Rifampicin-immunosuppression interaction:
o Rifampicin and transplant-associated immunosuppression interaction
o Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein
o Rifampicin decrease the levels of CNIs, mTOR inhibitors, and affects glucocorticoids
o CNIs and mTOR inhibitors levels should be closely monitored during rifampicin-based regimen
o The dose of CNIs and mTOR inhibitor should be increased between 3-5 folds and the glucocorticoid dose should be doubled during treatment
Adverse effects of TB therapy:
The most common adverse event is hepatotoxicity (liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter)
1. Hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol)
2. Neurotoxicity (isoniazid, ethambutol)
3. Cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol)
4. Visual disturbances (rifabutin, ethambutol)
5. Skin lesions (rifampicin)
6. Hyperuricemia (pyrazinamide)
7. Interstitial nephritis (rifampicin, pyrazinamide)
Severe TB or when a vital organ is involved:
Reduce immunosuppression (risk of immune reconstitution inflammatory syndrome, which is associated with the reduction of immunosuppression and the use of rifampicin)
Would your management differ if the disease was mild and affected one lung?
o ESCMID guidelines treatment: in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid (the 2-month intensive phase contains isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid ande thambutol or pyrazinamide)
o Rifabutin, a rifamycin with weaker inducer of cytochrome P450 3A4 and P-glycoprotein, is an alternative for rifampin (as effective as rifampin for the treatment of TB in trials conducted in non-transplant patients). Immunosuppression doses could be modified, and levels should be closely monitored
o Another safe and effective alternative to rifampicin is treatment with fluoroquinolones
References
1. Sorohan, B.M.; Ismail, G.; Tacu, D.; Obris ,ca˘, B.; Ciolan, G.; Gîngu, C.; Sinescu, I.; Baston, C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens 2022, 11, 1041. https://doi.org/10.3390/ pathogens11091041
2. 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.
Exellent.CORRECT to exclude distant organ spread in this case with miliary TB.
Thank you prof., ok.
The CXR shows multiple small nodules characteristic of miliary TB. His symptoms of night fevers, productive cough and weight loss are characteristic of TB. He is post-transplant and studies have shown that patients post-transplant have a higher risk of developing compared to the general population
The differential diagnosis is:
Management of the case:
He will need further investigations:
Treatment:
Once the diagnosis is confirmed, he will need to be started on rifafor (Isoniazid, rifampin, pyrazinamide and ethambutol) with pyridoxine. The rifafor dose is weight based
The dose of the CNI will need to be monitored very closely as the rifampin will increase the metabolism of tacrolimus reducing the levels. In most cases, the dose tacrolimus is doubled to achieve the appropriate trough concentrations.
The patient will also need to be informed that his body secretions will change color – due to the antiTBs
His liver function need to be monitored
After 2 months and appropriate clinical response, the patient gets the continuation phase of the Tb regimen – isoniazid and rifampicin for four months
The management is the same even if only one lung was affected. The therapy will be:
Intensive phase for 2 months and continuation phase for four months
Thankyou well done.
1. How would you manage this case?
The CXR and CT: bilateral fine nodular opacities, which is typical of millet. In addition there is rounded perihilar shadowing (LNs)
Based on the presence of fever, night sweats, occurring in renal transplant recipient 1 year post transplantation, miliary TB is highly suggestive.
Other differential diagnoses to be considered
Viral pneumonias especially HZV and CMV Fungal pneumonias, histoplasmosis Bronchoalveolar carcinomaLymphangitic carcinomatosisHistory:
In the recipient: DM, LTBI, past history of active TB or contact with a patient with active TB and history of travel to an endemic area and duration of stay.In the donor: history of untreated and latent TB.Type of IS treatment, any AR.Examination
· Looking for lymph nodes elsewhere, or primary malignancy
Laboratory
CBC, ESR, CRPRFT, LFT Exclude other differential by PCR for HVZ , CMV in respiratory samplesFor fungal staining, PCR and cultures in respiratory samples and serology. Sputum for AFB by stain and send for culture and drug sensitivityRespiratory samples also tested for cytology BAL samples may be needed if sputum is not yielding The rapid molecular testing, Xpert MTB/RIF assay, this test is highly specific.Treatment
· For active TB, the recommendation is to follow the local guide lines for the general population.
4-drug regimen is recommended in most cases INH and rifampicin are the first-line drugs against TB.
Rifampicin leads to a reduction in the blood levels ta crolimus, cyclosporine, sirolimus, everolimus, and corticosteroids. A lower blood level of these drugs is associated with higher risk of graft rejection. Rifabutin, which has a weaker enzyme induction is an alternative for rifampin. It has been demonstrated to be as effective as rifampin for the treatment of TB in non-transplant patients. When rifabutin is used, drug monitoring of immunosuppressive is also indicated as for rifampicine Looking for side effects of anti tuberculous medications, importantly is hepatic toxicity, peripheral neuropathy( pyridoxine is given with INH) and ethambutol optic neuropathy The optimal length of treatment of disseminated TB as in this index case treatment duration should be at least 9 months. The response to treatment should be followed closely and treatment should be shared with an expert in management of TB. How would the treatment differ if it is a milder form:
May use a riampicine free regimen if there is no local INH resistance. The regimen should be longer than 6 month. Always we should involve experts who are familiar with the local guidelines and drug resistancebof TBI.
Well done for considering other pathologies.
1-How do you manage this case?
Regarding clinical approach of this case;
-CXR—–showed bilateral reticulonodular shadows with perihilar infiltrate and opacities represent mediastinal LNs.
-HRCT—showed numerous small sized nodules distributed throughout both lungs, (most likely military TB).
For confirmation Diagnosis;
–The diagnosis of TB requires a high index of suspicion based on the epidemiological risk, personal history, manifestations and imagistic lesions,
-Molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test (Xpert® MTB/RIF) could provide false negative results when mycobacterial load is low,
–Tuberculin skin test (TST) and interferongamma release assay (IGRA) are not useful in the diagnosis of active TB.
-Probability of association with other co-infections, so further investigations r/o other fungal or viral infections (CMV-EBV-HIV).
My Impression;
(Active pulmonary TB ; most probably 2ry to reactivation of LTBI in recipient).
Treatment;
–Patients should be isolated until he is improving clinically, or after 3 consecutive negative sputum smear results (guided by I.C. recommendation)
-The treatment of active TB should be promptly started immediately after the diagnosis has been established.
-The epidemiological features from the area of patient’s origin and drug resistance patterns should be assessed.
–The optimal period of treatment could vary from 6 to 24 months and, in some cases, based on experts’ opinion, the duration of treatment is recommended to be at least 9–12 months.
(AST-IDCOP) guidelines:
-The first-line treatment should be a four-drug regimen containing rifamycin.
-Intensive phase (for 2 months) of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by;
-Continuation phase (for 4 months) of isoniazid and rifampicin,
-Recommends that in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months,
-But if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months.
(ESCMID) guidelines:
-Suggests a standard regimen used for a period longer than 6 months, and, in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present.
If a regimen without rifamycin is used,
-Intensive phase (for 2 months) of isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by,
-Continuation phase (12–18 months) with isoniazid and ethambutol or pyrazinamide.
Challenges in the treatment of KT recipients with active TB:
1-Drug interaction between rifampicin and transplant-associated immunosuppression.
-An alternative to rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy , another safe and effective alternative to rifampicin in KT recipients is treatment with fluoroquinolones.
-Rifampicin usage decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection.
-When a rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin and mTOR inhibitor should be increased between 3-5 fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
-After the rifampicin is stopped, the immunosuppression doses should be reduced to the value before the start of rifampicin and then adjusted to obtain the therapeutic target.
2-Patients treated with anti-TB drugs should be closely monitored for hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol), neurotoxicity (isoniazid, ethambutol), cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol), visual disturbances (rifabutin, ethambutol), skin lesions (rifampicin), hyperuricemia (pyrazinamide) or interstitial nephritis (rifampicin, pyrazinamide).
During Treatment protocol of TB;
-Closely monitoring liver enzymes with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter ; as the most common adverse event associated with anti-TB therapy is hepatotoxicity.
-Creatinine clearance and adjust the doses for pyrazinamide and ethambutol.
-Reduction of immunosuppression in the case of severe TB should be considered.
Screening for donor;
-His brother should be screened for latent TB infection if it has not been done prior to KT ; using (TST/IGRA).
–Recognizing latent infection or undiagnosed active TB in the kidney donors is critical in preventing post-transplant infection.
–A careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors.
