Indian Journal of Transplantation

REVIEW ARTICLE
Year
: 2022  |  Volume : 16  |  Issue : 5  |  Page : 15--22

Evaluation and management of tuberculosis in solid organ transplant recipients: South Asian expert group opinion


Santosh Varughese1, Manisha Sahay2, Dibya Singh Shah3, Vasant Nagvekar4, Vivekanand Jha5,  
1 Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Nephrology, Osmania Medical College, Hyderabad, Telangana, India
3 Department of Nephrology, Grande International Hospital, Kathmandu, Nepal
4 Lilavati Hospital and Research Center, Mumbai, Maharashtra, India
5 Chair of Global Kidney Health, Faculty of Medicine, Imperial College, London; Conjoint Professor of Medicine, University of New South Wales, Sydney; Immediate Past President (2019-21), International Society of Nephrology

Correspondence Address:
Prof. Santosh Varughese
Department of Nephrology, Christian Medical College, Vellore - 632 004, Tamil Nadu
India

Abstract

Both tubercular and non-tubercular mycobacterial infections are common in South Asia. These are important pathogens in solid organ transplant recipients and hence prevention (when possible), prompt diagnosis, and early and optimum treatment is critical to reduce morbidity and prevent mortality. This article reviews available data to portray a possible approach to evaluation and management of mycobacterial infections in South Asian solid organ transplant recipients.



How to cite this article:
Varughese S, Sahay M, Shah DS, Nagvekar V, Jha V. Evaluation and management of tuberculosis in solid organ transplant recipients: South Asian expert group opinion.Indian J Transplant 2022;16:15-22


How to cite this URL:
Varughese S, Sahay M, Shah DS, Nagvekar V, Jha V. Evaluation and management of tuberculosis in solid organ transplant recipients: South Asian expert group opinion. Indian J Transplant [serial online] 2022 [cited 2022 Dec 8 ];16:15-22
Available from: https://www.ijtonline.in/text.asp?2022/16/5/15/358660


Full Text



 Introduction



Globally, a TB is the 13th leading cause of death and the second leading infectious killer after COVID-19 (above HIV/AIDS). In 2020, an estimated 10 million people fell ill with tuberculosis (TB) worldwide with 1.5 million deaths. 5.6 million men, 3.3 million women and 1.1 million children. TB is present in all countries and age groups. In 2020, the 30 high TB burden countries accounted for 86% of new TB cases. Eight countries account for two thirds of the total, with India leading the count, followed by China, Indonesia, the Philippines, Pakistan, Nigeria, Bangladesh and South Africa. South Asia, home to 25% of the total world population, has 40% of the global tuberculosis population. Hence, control of tuberculosis in this region is of global relevance.[1]

The disproportionately increased propensity of solid organ transplant recipients to tuberculosis is well documented. In addition to endemicity, this propensity is also increased by the simultaneous presence of other infections such as cytomegalovirus, Pneumocystis jirovecii, nocardia, and fungi.

Mycobacterium tuberculosis (MTb)[1] spreads by airborne route. Once inhaled by the human host, the bacillus may cause a primary disease, be cleared completely, or remain latent for years with a potential for reactivation. In the general population, TB reactivation occurs in 5-10% and this increases several-fold in immunosuppressed patients.[1],[2],[3],[4],[5],[6]

 Epidemiology



The risk of tuberculosis is linked to endemicity of M. tuberculosis infection and increased by 50-100 times in solid organ transplant (SOT) recipients.[7],[8],[9] Between 5.7-12.3% SOT recipients in South Asia develop TB.[4],[5],[6] Long transplant recipients are particularly vulnerable[10] The bulk of clinical disease is seen following reactivation of latent infection, with donor derived or de-novo post-transplant infections making up the rest.[11]

Presence of malnutrition, diabetes mellitus, allograft dysfunction, smoking,[10],[11],[12],[13] past untreated TB, long duration of pre-transplant dialysis, coexisting hepatitis C virus infection,[14] and chronic liver disease,[4] increase the risk of post transplant tuberculosis. Reactivation may occur, however, in the absence of any risk factor.

