Tuberculosis Posttransplantation: A Real-World Issue in Developing Countries

Defining the Extent of the Problem

Among recipients of solid organ transplants (SOTs), the incidence of TB after transplant is estimated to be 20–74 times more frequent than that in the general population. Incidence varies depending on the local endemicity of TB, with low endemic regions reporting rates of 0.5%–6.4% compared with rates as high as 15.2% in areas of high endemicity (1). Among kidney transplant recipients, the prevalence of TB ranges from 4.4% (1.3%–14.7%) in Asia and 2.4% (1.7%–4.5%) in Latin America to 0.5% (0.4%–1.6%) in Western Europe and 0.4% (0.3%–0.4%) in North America (2). Underreporting as well as underdiagnoses are significant problems in developing countries, and the actual burden of posttransplant TB may be higher than estimated (4, 5). For example, in the Indian subcontinent, nearly half of the adult population is thought to have been infected with Mycobacterium tuberculosis. With over 4000 kidney transplants occurring in this population every year and with as many as one in every seven recipients likely to be affected by TB after transplant, the absolute number of patients with posttransplant TB is presumed to be significant (6).

What Are the Risk Factors for Posttransplant TB?

In addition to the epidemiological risk factors, several other patient- and transplant-related factors contribute to the risk. Diabetes mellitus, chronic liver disease, malnutrition, past history of untreated TB, hepatitis C infection, and other co-existing infections are associated with higher risk of posttransplant TB in SOT recipients (6, 7). The organ transplanted is also a contributing factor, with lung transplant recipients at 5.6 times higher risk of posttransplant TB in comparison with other SOT recipients (1). Ethnicity may be an important determinant of risk, as studies in South Asians have shown an association between certain human leukocyte antigen (HLA) phenotypes and development of TB after transplant (8).

In most developing countries where reactivation of latent infection is the primary mode of acquiring posttransplant TB, the net state of immunosuppression plays a major role. Use of T cell-depleting antibodies and anti-rejection treatment is associated with higher risk of developing this infection (7).

The type and intensity of recipient screening for TB also determine the degree of posttransplant risk (1). Considering the high endemicity in developing countries, there is a need for better screening for TB among both transplant candidates and donors.

Why is posttransplant TB significant?

• Challenges in screening for latent TB

There is a paucity of evidence-based guidelines for screening recipients for latent TB in regions of high endemicity (7). Most international guidelines recommend one of the following tests, both of which are based on the demonstration of cellular immune response against Mycobacterium tuberculosis antigens, and provide indirect evidence of infection: tuberculin skin test (TST) or interferon-gamma release assay (IGRA). Although they have shown good predictive value in countries of low endemicity, there are several limitations to their routine use for screening in developing countries (1).

1. Both tests do not require the presence of viable bacilli, which are sources for future infection in transplant candidates (9).

2. In populations with widespread Bacillus Calmette–Guérin vaccination, childhood exposure to tubercle bacilli, and significant anergy to TST among end stage kidney disease patients, the utility of these tests to predict posttransplant TB is limited by low likelihood ratios (10, 11).

3. Although IGRAs may be preferred, they are limited by high cost in resource-limited settings.

• Chemoprophylaxis for latent TB—risks vs benefits

Studies from the Indian subcontinent have demonstrated the benefit of chemoprophylaxis in reducing the risk of posttransplant TB (10, 12). However, this must be balanced against the risk of emergence of isoniazid (INH) resistance in highly endemic countries, which has been noted to be as high as 25% in India. The hepatotoxicity of anti-tuberculous medications should also be considered (7). Neither universal screening for latent TB in recipients nor chemoprophylaxis is recommended in a recent publication of a South Asian expert group opinion (7). In highly endemic regions, transplant candidates should undergo thorough evaluation for the presence of active TB, and anti-tuberculous treatment should be reserved for this group.

• Diagnostic challenge

The clinical presentation of posttransplant TB is often varied and atypical. It may present with non-specific symptoms of unknown origin, such as pyrexia, or only with allograft dysfunction. Extrapulmonary involvement and disseminated TB are not uncommon (13). Therefore, TB was not among the initial suspicions in nearly one-third of the patients with posttransplant TB, and up to 5% may be detected only after a recipient's death (1). Immunodiagnostic tests are not useful in diagnosis in most tropical endemic regions, and the diagnosis requires histopathological or microbiological confirmation. Several infections in the transplant population can also mimic TB, making the diagnosis difficult. Furthermore, in the tropics, infections do not follow the dictum of “Occam's razor” with the possibility of another infection co-existing with TB (10).

• Therapeutic challenge

Use of rifampicin in the anti-tuberculous regimen is limited by its drug interactions. As an inducer of cytochrome P450 (CYP) enzymes, it results in significant reduction in levels of calcineurin inhibitors, steroids, and mammalian target of rapamycin (mTOR) inhibitors. Extended therapy with non-rifampicin-containing regimens including rifabutin or fluoroquinolones may be used. The toxicity of each drug is also a consideration, with INH-associated hepatotoxicity being a significant problem in liver transplant recipients, occurring in as many as 41% of patients (7).

• Effect on patient and graft survival

TB in the transplant population has 10 times higher risk of mortality compared with that in the general population, with mortality rates of 19%–40%. Much of this fatality is usually attributable to TB occurring due to delayed diagnosis and a higher proportion of disseminated disease. Drug interactions causing a reduction in levels of immunosuppression may be associated with risk of rejection, with graft loss occurring in approximately one-third of patients with posttransplant TB (1).

Conclusion

In the posttransplant period, a high index of suspicion in this at-risk population would enable early diagnosis and appropriate treatment for TB. Further research is required to determine methods to predict the development of TB after transplant in prospective recipients and establish differential preventative strategies specific for these highly endemic regions.

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