–Current guidelines provide recommendations for latent TB screening in all KT candidates and donors before transplantation.
2-Would your management differ if the disease was mild and affected one lung?
-The same treatment if no proven drug resistance , but the duration may be different;
-According to AST-IDCOP, the first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases.
-Rifamycin is recommended for its sterilization capacity and efficiency but also to reduce the risk of resistance.
-(AST-IDCOP) guidelines recommends that in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months.
–Severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months.
-Patients with central nervous system involvement should be treated for at least 9–12 months.
References;
–Morris, M.I.; Daly, J.S.; Blumberg, E.; Kumar, D.; Sester, M.; Schluger, N.; Kim, S.-H.; Schwartz, B.S.; Ison, M.G.; Humar, A.; et al. Diagnosis and Management of Tuberculosis in Transplant Donors: A Donor-Derived Infections Consensus Conference Report. Am. J. Transplant. 2012, 12, 2288–2300.
–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.
Thankyou for an exellent review but please note:
The picture is very suggestive of miliary TB which is usually not open so depending on sputum culture is not always helpful, but all other criteria are useful to take the decision.
If that shown lesion is unilateral then it is difficult to categorise it as miliary and other pathologies should be excluded.
Well done.
CXR showed bilateral reticulonodular shadow involved both lung field. Perihilar infiltrate and opacities likely represent enlarged LN.
CT showed numerous small, uniform millet-seed sized nodules distributed throughout both lungs, making tree in bud appearance (military TB).
The clinical symptoms of (fever, productive cough, and weight loss) with the radiological findings is highly suggestive for pulmonary tuberculosis.
Other differential includes: fungal infection, pulmonary metastasis , viral pneumonia; CMV, VZV.
Active TB usually appears in the first year after KT, at a median time of 11.5months in the case of reactivation after latent infection and earlier in the case of donor derived infection (in the first 3months
The diagnosis of Pulmonary TB relies on the detection of M. tuberculosis bacilli by direct observation, by culture and nucleic acid testing.
A-Confirm the diagnosis.
– Thorough history including; contact with active TB, previous history of TB and TB treatment, being in endemic areas, previous TST result.
– Full examination to rule out extrapulmonary TB.
Work up:
– CBC, ESR, CRP.
– Kidney function and LFT.
– Drug levels.
– Sputum for AFB smear, Culture and drug sensitivity ( it will take long time and decision need to be taken rapidly).
– BAL may be required it will increase the yield of diagnosis.
– Rapid molecular test (Xpert MTB/RIF assay): It is highly specific and sensitivity and allows detection of rifampicin resistance, which is highly predictive of MDR-TB.
-Exclude fungal infection cultures, staining and PCR.
– Viral screening; EBV, CMV, VZV and HIV.
– Neither TST nor IGRAs are recommended for diagnosing active infection as both test may be falsely negative in immunocompromised patients and in active TB, as these test assess the immune response of the body to MTB.
Treatment of Active TB:
– Treatment depend on epidemiological data and the pattern of local resistance.
– The recommendations for 1st line therapy in the transplant patient are the same as for the immunocompetent host.
Intensive phase (2 months) First line 4‐drug regimen; of isoniazid, rifampin (or rifabutin) pyrazinamide, and ethambutol
Continuation phase: isoniazid and rifampin alone for an additional 4 months
-Ethambutol can be discontinued once susceptibility to isoniazid, rifampin, and pyrazinamide is confirmed.
-Moxifloxacin and levofloxacin; currently listed as second‐line agents for active TB treatment
– Rifamycin‐containing regimen is strongly preferred due to sterilizing activity. It is enzyme inducer metabolize most IS drugs.
– Rifabutin if available can replace rifampin as it has similar activity against but is a much less potent enzyme inducer, which make IS easier to maintain
-If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.
– INH should be co-administered with pyridoxine
Treatment duration
– Treatment durations of active TB after SOT reported in the literature range between 6 and 24 months.
– Longer durations considered if the response to treatment is slow, if second‐line drug replacements are used or if there is resistance to rifampin ± other drugs.
AST-IDCOP recommendation:
– Uncomplicated pulmonary TB is at least 6 months.
– But longer course (9 months)for cavitary disease or disease with persistent sputum culture‐positive status after 2 months of therapy
– Bone and joint disease (6‐9 months), CNS (9‐12 months), and severe disseminated disease (6‐9 months)
Immunosuppression management:
– In sever TB , vital organ involved, fatal infection not responded to treatment, we may reduce IS, reduce antimetabolite by 50 % or can be stopped completely.
– Rifampicin usage decrease the levels of CNI, mTORi and affects glucocorticoids metabolization, which increases the risk of rejection
– Increase CNI by 3-5 fold, monitored by the level.
– Double the dose of glucocorticoid dose.
Monitor:
– Immunosuppressant levels must be closely monitored closely at the start and end of rifamycin therapy SOT.
– IS should be adjusted during and after completion of therapy.
– Graft function as there is a risk of rejection
– Hepatotoxicity serious side effect, therfore monitor LFT regularly and more frequently.
– Treatment adherence; DOT programs are recommended for transplant recipients.
– Screen household contact for LTBI.
Would your management differ if the disease was mild and affected one lung?
-Treatment should be guided by drug susceptibility.
– AST-IDCOP and ESCMID suggests a standard regimen used for a period longer than 6 months, and, in cases of localized non-severe TB.
– Regimen without rifampicin could be used if no resistance to isoniazid is present. Options include:
-INH and ethambutol and pyrazinamide or levofloxacin are used for 2 months, followed by INH and either ethambutol or pyrazinamide for 12 to 18 months
–INH and ethambutol and pyrazinamide or levofloxacin are used for 12 months.
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.
Well done Dr Hadeel Badawi. Points of excellence:
1- Radiological description of lesions
2-Difference between Rifampicin and Rifabutin
3-The need to start treatment pending results of investigation which can take longer time
You referred to hepatotoxicity but did not refer to potential side effects of other anti TB medications other than Rifampicin. Clearly this patient requires counselling. One of the important piece of information from history is his donor history of TB.
From this radiological findings, do you think this patient is at high risk of any other organ involvement and what haemodynamic complication would be?
donor source of TB more in DD as usually living donor will be thoroughly investigated including IGRA test for latent TB infection as part of the protocol for screening the donor and recipient, in addition, if his brother the source it would be present earlier with the introduction of IS, i think in history here we should focus on recipient previous history of TB or LTBI and previous treatment of TB and now presented with MDT complicated course
Thank you Prof. Mohsen.
Other side effects definitely need to be monitored and patient should counselled in this regards.
S/E includes:
-Hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol).
-Neurotoxicity (isoniazid, ethambutol), cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol)
-Visual disturbances (rifabutin, ethambutol).
-Skin lesions (rifampicin).
-Hyperuricemia (pyrazinamide) or interstitial nephritis (rifampicin, pyrazinamide)
The most common sites of involvement include lungs (>50%) the lymphatic system, bones and joints, liver, CNS (15-20%) , and adrenal glands (1% reported cases, however, 40 % in autopsies).
Hemodynamic complications:
– Multiorgan system failure.
– ARDS
– Adrenal insufficiency ( crises with hypotension and shock)
– Syndrome of septic shock
References:
– Ahuja SS, Ahuja SK, Phelps KR, Thelmo W, Hill AR. Hemodynamic confirmation of septic shock in disseminated tuberculosis. Crit Care Med. 1992 Jun;20(6):901-3. doi: 10.1097/00003246-199206000-00031. PMID: 1597048.
How do you manage this case?Through history and examination to exclude extrapulmonary TB (blood pressure, meningeal sign, encephalopathy.
Relevant history- prior history of TB, history of TB in donor pre and post donation, BCG vaccination
Care Airway Breathing and circulation (some time present with adrenal insufficiency)
O2 inhalation, protect airways, care of blood pressure.
Investigation
Sputum AFB1, AFB 2, (Z-N staining), C&S(BACTEC or L and J)
PCR for MTB in sputum or blood
Xene expert in drug resistant area
Montoux test
if sign of meningeal irritation- CSF( tlc, dlc, sugar, protein,ldh, ADA, pcr, cob web on standing)
serum cortisol if hypoglycemia, hypotension
LFT- disseminated TB or base line LFT before starting treatment.
uric acid-before starting treatment can in BY pyrazinamide.