As with other infections, the intensity of immunosuppression is linked with disease risk. Latent infection is not a stationary phase, but rather a cyclic change between replication and immune containment. Use of depleting induction or anti-rejection therapy increases the risk.[10],[13] Differential risk has also been documented with different immunosuppressive agents, with tacrolimus carrying a lower risk compared to cyclosporine[15] and use of mycophenolate showing a stronger association compared to azathioprine.[16] One study showed greater risk of TB in South Asians carrying HLA A68 (28)/A69 (28) allele.[17]

In kidney transplant recipients, allograft dysfunction (serum creatinine >2 mg/dl) and a high daily dose of corticosteroids (prednisolone >20 mg) increased the likelihood of tuberculosis. Those on calcineurin inhibitors have a 2.5 increased risk compared to the earlier prednisolone and azathioprine based immunosuppression. Moreover, TB develops earlier and is more likely to be disseminated.[4]

 Clinical Features



Between half to two-third of cases occurs in the first post-transplant year, the median time of presentation being in the latter half of the first year after transplantation.

Atypical and insidious presentations are more frequent in SOT recipients. The classic triad symptoms of fever, loss of weight and night sweats is rare. Just about two-third of patients present with illness localisable to an organ. Pleuropulomary involvement is encountered in less than 40% patients, 20% show disseminated disease and isolated lymph node involvement is seen in about 5%. A range of X-ray manifestations can be seen, including atypical non-apical and diffuse interstitial infiltrate, miliary pattern, nodules, and pleural effusions. About one-fifth present with fever of unknown origin.

[Table 1] shows the pattern of TB in a South Asian cohort over a 13 year-period.[4] Unusual presentations include pyomyositis, tenosynovitis and skin ulcers. Gut involvement should be suspected in those with lower gastrointestinal bleeding, fever and abdominal pain being. Other presentations include abdominal mass, ulcerative mucosal lesions, or intussusception.[18] Peritonitis and granulomatous interstitial nephritis have also been reported.{Table 1}

Older studies showed a mortality rate of 20-30% amongst allograft recipients infected with tuberculosis.[19],[20] The risk of death appears to be higher in allograft recipients who have received T-cell depletion antibodies, had previous allograft rejection and those who have disseminated tuberculosis.[19],[21] Although apparently counter-intuitive, one paper suggests that patients receiving lytic induction with rabbit anti-thymocyte globulin have decreased risk compared to those who receive induction with basiliximab.[22] The mortality risk have come down substantially as advanced imaging techniques and invasive diagnostic tools allow early identification of the cause and timely institution of treatment.[23] A high index of suspicion in endemic regions allows institution of empirical anti-tubercular treatment. In such cases, the diagnosis is made retrospectively after observing response to treatment.

 Diagnosis of Active TB Infection



All prospective transplant recipients should be screened for active tuberculosis. The diagnostic approach starts with a careful history – any past treated, untreated or partially treated tuberculosis must be carefully documented. History of travel or past infection in a family member may not be as important in South Asian countries as it is in the developed world, given the endemic nature of the infection in this region. However, history of recent exposure to any patient with active tuberculosis, either in family or at work must be specifically asked for.

Apart from fever and weight loss, the symptoms depend on the nature of organ involvement. Chest X-ray and abdominal ultrasound as a part of routine workup can reveal active disease.

The diagnosis relies on the detection of M. tuberculosis bacilli by direct observation under microscope (Ziehl Neelsen staining), culture, or nucleic acid testing in fluids (e.g. cerebrospinal fluid, abscess fluid, ascitic fluid, bronchoalveolar lavage fluid) or tissue (e.g. bone marrow trephine biopsy specimen, transbronchial lung biopsy, pleural biopsy etc).[24],[25] Another option, especially useful in children, is testing early morning gastric aspirate.[26] Studies have reported higher sensitivity of gastric juice aspirate AFB smear.[27] Given that growth in culture takes six weeks or more, early use of invasive diagnostic procedures to obtain tissue and stain it for acid fast bacilli is critical. In many cases, the diagnosis is by made by demonstration of caseating granulomata, and AFB maybe absent. Given the endemicity of TB, this is sufficient to make a positive diagnosis in the region.

In many laboratories, ZN staining is being replaced the Auramine–Rhodamine technique. This technique requires fluorescence microscopy, enables rapid screening of the specimen slides and requires fewer mycobacteria per ml of sputum, making it a more sensitive test.

The automated molecular Gene Xpert MTB/RIF, a rapid nucleic acid and amplification technique, is another tool in the rapid diagnosis of tuberculosis.[24] This test is highly specific and has an estimated sensitivity in smear positive and smear negative respiratory samples of 98% and 67%, respectively.[28] A similar performance has been observed when testing non-respiratory samples, such as tissue biopsies and cerebrospinal fluid. This test has the added benefit for the detection of primary multi-drug resistant tuberculosis as the tests additionally detects resistance to commonly used anti-tubercular drug rifampicin. However, GeneXpert can stay positive for up to 4 years even after effective treatment, possibly due to the presence of residual mycobacterial DNA in the respiratory tract and the detection of non-viable organisms.