Treatment
Intensive phase-
INH 5 mg/kg
Rifampicin 10 mg/kg
Ethambutol 15 mg/kg
Pyrazinamide 20 mg/kg
Duration of treatment : 9 month if brain involvement 9-12 month
Adjuvant- steroid, pyridoxine in high acetylation population
Monitoring for adverse drug effects such as hepatotoxicity, peripheral neuropathy (INH), optic atrophy (ethambutol), monitor graft function.
Immunosuppressive agents
Tacrolimus- need to increase the dose to (3-5 fold) and monitor trough level after starting and after stopping (interaction with rifampicin and INH)
MMF- though AUC is changed in withdrawal of rifampicin dose is not change in clinical practice but can be hold till sputum comes negative till 2 to 4 weeks
increase dose of steroid if in chronic use-
Screening of donor with IGRA- to rule out latent tuberculosis if he had not manifested the disease.
Would you manage differ if the disease was mild and affected one lung?
Duration of treatment – 6 months-short
Can use less interaction drugs – HZE with or without fluroquinolone in intensive phase and continuation phase HE (18 month) or HE plus z or levofloxacin for 12 months
z (pyrazinamide) H isoniazid E ethambutol
Reference
José María Aguado, Julián Torre-Cisneros, Jesús Fortún, Natividad Benito, Yolanda Meije, Antonio Doblas, Patricia Muñoz, David R. Snydman, Tuberculosis in Solid-Organ Transplant Recipients: Consensus Statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology, Clinical Infectious Diseases, Volume 48, Issue 9, 1 May 2009, Pages 1276–1284, https://doi.org/10.1086/597590
Annapandian VM, Fleming DH, Mathew BS, John GT. Mycophenolic acid area under the curve recovery time following rifampicin withdrawal. Indian J Nephrol. 2010 Jan;20(1):51-3. doi: 10.4103/0971-4065.62091. PMID: 20535273; PMCID: PMC2878413.
Thank you for comprehensive answer. You referred to Relevant history- prior history of TB, history of TB in donor pre and post donation, BCG vaccination. This piece of information is vital but what did you mean history of TB pre and post donation? I understand pre and what about post?
You mentioned care airway in many occasions do you suspect this patient will suffer from airway obstruction?
You referred to ‘Can use less interaction drugs – HZE with or without fluroquinolone in intensive phase’
I’m not clear about less interaction drugs? Do you think INH would be enough with short course in a case similar to this?
Thank you for the question, sir and suggestion –
1)If the donor had TB post donation – we can think he might have latent tb in him before donation.
2) Taking care of airway- i mean to say patient need to be well oxygenated, if spo2 is low need to supplement. (Will take care next time sir will try to write so that it will be easily understandable.)
3)INH only will not be enough but to use this drug with combination with other drug like pyrazinamide, ethambutol, moxifloxacin, levofloxacin, linezolid which are less interacting than rifampicin with tacrolimus.
How do you manage this case?
Pulmonary tuberculosis is the most likely diagnosis in this case based on the following:
Time since transplant: over 2/3rd reported cases of active tuberculosis in transplant recipients present within the first year, with median time between 6 to 11 months. (1,2)
Signs/symptoms: Night fever, productive cough, and weight loss
CXR and CT chest: Bilateral, diffuse involvement of lungs. CT film suggestive of tree in bud appearance
Confirmation of diagnosis:
Treatment (3):
First-line treatment for active tuberculosis: same as for immunocompetent hosts
Second Line agents:
Daily administration of active TB therapy
Longer therapy in cases of:
DOT program
Pyridoxine
Main Challenges in treating TB in post-transplant:
Despite this, rifamycin containing regimen is strongly preferred due to the potent MTB sterilizing activity of this drug class.
Overcoming challenges with Anti TB drugs in post-transplant period
Would your management differ if the disease was mild and affected one lung?
I would like to treat it in similar fashion as mentioned above
References:
I like your comment, “if the disease was mild and affected one lung: I would like to treat it in similar fashion as mentioned above.”
My suggestion: pharmaceutical approach would be different if there is suspicion or proof of drug resistance.
I like your detailed summary. I appreciate your debate regarding the uncertainty on optimal duration of therapy
This kidney recipient presented with night fever, cough, dyspnea and both CXR and Ct chest show diffuse bilateral reticulonodularv lesions , He mostly have pulmaonary TB.
Other DD
1- PTLD
2- PJP pneumonia
3- CMV pneumonitis
4- Drug induced pneumonitis , if he was treated with m TOR.
5- Other bacterial and opportunistic pneumonia.
I- To confirm diagnosis of TB
1- History : previous TB disease , vaccination , contact with TB patient or travel to endemic area.
2- Thourou history and examination to exclude extrapulmonary TB .
3- Sputum C&S with Z-N stain to detect acid fast bacilli .
4- PCR for TB in sputum or blood .
5- Investigation for other causes as PJP with bronchoscopy ,BAL and PCR
6- CMV PCR .
II- Treament
A- IS drugs modification : stop antiproliferative drugs and increase steroid dose.
B- Start anti TB protocol :with
– Rifampicin
– INH
– Ethunamide
– Pyrazinamide
– Duration of treatment : Several protocols with variablr durations exist ,but its better to continue treatment for 9 months to prevent relapase.
– Monitoring for adverse drug effects such as hepatotoxicity ,specially during first 2 months of therapy ,it should be biweekly.
C- Monitoring of IS trough level closely due to drug-drug interaction between IS and antiTB drugs specially rifambicin which is a strong enzyme inducer or replace with rifaximin
D- Monitoring of graft function.
Would you manage differently if it was localized to one lung:
– The Spanish Society of Infectious Diseases and Clinical Microbiology recommend For treatment of localized , non severe TB infection and with out evidence of INR resistance to initiate treatment with (INH, ethambutol and pyrazinamide or levofloxacina and avoid the use of rifamycins to avoid their interaction with IS (AII).
– For maintainance : either 12-18months of two drugs (INH and ethambutol or pyrazinamide) orshorter duration of 12 months using three drugs (INH+ either ethambutol or pyrazinamide + levofloxacin (CIII).
Ref
1- Bednarova K, Slatinska J, Fabian O, Wohl P, Kopecka E, Viklicky O. Tuberculosis dissemination in kidney transplant recipient treated with anti-CD40 monoclonal antibody: a case report. BMC Nephrol. 2022 Aug 19;23(1):290.
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 Feb;102(2S Suppl 2):S60-S65.
3- Machuca I, Vidal E, de la Torre-Cisneros J, Rivero-Román A. Tuberculosis in immunosuppressed patients. Enferm Infecc Microbiol Clin (Engl Ed). 2018 Jun-Jul;36(6):366-374. English, Spanish.
I appreciate your debate regarding the uncertainty on optimal duration of therapy
-A case of Miliary TB after possible reactivation of LTBI
The patient need to be evaluated precisely taking medical history and clinically assessed regarding his oxygen saturation and his general status to decide if he will need ICU admission for close monitoring of his vitals and respiratory status as he can need oxygen supply as well as isolation in negative pressure room.
Investigations
AFB smear testing from sputum samples as well as sputum and blood culture for TB
Xpert® MTB/RIF for Rifampicin resistance testing can be done soon too
Along with other basic labs CBC, LFT,KFT ,eGFR to evaluate the graft status
Pan CT is needed to detect the disseminated TB in different organs
Treatment
Quadruple therapy need to be started soon in the forum of INH with pyridoxine ,Rifampicin, pyrazinamide and ethambutol for 2 months then INH with pyridoxine and rifampicin for 4 months in fact therapy can be extended with severe disseminated TB, to 9 month or longer duration of treatment may be preferred with response to AntiTB therapy ,Risk of recurrence is lower with extending therapy after 12 months
Bone and joint disease and severe disseminated disease are treated for a total of 6-9 months. Central nervous system disease involvement necessitate treatment duration of 9-12 months
With monitoring of liver function tests / 2weeks if stable very 6 weeks then on further bases Baseline and monthly visual acuity and red-green discrimination testing should be done with ethambutol use.
European guidelines recommend sputum smear and culture at least at two months and four months of treatment, at the end of therapy and on two further occasions until the end of 12 months. Extra-pulmonary TB is followed clinically.
Immunosuppressive drug levels need close monitoring as rifampicin is an enzyme inducer also drug interaction monitoring with other Anti TB has to be done
Also his brother the donor has to undergo investigation for LTBI as TST or IGRA and to start therapy if needed.
-Treatment regimens for milder cases is the same quadruple therapy but duration of therapy can be 6 months instead of longer durations indicated in severe diseases with extrapulmonary involvement.