The increasing availability of the BACTEC MGIT 960 (Mycobacteria Growth Indicator Tube system 960) culture system has shortened the time taken for growth of mycobacteria in culture to about two weeks and has enabled early initiation of anti-tubercular therapy.

Tuberculin Skin Testing or Interferon Gamma Release Assays (IGRAs) are not recommended for diagnosing active infection. Their role in the diagnosis of latent TB is discussed below.

Probably the most challenging is the extraordinary reliance on clinical suspicion of active infection. TB infections in SOT recipients may present with unusual manifestations, with a greater proportion of extra-pulmonary organ involvement. TB should be considered in the differential diagnosis of every patient presenting with fever of unknown origin.

 Treatment of Tuberculosis



For successful treatment of TB, using a multidrug regimen for an appropriate duration is imperative. The list of drugs currently being used are listed in [Table 2].[29] The first-line treatment of tuberculosis in SOT recipients is similar to that in the general population, consisting of an intensive phase consisting of four-drug regimen followed by a continuation phase of two or three drugs. As mentioned above, in order to minimise risk of immediate post-transplant infection, wherever possible, tubercular infection must be identified and treated prior to transplantation.{Table 2}

The common anti-tubercular regimens use isoniazid, rifampicin, ethambutol and pyrazinamide. Two months of treatment with isoniazid, rifampicin, ethambutol and pyrazinamide followed by six months of treatment with isoniazid and rifampicin is the standard treatment.[24]

Wherever possible, TB should be fully treated in the pre-transplant period. In circumstances where early transplant is desired, it should be undertaken following completion of the intensive phase. Administration of rifampicin in the post-transplant period is challenging owing to it being a potent inducer of the P450 family of enzymes, which are responsible for the hepatic metabolism of CNIs and mTOR inhibitors. Consequently, the circulating levels of these drugs go down to half to one fifth.[23] Moreover, the reduction is unpredictable leading to the need of frequent therapeutic level monitoring. In combination, they raise treatment costs, making it unaffordable.[30] In these situations, rifampicin can be replaced by a fluoroquinolone like levofloxacin or ofloxacin. Maintenance therapy with isoniazid, a fluoroquinolone (with or without ethambutol) is continued for 9-12 months. Another option is to substitute rifampicin with rifabutin as the latter induces the P450 enzyme induction to a lesser dgree while possessing similar efficacy against Mycobacterium tuberculosis. The dosage of Rifabutin is similar to Rifampicin.[31] The need for more frequent therapeutic drug monitoring persists, however. Post-treatment isoniazid prophylaxis is not recommended. There has been an increase in drug resistance to anti-tubercular therapy including community acquired resistant tuberculosis-multi-drug resistant (MDR) tuberculosis (resistant to isoniazid and rifampicin) and eXtremely Drug Resistant (XDR) tuberculosis (resistant to isoniazid, rifampicin, and fluoroquinolone). The diagnosis of both MDR and XDR tuberculosis can be established only by culture and sensitivity. Infectious diseases specialists should be consulted. A single new drug should not be added to a failed anti-tubercular therapy regimen as it is likely to result in inadequate or under-dosing of therapy. The need for enforcing adherence to the complete duration of therapy cannot be overstated.

Patients on anti-tubercular therapy need to be closely monitored for development of drug toxicities. Hepatotoxicity may occur with isoniazid, rifampicin or pyrazinamide. If hepatotoxicity develops, all three drugs are stopped and non-hepatotoxic drugs are substituted. Reintroduction of these drugs is done one at a time and at smallest doses possible and with slow escalation beginning with Isoniazid. In one series, 41% of liver transplant patients reported isoniazid induced hepatotoxicity while it was 2.5%, and 4.5%, in kidney and heart and lung allograft recipients necessitating stoppage of the drug.[19] The other major toxicity of isoniazid is peripheral neuropathy, which can be prevented by routine co-administration of 10 mg pyridoxine every day. If symptoms of peripheral neuropathy appear despite prophylaxis, the dose of pyridoxine should be increased. Ethambutol dose needs to be adjusted with declining kidney function. Further, it may cause dose-dependent optic neuropathy and periodic retinal examination is advised. Pyrazinamide could decrease the exposure to cyclosporine, an effect that has not been reported with tacrolimus.