Reference
-Bumbacea D, Arend SM, Eyuboglu F, Fishman JA, Goletti D, Ison MG, Jones CE, Kampmann B, Kotton CN, Lange C, et al. The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement. Eur Respir J. 2012;40:990–1013.
– Anand M, Nayyar E, Concepcion B, Salani M, Schaefer H. Tuberculosis in kidney transplant recipients: A case series. World J Transplant. 2017;7(3):213-221. doi:10.5500/wjt.v7.i3.213
Do you think GeneXpert in comparison to IGRA has a better higher LR ratio?
GeneXpert is highly specific 100% and 84% sensitive
Reference
Saeed M, Ahmad M, Iram S, Riaz S, Akhtar M, Aslam M. GeneXpert technology. A breakthrough for the diagnosis of tuberculous pericarditis and pleuritis in less than 2 hours. Saudi Med J. 2017;38(7):699-705.
Management of the case
This a case of LTBI reactiation after kidney transplantation
The picture show active pulmonary TB
Investiigation should include;
According to the WHO 2018;
Challenges with the treatment;
If the disease is mild and categoried as Latent infection reactivation with no active disease;
Refferences;
Tonelli, M.; Wiebe, N.; Knoll, G.; Bello, A.; Browne, S.; Jadhav, D.; Klarenbach, S.; Gill, J. Systematic Review: Kidney Transplantation Compared with Dialysis in Clinically Relevant Outcomes. Am. J. Transplant. Off. J. Am. Soc. Transplant. Am. Soc. Transpl. Surg. 2011, 11, 2093–2109. [CrossRef] [PubMed] 2. Gill, J.S.; Abichandani, R.; Kausz, A.T.; Pereira, B.J.G. Mortality after Kidney Transplant Failure: The Impact of Non-Immunologic Factors. Kidney Int. 2002, 62, 1875–1883. [CrossRef] [PubMed] 3. Kim, J.; Watkins, A.; Aull, M.; Serur, D.; Hartono, C.; Kapur, S. Causes of Graft Loss After Kidney Transplantation Following Rabbit-Antithymocyte Gobulin Induction and Steroid-Sparing Maintenance. Abstract# 2922. Transplantation 2014, 98, 146. 4. Chan, S.; Pascoe, E.M.; Clayton, P.A.; McDonald, S.P.; Lim, W.H.; Sypek, M.P.; Palmer, S.C.; Isbel, N.M.; Francis, R.S.; Campbell, S.B.; et al. Infection-Related Mortality in Recipients of a Kidney Transplant in Australia and New Zealand. Clin. J. Am.
I like your analysis.
Do you think GeneXpert in comparison to IGRA has a better specificity and therefore higher LR ratio?
A 47-year-old CKD-5 patient receives a kidney transplant from his brother with a mismatch of 111 and no DSAs. Superior renal function. A year later, he arrived with a nighttime temperature of 39 degrees Celsius, a productive cough, and weight loss. Several shadows were detected in both lungs. This clinical situation and imaging findings are suggestive of active pulmonary tuberculosis, specifically miliary tuberculosis.
In the diagnosis of Tb, some factors make the diagnosis challenging, such as the IGRA and the tuberculin test, which are typically negative.
Although you have active TB, sputum smear results are typically negative.
Less than 5% of transplant recipients experience the typical cavitary changes seen in immunocompetent patients, whereas 40% of recipients experience focal infiltrates, 22% have miliary patterns, 15% have nodules, 13% have pleural effusions, and 5% have diffuse interstitial infiltrates.
Before treatment, baseline laboratory studies should be taken, including liver function tests, renal function tests, and cultures.
Therapy for drug-susceptible tuberculosis includes Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol, which is administered for 2 months followed by Isoniazid and Rifampin for 4 months in all cases aside from osteoarticular and nervous system diseases. Osteoarticular and nervous system diseases necessitate prolonged maintenance therapy that lasts at least nine months.
Treatment for milder diseases includes the same drug combination regimen, quadruple therapy.
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.
Full assessment, sepsis work up, Bilateral lung infiltration sparing lung periperhy, lung TB is Differntial diagnosis, other DD can include CMV, interstitial lung disease.
Sputum MC&S or BAL for AFB, Molecular tests like (Xpert® MTB/RIF
Treatment for localized non severe disease consider following the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) for a regimen without rifampicin. Two month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide
Screen his brother for latent TB infection if it has not been done prior to Tx.
I like your suggestion: Screen his brother for latent TB infection if it has not been done prior to Tx.
This is a presumptive case of pulmonary tuberculosis, likely miliary tuberculosis because of the widespread reticulonodular opacities of millet size.
Investigation
Serum electrolytes – serum sodium may correlate with disease severity and may suggest syndrome of inappropriate ADH secretion or Addison disease. Baseline kidney function is essential before starting treatment.
Liver Function Test – may be deranged in disseminated TB. Baseline is required before starting treatment.
Full blood count – his may show leukocytosis of leukemoid reaction.
ESR – This may be elevated in 50% of cases and tends to reduce as effective treatment commences.
Sputum GeneXpert – This is a fast method of diagnosis of tuberculosis for fast commencement of treatment. It can also detect resistance to rifampicin.
Cultures – Sputum, blood and urine. This is necessary to isolate the organism and test for drug sensitivity. Culture generally takes time as MTB is slow growing, however, treatment with first line anti-TB medications can be commenced without delay.
Treatment
Rifampicin, Isoniazid, Pyrazinamide and Ethambutol (RHZE) – this is given for 2months intensive therapy and RH for 4 months in all forms of drug susceptible tuberculosis other than osteoarticular and nervous system disease. Osteoarticular and nervous system disease will require extended period of maintenance therapy for 0 months.
Rifampicin is a cytochrome p450 enzyme inducer, hence the dose of tacrolimus and cyclosporin should be adjusted. Rifabutin has less effect on enzyme induction and can be used instead.
My management will not change if it was milder or affecting one lung. However, other differential diagnosis has to be considered.
I love that reply.
Mild or severe disease, medication remains same. The regimen would change if there is suspicion (or proven) of drug-resistance.
Ajay
Based on the epidemiological risk, personal history, symptoms, and imagistic lesions, TB diagnosis requires a high index of suspicion.
CBC, CRP, chest x-rays, CT chest.
tuberculin skin test (TST) and
interferon-gamma release assay (IGRA
invasive procedures
(bronchoscopy with bronchoalveolar lavage, derangement of fluid samples assessed thereafter by smear, mycobacterium culture, and histological examination
Treatment.
Plane 1 with rifampicin
After a 2-drug treatment of Rifampicin + INH for 2 months, a 4-drug regimen of Rifampicin + INH is administered.
Plan without rifampicin
Following a 2-drug regimen of INH + either ethambutol or pyrazinamide for 12 to 18 months, a 3-drug regimen of INH+ ethambutol+pyrazinamide or levofloxacin is utilized for 2 months.
Plan 2
For 12 months, 3 medications (INH+ ethambutol+ pyrazinamide or levofloxacin) are administered.
Plan3
Rifabutiun can be used instead of rifampicin since it has less of an impact on cytochrome p450, resulting in fewer medication interactions, but there isn’t much experience with it being used in transplantation, even though HIV/TB patients seem to benefit from it.
Chanlange in this case is ;
Adjustment of immunosupression and with anti-TB drugs and keeping eye to their torget and dosage fopr the preventation of graft
Thankyou ,if you are dealing with this case as active TB with 4 drug start, then what is your plan for a milder case :
which drugs to use
for how long.
In mild cases two drug combiniton INH with ethambutol or pyrazinamide for 6 to 9 months
In the current scenario, after 1 year of transplantation patient is presented with night fever, weight loss and chest lesions , this raise the possibility of active tuberculosis
Other infections can cause the same picture including aspergillosis although it occur early in transplantation
Malignancy should be ruled out (PTLD)
Active TB after solid organ transplantation
The prevalence of active TB is significantly higher than general population, it differ according to geographic area, it ranges from 1.2-2.6% in developed countries and in 10-15% in endemic regions (1,2)
Mode of transmission (3,4)
Timing after transplantation
Clinical presentation
Diagnosis
The diagnosis is challenging due to the following
So …
Treatment
The treatment of TB in SOT is challenging due to the following
Protocols used in treatment of TB
I- Rifampicin containing regimen
Regimen A– 4-drug regimen of Rifampicin+ INH+ ethambutol + pyrazinamide for 2 months, followed by a 2-drug regimen of Rifampicin + INH for 4 months
It is recommended to increase the duration of treatment to at least 9 months if one of the following is present
II- Rifampicin free regimen
Regimen A – 3-drug regimen of INH+ ethambutol + pyrazinamide or levofloxacin are used for 2 months, followed by a 2-drug regimen of INH + either ethambutol or pyrazinamide for 12 to 18 months
Regimen B – 3 drugs (INH+ ethambutol + pyrazinamide or levofloxacin are used for 12 months
Regimen C – Rifabutiun can be used instead of rifampicin due to its lesser effect on cytochrome p450, so minimal drug-drug interactions but experience is little when using this drug in transplantation, although it seems effective in HIV TB patients.(9)
How do you manage this case?
Would your management differ if the disease was mild and affected one lung?
References
1. Lopez de Castilla D, Schluger NW. Tuberculosis following solid organ transplantation. Transpl Infect Dis 2010; 12:106.
2. Abad CLR, Razonable RR. Mycobacterium tuberculosis after solid organ transplantation: A review of more than 2000 cases. Clin Transplant 2018; 32:e13259.
3. Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clin Infect Dis 1998; 27:1266.
4. Muñoz P, Rodríguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clin Infect Dis 2005; 40:581.
5. Torre-Cisneros J, Doblas A, Aguado JM, et al. Tuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort. Clin Infect Dis 2009; 48:1657.
6. Fiske CT, Griffin MR, Erin H, et al. Black race, sex, and extrapulmonary tuberculosis risk: an observational study. BMC Infect Dis 2010; 10:16.
7. 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; 33:e13513.
8. Aguado JM, Herrero JA, Gavaldá J, et al. Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Spanish Transplantation Infection Study Group, GESITRA. Transplantation 1997; 63:1278.
9. Aguado JM, Torre-Cisneros J, Fortún J, et al. Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clin Infect Dis 2009; 48:1276.
10. Sun HY, Munoz P, Torre-Cisneros J, et al. Mycobacterium tuberculosis-associated immune reconstitution syndrome in solid-organ transplant recipients. Transplantation 2013; 95:1173.
Thankyou Sherif for your well organaised review and good choice decision.
It will be complete if you included information of LATENT cases ,diagnosis and prophylactic treatment in SOT as they constitute the major cause of activation post TX.
Well done.
Diagnosis of latent TB
Which test to use?
Interpretation of the result
Indications of treatment of latent TB in transplant recipient and donor
Protocol for treatment of latent TB
Ideally, regimen should be started before transplantation, but if it started after transplantation, Rifampicin containing regimen should be avoided
Patient should be monitored for liver enzymes and bilirubin at baseline, every 2 weeks for 6 weeks then monthly, if there is 3 fold rise of liver enzymes with symptoms or 5 fold rise without symptoms , INH should be stopped
Case of cough, weight loss and fever in immunosuppressed patient with changes on chest xray and CT scan of bilateral reticulonodular changes and cavitatory lesions. These finding are high suggestive of pulmonary TB.
Other possible causes:
Bacterial Pneumonia
Viral pneumonia like CMV
Fungal pneumonia like PCP
Firstly, we need to confirm the diagnosis by careful, history and investigations.
After initial routine basic investigation, CBC, Chemistry, CRP, ESR.
Specific confirmatory tests include sputum for AFB, Sputum culture, TB PCR from sputum, TB culture, and if needed BAL.
If confirmed to be pulmonary TB, then we need to start treatment and manage the immunosuppressive medications and monitor for side effects and drug interaction.
Regarding treatment regimen, American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) guidelines recommends that in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months.
2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin. Rifamycin is recommended for its sterilization capacity and efficiency but also to reduce the risk of resistance. Monitoring for side effects and CNI level is essential, especially liver function tests and graft function. CNI dose needs to be increased 3-5folds when using this regimen.
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) suggests a standard regimen used for a period longer than 6 months, and, in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present. If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide. Additionally, if second-line drugs are used, a longer period of treatment is recommended.
References.
1-Sorohan, B.M.; Ismail, G.; Tacu, D.; Obris, c ˘a, B.; Ciolan, G.; Gîngu, C.; Sinescu, I.; Baston, C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens 2022, 11, 1041. https://doi.org/10.3390/ pathogens11091041
You prefer 18 months of therapy, while other colleagues, prefer 6 or 9 months of ATT, after 4 drugs for 2 months.
What is your reasoning?
Thanks prof Ajay..
the longer period is preferred for localized disease when less medications are used, ie without rifamycin and when second-line medications are used. I’ve quoted the American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) sentence. But for others, I’ve mentioned in the answer to the 1st question the duration 6 months.
History
====================================================================
Differential Diagnosis
Bacterial pneumonia
Bronchogenic carcinoma
Brucellosis
Hodgkin lymphoma
Mycoplasmal pneumonia
Miliary TB
====================================================================
How do you manage this case?
History :-
Plan manegement
====================================================================
Would your management differ if the disease was mild and affected one lung
====================================================================
Reference
How much dose reduction in MMF and for how long?
Typing whole sentence in bold or typing in capitals amounts to shouting.
Many thanks Prof.Sharma
How much dose reduction in MMF and for how long?
=========================================================
Reference
One year after living donor kidney transplant, night high grade fever , weight loss, and productive cough
Chest X ray= diffuse bilateral nodular pattern with hilar lymphadenopathy.
Chest CT = diffuse nodular pattern with peri-hilar lymphadenopathy.
Differential diagnosis:
Military TB.
Lymphangitic spread of lung cancers.
Bronchiolitis
Sarcoidosis
Atypical bacterial/fungal/viral infections
How do you manage this case?
The patient history and symptoms with radiological findings put high on the list of differential diagnosis Tuberculosis.
From the history – vaccination history, history of contact with TB patient, is he in and endemic area are important.
Review of his previous chest X ray.
Laboratory tests:
CBC, BUN , creatinine , Na,K , Calcium, total serum protein and albumin, liver function test (ALT,AST, Alkaline phosphatase, bilirubin, PT, PTT,INR), early morning sputum for AFB, gram stain, an culture.
Blood culture, urinalysis and culture.
Broncho-alveolar lavage, for analysis, culture, and PCR testing for CMV, PCP, TB…. etc
Multidisciplinary team approach= Radiologist, Pulmonologist, Infectious disease and transplant physician.
Thorough clinical examination is a must including signs of meningism, if present consider lumbar puncture, hepatosplenomegaly.
Admission to medical ward IV antibiotics with broad spectrum coverage.
Would your management differ if the disease was mild and affected one lung?
Yes, start him on antibiotics checking the BAL, and lung biopsy while keeping him on IV broad spectrum antibiotics
References:
(1) Wang W, Wang AS, Wang ZY, Wang JH, Lin MG, Zhang T, Li J, An HR, Li YF. [Tuberculosis after organ transplantation: clinical analysis and literature review]. Zhonghua Jie He He Hu Xi Za Zhi. 2007 Feb;30(2):124-6. Chinese. PMID: 17445475.
(2) Rattazzi LC, Simmons RL, Spanos PK, Bradford DS, Najarian JS. Successful management of miliary tuberculosis after renal transplantation. Am J Surg. 1975 Sep;130(3):359-61. doi: 10.1016/0002-9610(75)90402-x. PMID: 1101720.
(3) UpToDate-tuberculosis in solid organ transplantation candidate and recipient.
Lung biopsy?
How much dose reduction in MMF and for how long?
Thank you Prof. caseating granuloma, suggestive of TB in lung biopsy.
the reduction is by 25-50% with continuous blood testing for drug toxicity and levels
MMF and other immunosuppression reduced and even stopped in life threateining infection until the control of disease symptomatic or negative smear
This patient is a post kidney transplant patient from his brother 111 mismatch present one year after transplantation with fever ,night sweat,productive cough and weight loss which is highly suggestive of pulmonary TB Imaging showed bilateral diffuse lung infiltrates .
Management :
-MDT includes (pulmonologist ,ID ,clinical pharmacist and nephrologist) first assessment regarding respiratory and hemodynamic support then proper full detailed history and examination .
-Full blood count ,baseline graft function and liver function test .
.
According to AST-IDCOP, recommendation the treatments is :
2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin .
– If cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months.
Drug interaction :
-Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein, it decrease the levels of CNI (cyclosporine, tacrolimus), and the (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection .
– Calcineurin and mTOR inhibitors levels should be closely monitored if rifampicin-based regimen is used, the dose of calcineurin and mTOR inhibitor should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
– After the rifampicin is stopped, the immunosuppressive doses should be reduced to the value before the start of rifampicin and then adjusted to obtain the therapeutic target .