Summary recommendations:

First-line therapy for transplant candidates with active TB disease is the same as for immunocompetent subjects with TBTreatment duration for uncomplicated pulmonary TB in kidney transplant candidates or recipients is at least 9 monthsA longer period of treatment (upto 18 months) may be needed if the rifampicin is excluded from the regimenIn 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 rangeWhen 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.

 Latent TB



Definition

Latent TB is said to be present when a person has been infected with M. tuberculosis at some earlier time with viable organisms remaining in a dormant state somewhere in the host but with no clinical or radiological evidence of active TB. Evidence of prior TB infection is obtained by detecting evidence of persistent immune response to stimulation by Mycobacterium tuberculosis antigens.[32]

Transplant recipients

Indications for screening

South Asia is a high endemicity region for tuberculosis. About 40% of the Indian population is estimated to have latent TB infection (LTBI). While the Revised National TB Control Program (RNTCP) of India does not recommend universal screening for LTBI in general population, WHO recommends that patients on dialysis and those planned for organ transplantation be screened for TB[13],[32] as they are at a very high risk of progressing from latent infection to active disease, and this progression could be prevented by treating LTBI. However, this recommendation is not followed in practice.

Most of the current global clinical practice guidelines recommend[33] screening and treatment of LTBI in high risk individuals.[34] The definition of high-risk includes anyone living in high incidence regions (>100 per 100,000 population), or on the basis of individual risk assessment.

Such recommendations are based on the assumption that a. individuals with LTBI are at a high risk of progression to active tuberculosis following transplantation; b. a screening test would be reliably able to identify those with LTBI with a high degree of sensitivity and specificity; and c. safe and effective chemoprophylactic approaches are available.

Current evidence supporting these assumptions in transplant recipients in high endemic regions of South Asia is limited, and recommendations are largely expert opinions. Better clinical evidence needs to be generated to guide evidence-based clinical practice in this regard.

A relatively small proportion of patients are impacted by these guidelines in high income countries where the population of prevalence is tuberculosis is low, but the implications (financial, logistic, increased burden on health system) are significant for low resource countries of South Asia with high population prevalence. If the currently available recommendations were to be followed, all transplant recipients should either be given chemoprophylaxis or be screened for LTBI. Given the low predictive value of tuberculin skin test, interferon Gama release essays are the only possible approach (see below). As stated earlier, the predictive ability of this essay has not been tested in transplant population in this region. Further, these tests are expensive. Finally, widespread use of chemoprophylaxis has major implications for the development or worsening of drug resistance in a setting with already high baseline drug resistance. The First National Anti-Tuberculosis Drug Resistance survey in India showed that 23% of new cases had resistance to any drug, with isoniazid resistance in 11% and 25% in new and previously treated tuberculosis cases, respectively. Indeed, resistance to INH, the cornerstone of chemoprophylaxis, has been identified as the biggest challenge affecting TB control in India. Widespread use of INH alone is likely to further fuel resistance.

Research recommendation:

Predictive value of IGRA positivity before transplant for post-transplant TBRCT of treatment vs no treatment of LTBI IGRA positive transplant candidates.

 Screening Tests for Latent TB



Prospective transplant recipients

The identification of LTBI in high endemicity South Asia is different from that proposed in high income countries. For example, radiological abnormalities unlikely to be useful in identifying LTBI. As the bacterial burden is very low, acid-fast bacilli are rarely seen and tubercle bacilli are not found in cultures.

There are two choices for a screening test-TST (Tuberculin Skin Test) or IGRA assays. The former is limited by the high likelihood of cutaneous anergy making the test false negative even in those with latent infection. In a study of 108 patients of kidney failure in India, a high incidence of anergy was noted. There was a relationship between cutaneous anergy and the nutritional status of the study subjects. Furthermore, pre-transplant Mantoux positivity had low sensitivity and specificity for predicting post-transplant tuberculosis.[35]

IGRA depends on IFN-γ production following stimulation of effector T-cells by proteins unique to M. tuberculosis. IGRA results can be read in a few hours, and the test is not affected by the BCG vaccination. However, there are no studies on the use of IGRAs in patients with kidney failure and transplant recipients in South Asia and its predictive value for tuberculosis in kidney failure or transplant population. Even from other regions, these studies have been largely inconclusive.[36],[37],[38],[39]

There have been a couple of studies from South Korea (an intermediate endemicity country) which have shown conflicting results. Given the public health importance of this recommendation, appropriately designed studies are needed to ascertain the positive predictive values of IGRA in kidney failure populations in this region.

Should we treat LTBI?