Isolation :
Patients should be isolated until it has been shown that the patient does not have TB ; if the patient is improving clinically after clinically , and has 3 consecutive negative sputum smear results. .
-Since it is proven to be active TB but localized and mild I will provide rifampicin free regimen using fluoroquinolone or rifabutin instead to minimize the risk of rejection .
REFERRENCE :
I like your pragmatic and scientific clinical approach well supported by relevant references.
Half-hearted treatment without rifabutin in transplant patients (or without rifampicin in non-transplant patients) may be responsible for drug resistance.
What is your basis for this recommendation?
Thank you prof Ajay.
👉 The current case presented with night fever, weight loss and bilateral diffuse infiltration in CT chest is highly suggestive of miliary pulmonary TB. Onset after 1 year suggests that it is mostly activation of latent TB in the recipient or may be exposure to open TB case after transplantation.
👉 Management is to confirm diagnosis of TB by:
_Sputum analysis and smear staining with ZN stain for acid fast bacilli and culture on BACTEC system.
_Culture is more sensitive but takes 4-6 weeks to give results which is too long and the patient will deteriorate through this long waiting time.
_Molecualr analysis (Gene Xpert from the blood, sputum or urine).and DNA amplification will be reasonable and fast diagnosis.
_No role of tuberculin skin test (TST) or IGRA (Interferon gama release assay) on diagnosis of active TB as they represent immunological reaction to TB antigen which is already impaired in such immunocompromised individual under the effect of IS medications.
👉 Treatment of active TB in KT is the same or derived from treatment in immunocompetent hosts as 2 months initial therapy of 4 anti tuberculous therapy (INH, rifampin , ethambutol and pyrazinamide ) followed by 10 months of dual therapy (INH and rifampin).
⭐ Rifampin is mandatory here in such severe case with multi-lobar affection.
⭐ Rifampin is cyt 3A4 inducer, so it will reduce the plasma concentration of CNI , sirolimus and even steroids , so close monitoring of trough level and increase dose of CNI 3-5 times guided by trough level is warranted also increasing dose of steroids to avoid allograft rejection and loss.
⭐ Rifabutin is an alternative with less drug drug interaction but not well studied as effective alternative to rifampin.
⭐ Follow up of liver enzymes to avoid hepatotoxicity of INH and graft function as rifampin is nephrotoxic.
⭐ IRIS (immune reconstitution inflammatory syndrome) is well described complication of rifampin use in treatment of active TB (due to relief of immunosupression state by anti tuberculous therapy leading to worsening of pulmonary symptoms, intense fever and pleurisy together with possible graft dysfunction.
👉 Treatment in case of unilateral affection:.
_Avoiding rifampin and saving it to severe cases.
_use of INH ,ethambutol and pyrazinamide (tripple therapy) for 12 months or use initial (INH, pyrazinamide plus ethambutol or levofloxacin for 2 months ) followed by dual therapy (INH plus either pyrazinamide or ethambutol for 12-18 months).
I want to ask about the role of reduction of dose of anti proliferative or stopping it in case of severe case of active TB
What is your practice in this regard Dr Mai?
What is the right approach?
Thanks dear professor
Unfortunately, I don’t have experience in TB in transplantation.
I am pediatric nephrologist.
Findings on chest xray and CT scan:
Bilateral pulmonary reticulo-nodular shadow diffuse and involving both lungs with no pleural effusion, on a background of a febrile illness associated with productive cough night sweating and weight loss in a middle-aged kidney transplant recipient.
primary impression, Differential diagnosis:
Bronchopneumonia.
Miliary tuberculosis.
pulmonary fungal infection, Histoplasmosis
malignant infiltration. either secondary, commonly from thyroid , breast, colonic , and renal cell carcinoma
Hemosiderosis
viral pneumonia , Varicella pneumonia.
Work up :
Blood tests: CBC, CRP, blood culture.Results of blood tests are nonspecific and varies from leukopenia, to leukocytosis and lymphocytosis. Leukemoid reaction might be prominent as well. Fundal examination revealing choroid tubercles is diagnostic of milliary TB
sputum for AFB and fungi, with ZN stain, or using auramine-rhodamine dye. Culture in the solid LJ media or the liquid Bactec media which is usually yielding the result within 1-2 weeks.
PCR can be utilized for diagnosing TB.
CT scan and PET scan are advised to screen for involvement of other organs .
Bronchoscpy and lung biopsy might be indicated to prove the diagnosis.
Tuberculine skin test is usually negative. Bone marrow biopsy, echocardiography
Treatment:
6 months of induction with Rifampicin, INH, Pyerazinamide and Ethambutol and maintenance INH and Rifamipicin for 4 months.
Unilateral involvement denotes pulomonary TB. management would be varied from Miliary TB management in the term of duration of therapy and co-therapy with Corticosteroid.
References:
1]Kamila Bednarova et al. Tuberculosis dissemination in kidney transplant recipient treated with anti-CD40 monoclonal antibody: a case report.BMC Nephrology volume
23, Article number: 290 (2022)
How useful would it be, in the absence of symptoms involving organs other than lungs, to do CT scan and PET?
it’s useful to determine which organ or site to biopsy in order to early diagnose TB
Why do you suspect leukemoid reaction as a prominent feature (as you state) in TB?
Its a sign of severe infection reported in the context of miliary TB.
Given the clinical presentation of this patient, the presence of bilateral diffuse nodular infiltrates strongly suggests the presence of tuberculosis.
DD: fungal infection
pulmonary metastases.
inflammatory processes (e.g., granulomatosis with polyangiitis),
Lymphoma
Patients with relevant clinical signs (cough, lymphadenopathy, fevers, night sweats, weight loss) and epidemiologic variables (such as a history of past TB infection or illness, known or probable TB exposure) should be suspected of pulmonary TB.
investigations:
Treatment:
Rifampicin is commonly given to SOT patients, particularly kidney recipients, although its use is contentious.
European kidney transplantation guidelines propose 2 months of isoniazid, rifampicin, and pyrazinamide (with ethambutol for 14% isoniazid resistance), followed by 4 months of isoniazid and rifampicin.
Rifampicin lowers tacrolimus, cyclosporine, rapamycin, everolimus, and corticosteroids (although there is less information about corticosteroids). Binding rifampicin and CNI increases the likelihood of graft rejection, graft loss, and overall TB-related mortality. Hence, the dosage of calcineurin inhibitors should be raised 3–5-fold, and levels should be monitored
Rifabutin induces cytochrome P450 less than rifampicin. Despite proper supervision.
supplementing pyridoxine.
The radiological presentation does not affect the treatment. Our patient is immunocompromised. even with a mild form of TB. As long as the culture is positive, he will start treatment on 4 drugs for 2 months and maintain it for a total of 6–9 months. depend on the culture and radiological response.
References:
Aguado, José María, et al. “Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology.” Clinical infectious diseases 48.9 (2009): 1276-1284.
TBNET and ESCMID recommend a non-rifamycin regimen for localized ( pulmonary) nonsevere TB in the absence of isoniazid (INH) resistance.
In patients without rifamycin, a three-drug combination of INH, ethambutol, and either pyrazinamide or levofloxacin for two months is followed by a two-drug regimen for 12 to 18 months. A three-drug regimen may be completed in 12 months.
Half-hearted treatment without rifabutin in transplant patients (or without rifampicin in non-transplant patients) may be responsible for drug resistance.
What is your basis for this recommendation?
This recommendation is from the European Society on Clinical Microbiology and Infectious Diseases.
For our center: we are giving INH and rifampin.
A 47-year-old CKD 5 has kidney transplantation from his brother, 111 mismatch, and no DSAs. Excellent kidney function. One year later, he presented with a night fever of 39 C, productive cough, and weight loss. Imaging showed multiple shadows in both longs.
How do you manage this case?
TB should be considered in all transplant recipients with unexplained fevers, night sweats, and weight loss .
History:-
Contact with patient with active pulmonary TB.
Past history of TB.
Full clinical examination .
Investigations:
(CBC, RFT, LFT, CRP, and Staining and culture for acid-fast bacilli should be performed on all induced sputum and bronchoscopy specimens in such patients.
Nucleic acid amplification methods can increase the rapidity of diagnosis).
Radiological:
CXRY showing military pattern of TB.
Renal USG and may or may not PET scan to exclude and collection of TB abscess in other systems or lymph nodes.
Treatments:
Treatment of active drug susceptible TB usually involves two months of INH, rifampin/rifabutin, pyrazinamide, +/- ethambutol, followed by a continuation phase therapy of four months of INH and rifampin, with a total duration for six months.