Other (western) guidelines recommend treatment of LTBI as identified by a screening test (TST or IGRA) and in patients who have been in recent close contact even if the screening test is negative. INH monotherapy is given for 6 months or Rifampician and INH combination for 3 months are most commonly used in the Western world.

There are no data that show whether this approach is appropriate for the South Asia kidney failure population. A few studies from India/Pakistan show that although INH decreases risk of developing TB post-transplant there is no effect on all-cause mortality but there is however a substantial risk of hepatotoxicity. Of those who developed hepatotoxicity, 25% died of hepatic failure.[40] Moreover, the impact of a single drug on the risk of development of drug resistance is not known.

Hence, we do not recommend either screening for LTBI in kidney transplant candidates, or universal post-transplant chemoprophylaxis. There should be a high index of suspicion in patients with symptoms and all efforts should be done to diagnose and treat active TB.

TB in transplant donors

Diagnosis and management of TB in living solid organ transplant donors

MTB can be transmitted from living organ donors with to recipients. In all potential donors, a history of active tuberculosis should be obtained. All the potential donors for solid organ transplantation should be screened for active tuberculosis. Surgery should be deferred if the donor is found to have active disease until they are fully treated and declared cured.

Screening for latent TB in deceased donors

Any potential deceased donors found to have active TB should be excluded from donation (evidence level C). As per western guidelines there should be high index of suspicion for latent TB and all donors should be screened, especially in the case of lung transplantation.[13] TST cannot be used in deceased donors. IGRAs may have potential to be used for LTBI screening but has not been formally tested in deceased donors. If LTBI is thought to be present in a deceased donor, the recipient of the lung transplant should be treated for LTBI. In South Asia, as in the West, donors with active TB are excluded. Screening for latent TB is controversial and varies with centre but is currently not the standard of care. Recipient should be closely followed for any active TB post transplant.

Research recommendation

RCT of treatment vs no treatment of LTBI in transplants from donors who are IGRA positive can be an area of research.

 Non-Tubercular Mycobacterial Infections



Introduction

Infection with non tuberculous mycobacteria (NTM), though rare overall, are more frequently encountered in the immunosuppressed SOT recipients compared to the general population.[41],[42] Of over 180 species and sub species of NTM, 25 have been reported to cause disease in solid organ transplant recipients causing either localised or disseminated disease.[43],[44],[45],[46],[47],[48] Although infection with NTM is rare, it does have major implications with regards to morbidity and mortality. There is increased incidence over the years either because of better physician awareness resulting in higher index of suspicion or better diagnostic modalities.[42] Diagnosis requires a high index of suspicion, isolation of NTM, growth from tissue specimens and body fluids; or demonstration of a compatible histopathology.

All prospective lung transplant recipients are recommended to be screened thoroughly for tubercular and NTM. Bronchoalveolar lavage may be difficult in prospective lung transplant recipients due to respiratory distress and high oxygen requirements and only sputum samples for acid fast bacilli smears and mycobacterial cultures are available. Presence of NTM cannot be completely ruled out when transplant is done urgently as smears may be negative and cultures take 7 to 10 days in rapid growing NTM and 6 to 8 weeks in slow growing NTM[49] and may result in a worse clinical outcome.

Eradication of NTM prior to lung transplants is ideal. However, there are no definitive guidelines for pre-transplant management. In patients who are suspected to have NTM infection and are awaiting urgent SOT especially lung transplant, a multidrug regimen can be given awaiting bronchoalveolar lavage results.[48] Patients with past pleuropulmonary NTM infections awaiting lung transplants should be considered for bilateral lung as the residual diseased lung may serve as a nidus for reactivation. Strict infection control practices should be followed, especially disinfection of bronchoscopes.[50]

Prevention of NTM infections

Patients and caregivers should be counselled about possible sources of infection in post transplant period e.g., tap water, ultrasonic humidifiers, etc. They should be counselled to use gloves while handling fish or soil while gardening. Decorations containing water should be removed from hospital rooms and homes; and only sterile water should be used for oral and respiratory care.[51] Getting tattoos and cosmetic surgeries predispose to cutaneous NTM infection and should be avoided.[52]

Multiple factors are known to affect the treatment course of NTM infections viz. the organism involved, the antibiotic susceptibility, and the host's ability to tolerate the multi drug therapy. Also there are no specific guidelines for the duration of therapy since no controlled studies have done in SOT recipients. Available recommendations are based on studies in the non-transplant population. Usually a multi drug regimen is continued for months to years [Table 3].[42]{Table 3}

Treatment: (Adapted)

Antibiotic treatment of common non-tuberculous mycobacterial lung disease on the basis of species identified.[47]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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