We should bear in mind the drug-drug interaction as Rifampin is a strong inducer of CYTP3A4 leading to increased metabolism of calcineurin inhibitors, mammalian target of rapamycin (mTOR) inhibitors, Mycophenolate mofetil and corticosteroids, so we should closely monitoring the drug level.
Will follow up ATT side effects .
Would your management differ if the disease was mild and affected one lung?
Once, our patient diagnosed as active TB case should be treated as mentioned above also if any recipient diagnosed as Latent TB case should be treated with isoniazid (300 mg/day), supplemented with vitamin B6 for 9 months.
References:
1-Anand M, Nayyar E, Concepcion B, Salani M, Schaefer H. Tuberculosis in kidney transplant recipients: A case series. World J Transplant. 2017;7(3):213-221. doi:10.5500/wjt.v7.i3.213.
2- José María Aguado, Julián Torre-Cisneros, Jesús Fortún, Natividad Benito, Yolanda Meije, Antonio Doblas, Patricia Muñoz, David R. Snydman, Tuberculosis in Solid-Organ Transplant Recipients: Consensus Statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology, Clinical Infectious Diseases, Volume 48, Issue 9, 1 May 2009, Pages 1276–1284, https://doi.org/10.1086/597590.
You prefer 6 months of therapy (including 4 drugs for 2 months) for those without INH resistance, while other colleague such as Dr Abiola, as below, prefers 9 months of ATT.
Half-hearted treatment without rifabutin in transplant patients (or without rifampicin in non-transplant patients) may be responsible for drug resistance.
What is your basis for this recommendation?
How do you manage this case?
The above radiological images show fine granular diffuse military infiltrates that are widely scattered throughout both lung fields.
Also with clinical symptoms of fever, productive cough, and weight loss post-KTP
The most likely diagnosis is military pulmonary Tuberculosis
Differential Diagnosis
Investigations
Treatment
How will you manage if is mild and affects one lung?
This may be a primary pulmonary Tuberculosis with the presence of likely Ghon focus in the lung
I will still manage as above with the exception of the duration of treatment for six months
References
Correction on the second question
According to TBNET and ESCMID, a non-rifamycin regimen is preferred if:
Regimen
Reference
Half-hearted treatment without rifabutin in transplant patients (or without rifampicin in non-transplant patients) may be responsible for drug resistance.
What is your comment on this statement of mine. You may or may not agree with me.
Thank you Prof Ajay for your response.
The American Society of Transplantation recommends that rifamycin containing regimen is strongly preferred for both severe and localized nonsevere TB due to its potent sterilizing activity and more importantly it prevents the emergence of drug resistance.
I completely agree with you prof.
I like your pragmatic and scientific clinical approach well supported by relevant references.
Q1.
Suspicion of TB
Other differential diagnosis of respiratory infections after 6 months posttransplantation
As soon as TB is confirmed
Sometimes there is an option of therapeutic trial in difficults cases in endemic areas i.e., diagnosis after treatment.
Q2.
Source, Nephrology secret fourth edition, TB infection after kidney transplantation (Bogdan Marian Sorohan et al.)
Thanks, Ben
Let us wait and see the other colleagues.
Wlcm, prof
This chest X ray shows diffuse bilateral reticulonodular infiltration consisting of miliary TB
Laboratory studies for CBC, ESR, CRP, Drug level and DSA level
RFT and serum sodium level and serum calcium level.
Smear and culture examination of spontaneously expectorated or induced sputum.
Tuberculin test
Interferon-gamma release assays
CT chest
Ultrasound to role out disseminated of disease to internal organ like liver and spleen.
Trans bronchial lung biopsy to confirm miliary TB.
Treatment reduce immunosuppressive therapy to half and keep steroid dose
Anti tuberculosis regime for 6 to 9 months depend on recommended protocols.
TB guidelines suggest 6 months of treatment (2-month intensive phase with isoniazid, rifampicin, pyrazinamide, and ethambutol or streptomycin, followed by a 4-month maintenance phase with isoniazid and rifampicin).
No need to reduce immunosuppressive dose in mild form.
How do you manage this case?
It is a patient with a disseminated nodular pulmonary condition, very suggestive of pulmonary tuberculosis. Histoplasmosis can present a similar picture, even if immunosuppression is more pronounced and if there is an epidemiological context (caves, chicken coops, rural areas with old houses).
The positivity of blood tests is low in this context. The ideal would be a bronchoalveolar lavage with a collection of genetic material for Tuberculosis (Gene Xpert), bacilloscopy, and transbronchial biopsy). Histoplasmosis in an immunosuppressed patient has been diagnosed with urinary or serum antigen with more than 90% sensitivity.
1. Measure serum levels of CNI and other immunosuppressants. As it appears in more immunosuppressed patients, we should reduce the dose of these drugs.
2. Avoid rifampicin in the scheme or adequately monitor serum levels of immunosuppressants if it is part of the scheme
3. Start the classic scheme. In Brazil, we use four drugs in combination. Rifampicin+Isoniazid+Pirazimanid+Ethambutol depending on weight for two months and four more months of Rifampicin+Isoniazid.
Would your management differ if the disease was mild and affected one lung?
If the disease was localized, it is suggestive of recent exposure and the people closest to you should be investigated. There would be no need to decrease immunosuppression unless there were serum levels to suggest it.
As the treatment has a high drug interaction, after starting the antituberculostatic regimen there is a need for serum monitoring, mainly CNI and mTor.
Thanks, Filipe
It is not clear to me how would you treat it if it is affecting a single lung.
Two-month RHZE
Four-month RH
I would change Rifampicine for Rifabutin to decrease drug interactions
Thanks, Filipe
Would you explain to us the fundamental difference between Rifampicine and Rifabutin in relation to the index case?
Rifampicin is the best drug for treating tuberculosis. In cases of disseminated disease, it should be the priority in the scheme. In localized diseases, we can switch more safely to Rifapentine, which is less toxic, fewer drug interactions with immunosuppressants and other drugs.
For disseminated disease I would prioritize Rifampicin
There are bilateral diffuse nodular infiltrates, highly suggestive of miliary TB, given the clinical scenario in this case.
A miliary pattern on chest imaging may be due to many conditions, including Histoplasmosis and Sarcoidosis.
Diagnosis: respiratory culture for Acid-fast smear and culture, lymph node biopsy if possible and molecular tests in regions where available. Molecular tests can be useful rapid diagnostic tools.
TREATMENT In general, the approach to antimicrobial therapy for the treatment of miliary TB consists of the traditional regimen (≥6 months) for the treatment of pulmonary TB.
Modifications to the standard drug regimen may be justified in the setting of drug-resistant TB.
Ref: Clinical manifestations, diagnosis, and treatment of miliary tuberculosis – UpToDate
Thanks, Fakhriya
You missed many points, looks like you are in a hurry. Your patient will become sensitised and lose the graft because of AMR. You treated TB, but you patient landed successfully on dialysis.
·How do you manage this case?
Treatment
Drug interactions
==========================
·Would your management differ if the disease was mild and affected one lung?
References
Thanks, Mohamed
It is not clear to me how would you treat it if it is affecting a single lung.
Thank you, dear Prof. Ahmed
Honestly, I am not sure of any differences in medical treatment of TB depending on whether one or both lungs are involved.
It may be relevant if surgical treatment is considered.
Lung transplantation may be indicated if a destructive disease affected both lungs.
night fever 39 C, productive cough, and weight loss in immunocompromised patient together with bilateral pulmonary infiltration can raise suspicion of pulmonary TB.
management:
1- sputum sample for AFB smear
2-PCR for TB
3-start antiTB medications four-drug regimen: pyrazinamide (three months); ofloxacin (nine months); INH and ethambutol (18 months). The dose of INH and ethambutol has to be adjusted for the degree of renal function. If rifampicin has to be used for those who are not on cyclosporine, prednisolone dose has to be doubled.
secondary prophylaxis should be considered after successful treatment.
non responding means atypical infection or multi drug resistance
no, the management will not differ if diagnosis of TB confirmed
Madhivanan Sundaram, Samiran Das Adhikary, George T. John, Nitin S. Kekre. Tuberculosis in renal transplant recipients. Indian J Urol. 2008 Jul-Sep; 24(3): 396–400.
Thanks, Riham
You missed many points, looks like you are in a hurry.
For example, how would you manage immunosuppression?
of course the tacrolimus is the cornerstone immunosuppressive medications in the renal transplant recipient and rifampicin is the cornerstone of anti TB medications , both interact with each others ; rifampicin decreases the trough level of tacrolimus expose the patient to risk of allograft rejection, so the dose of tacrolimus should be increased to adjust the trough level which should be monitored closely.
Rifampicin is a strong inducer of CYP3A4 and can lead to increase or enhance metabolism of CNI, mTOR, MMF and steroid
maximize the dose of CNI will be associated with more adverse effects and more cost
some add ketoconazole to decrease the dose of tacrolimus hence adjust trough level and decrease adverse effect and cost but this may decrease efficacy of antiTB medication
rifabutin is alternative drug to rifampicin but less interaction with CNI but mostly it is unavailable
close and frequent monitoring of trough level of CNI is very important to decrease the risk of graft rejection
Phyo Wai Lwin,Yi Yi Htun,2 Aung Kyaw Myint,Htar Kyi Swe. Posttransplantation tuberculosis management in terms of immunosuppressant cost: a case report in Myanmar. Korean J Transplant. 2021 Mar 31; 35(1): 48–52.
The presented radiological images show bilateral diffuse pulmonary infiltrates with perihilar basifications (mostly representing enlarged perihilar lymph nodes).
These findings, with the history of night fever, productive cough and loss of weight in an immunocompromised patient as in the presented case scenario, should raise the suspicion of pulmonary TB (miliary TB) (1).
– The first step will be to confirm the diagnosis:
The diagnosis of pulmonary TB is definitively established by isolation of Mycobacterium tuberculosis from a bodily secretion (eg, a culture of sputum, bronchoalveolar lavage, or pleural fluid) or tissue (pleural biopsy or lung biopsy) (2).
Sputum acid-fast bacilli (AFB) smear and nucleic acid amplification (NAA) testing are considered additional diagnostic tools for active TB infection. positive NAA test (with or without AFB smear positivity) is considered sufficient for the diagnosis of TB (2). An approach for the interpretation of the NAA test in suspicious case scenarios is illustrated in the attached algorithm (2).
Additionally, a tuberculin skin test (TST) or interferon-gamma release assay (IGRA) can be performed. A positive result supports (but cannot be used to establish) a diagnosis of active TB disease, and a negative result does not rule out active TB disease (2).
– The second step in management will be the initiation of the appropriate therapy:
1) Reduction of immune suppression will be a logical approach in the face of severe and potentially fatal infection. We will start by reduction of antimetabolite by 50%, with possible total withdrawal if the infection becomes progressive and not responding to treatment (3).
2) Because of the increase in multidrug-resistant (MDR) strains, appropriate therapy should include four agents: isoniazid (INH), rifampin or rifabutin, pyrazinamide, and ethambutol for at least two months or until susceptibility test results are available followed by up to 10 months of INH and rifampin (3).
3) Rifampin (and rifabutin to a lesser extent) markedly reduces cyclosporine and tacrolimus levels, and it may be difficult to achieve therapeutic levels for patients taking rifampin, the use of which should be avoided if at all possible. Pyrazinamide and ethambutol may reduce drug levels, and their use requires monitoring (3).
The American Society of Transplantation (AST) states that a rifamycin-containing regimen is strongly preferred for both severe and localized non-severe TB due to the potent sterilizing activity of such regimens and the importance of preventing the emergence of resistance (4).
Experts agree that rifamycins are indicated in patients with severe (eg, cavitary or multilobar disease) or disseminated TB or when there is suspicion or documentation of INH resistance (4).
Therefore, if the disease is mild and resistant strains of TB are unlikely (based on the patient history and discussion with the local microbiologist), I will recommend Rifamycin-free anti-tuberculous protocols with close monitoring of the patient’s condition and allograft function.
In our local practice, 5 years ago, we faced a challenging case with an open pulmonary TB (resistance could not be excluded). He was admitted in the isolation room and received quadrable therapy formed of isoniazid (INH), rifampicin, pyrazinamide, and ethambutol for three months till he had 2 sequential negative sputum samples. The patient maintenance immune suppression before infection was everolimus, MMF and steroid 5 mg daily. During the course of treatment, the everolimus was persistently undetectable despite multiplying the dose four times. We reduced the MMF dose by 75%, and the dose of prednisolone was increased to 15 mg daily (as a part of the management of stress resulting from generalized sepsis after a discussion with our infection control team).
The patient had a stable allograft function throughout the whole treatment course (possibly secondary to immune paresis), and he was discharged home with normal allograft functions. The patient is still following up in our transplantation clinic with the latest serum Cr around 90 umol/L. TB reactivation never occurred, and the anti-TB drugs were stopped completely after 12 months from the initiation of treatment.
References:
1) Jay A Fishman. Approach to the immunocompromised patient with fever and pulmonary infiltrates. © 2023 UpToDate (accessed on 25 February 2023).
2) John Bernardo. Diagnosis of pulmonary tuberculosis in adults. © 2023 UpToDate (accessed on 25 February 2023).
3) Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
4) 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;33(9):e13513.
The medications used in the treatment of active TB are illustrated in the attached table (1).
References:
1) Subramanian AK, Morris MI, AST Infectious Diseases Community of Practice. Mycobacterium tuberculosis infections in solid organ transplantation. Am J Transplant. 2013;13 Suppl 4:68-76.
The medications used in the treatment of active TB are illustrated in the attached table (1).
(( I am sorry for the duplication, but the table failed to be attached to the previous contribution))
References:
1) Subramanian AK, Morris MI, AST Infectious Diseases Community of Practice. Mycobacterium tuberculosis infections in solid organ transplantation. Am J Transplant. 2013;13 Suppl 4:68-76.
Thanks, Ahmed for your reply
“A tuberculin skin test (TST) or interferon-gamma release assay (IGRA) can be performed. A positive result supports (but cannot be used to establish) a diagnosis of active TB disease, and a negative result does not rule out active TB disease”.
Tuberculin skin test and IGRA represent immunological reaction of the body immune system to TB, so they are mostly negative in case of active TB, as actually reactivation of latent TB to active disease occurs in immunosupression state like kidney transplant recipients.
Dear Dr Ahmed,
I agree with the contribution of Dr Mai Shawky Korkor as both tuberculin skin test (TST), and interferon-gamma release assay (IGRA) are immunological assays which depend on the immune response of the patient’s immune system. Therefore, their results should be interpreted with great caution in immune-compromised patients like HIV-infected persons and Solid organ transplant recipients.
Additionally, false positive results of TST can occur secondary to effective BCG vaccination.
The attached table illustrates a comparison between TST and IGRA. It also mentions special situations with false negative results (1). Therefore, we can not rely on these tests alone for diagnosis or exclusion of active TB disease.
Expert opinion suggests using rifabutin in place of rifampin due to the less potent enzyme inducer effect (2). Additionally, some studies showed non-inferior outcomes of a four-month rifapentine-moxifloxacin regimen in the management of drug-susceptible pulmonary tuberculosis (3).
The aim is to minimize the drug interaction of traditional rifampin whenever possible.
References:
1) Dick Menzies. Lab Interpretation: Positive or uninterpretable interferon-gamma release assay in adults. © 2023 UpToDate (accessed on 26 February 2023).
2) Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
3) Dorman SE, Nahid P, Kurbatova EV, et al. Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis. N Engl J Med. 2021;384(18):1705.
Thanks, Ahmed and Mai for the excellent answers
How do you manage this case?
D/D
Miliary TB
disseminated fungal infections like blastomycosis, cryptococcosis, histoplasmosis or coccidioidomycosis.
primary lung malignancy like adenocarcinoma can mimic mottling
metastasis from highly vascular tumour like renal cell carcinoma and melanoma or from breast, thyroid and prostate neoplasms.
Sarcoidosis
pneumoconiosis (silicosis)
hypersensivity pneumonitis
rarely pulmonary alveolar microlithiasis.
Investigations
Routine blood labs
Chest xray
CT scan chest
tuberculin skin test
sputum for gram and acid-fast stain.
Sputum culture for bacterial and fungal infections
erythrocytic sedimentation rate
PCR tests on sputum
if still diagnosis not certain then Bronchial wash and transbronchial biopsy
if needed Computed tomography-guided needle biopsy
treatment
for military TB
INH x 18 months
Ethambutol x 18 months
Pyrazinamide x 3 months
Ofloxacin 9 months
Tuberculosis in renal transplant recipients
Madhivanan Sundaram et al
Polka dot lung: classical miliary mottling in an adult
Satish Swain et al
Would your management differ if the disease was mild and affected one lung?
No ,treatment remains same in military TB.