Mycobacterium tuberculosis Infections in Solid Organ Transplantation

Abstract

The diagnosis and treatment of tuberculosis (TB) in organ transplant recipients presents several challenges. Impediments to rapid and accurate diagnosis may lead to treatment delay and include negative or indeterminate tuberculin skin tests (TST) or interferon-gamma release assays (IGRA), negative sputum smear results despite active disease and atypical clinical presentations 1-3. Therapeutic challenges arise from drug related toxicities, metabolic interactions between immunosuppressive and antituberculous drugs and side effects from antituberculous medications 4. Increasing drug resistance and inadequate immune responses to Mycobacterium tuberculosis (MTB) due to exogenous immunosuppression increase the complexity of treating TB in this population 5. Recommendations for the diagnosis and treatment of latent TB infection and active TB disease in organ transplant recipients are made based on consensus guidelines formulated by experts in the field 6-11. Only a few controlled studies of treatment of latent or active TB in organ transplant candidates or recipients are available 3, 12-14. Case series and epidemiologic surveys of organ transplant patients with TB are often used for guidance in this area 15-26. It should be noted that the rates of TB reported in the transplant literature often reflect cumulative rates in populations of patients followed over a number of years and cannot always be compared to or converted to annual incidence rates. The frequency of active TB disease among solid organ transplant (SOT) patients is estimated to be 20–74 times that of the general population, but differs according to the organ transplanted 1. For active TB disease, the prevalence among SOT recipients in most developed countries is 1.2–6.4%, while the prevalence in SOT recipients in highly endemic areas has been reported to be up to 12% 1, 27. Over two-thirds of reported cases of active TB disease in transplant recipients occur in the first posttransplant year, with the median time for presentation of disease reported as 6–11 months 2, 28. Posttransplant TB has a crude mortality of 20–30% 2, 29. One study from Spain reported an attributable mortality of 10% 11, but this may be higher in other countries due to the challenges associated with diagnosis in a highly immunosuppressed population. In most cases, active TB disease is thought to arise by reactivation of old foci of infection, because primary infection has only been documented in a small number of cases posttransplant. TB may also be transmitted from the donor through transplantation. The US Organ Procurement and Transplant Network's Disease Transmission Advisory Committee (OPTN/DTAC) reviewed 22 recent donor reports of potential TB transmission. Acquisition of MTB from the donated organ was substantiated in at least 16 of 55 recipients of organs from these 22 donors. Donor-derived TB transmission has been reported in renal, hepatic and lung transplantation 2, 30-33. Although donor-derived TB accounts for less than 5% of all active TB cases in transplant recipients, it may result in significant morbidity and mortality. TB can be acquired after transplant, with the rate of primary infection likely greater in developing countries, although this has not been carefully evaluated. Nosocomial acquisition of MTB has been documented during an outbreak on a renal transplant unit, though such events appear to be uncommon 34, 35. Surprisingly, only 20–25% of all cases of active TB disease occurring after transplantation are in patients who had positive TST reactions before transplantation 1. This may in part be due to anergy in patients with end-stage organ failure and likely does not reflect posttransplant acquisition of infection. The precise frequency at which TST positive patients later develop active TB after transplantation has not been determined. Few risk factors have been defined for the occurrence of active TB disease after transplantation 1, 2, 10, 11. In general, TB risk increases with TB incidence in one's country of origin, and social and medical risk factors such as homelessness, incarceration, cigarette smoking, diabetes mellitus, chronic kidney disease, malnutrition and known contact with TB. Reported risk factors for active TB after transplantation include prior residence outside the United States, history of untreated TB, the presence of findings on chest radiographs suggestive of healed TB and intensified immunosuppression for treatment of allograft rejection. It is clear that certain immunosuppressive drugs (e.g. T cell depleting antibodies) are associated with a greater risk of TB than others 1. Risks after kidney transplant appear to be increased in those with longer pretransplant hemodialysis treatment and in those with hepatitis C 36. Lung transplant recipients have a greater risk of active TB compared to other transplanted organs, with a 5.6-fold increased risk seen in a large Spanish cohort 11. The same study found recipient age to be an independent risk factor for post transplant TB, at least in Spain, where TB in the general population has decreased significantly in recent years. It may be that older persons are more likely to have latent TB; this may be true in other regions where TB control programs have been successful. The clinical manifestations of TB in transplant recipients can differ from those in normal hosts 1, 2. Among SOT recipients, lung transplant patients are most likely to develop pulmonary manifestations of TB. However, about one-third to one-half of all cases of active TB disease after transplantation are disseminated or occur at extra-pulmonary sites, compared to only about 15% of cases in normal hosts 2. Classic symptoms of TB such as fever, night sweats and weight loss are usually seen, but may not always be present. One large series reported fever in 91% of transplant recipients with disseminated disease and in 64% of those with pulmonary disease 2. Atypical presentations may also be noted, such as pyomyositis, cutaneous ulcers or tenosynovitis. A minority of transplant patients have classic cavitary changes on chest radiograph. Radiographic findings of pulmonary TB in SOT recipients may demonstrate a focal opacity, a miliary pattern, nodules, pleural effusions, diffuse interstitial opacities and cavities. The mortality of TB after transplantation is increased compared to immunocompetent hosts, especially in patients who have disseminated disease, those with prior rejection or after receipt of anti-T cell antibodies 1, 2. The diagnosis of active TB disease after transplantation requires a high index of suspicion and in practice is frequently delayed. A diagnostic invasive procedure, such as bronchoscopy with bronchoalveolar lavage or lung biopsy in pulmonary TB, or biopsy of skin lesions or abscess fluid in patients with skin and soft tissue involvement is often required 37. Specimens should be sent for smear and culture for acid-fast bacilli, along with histopathological evaluation. The use of rapid nucleic acid amplification techniques, such as Xpert MTB/RIF (Cepheid Inc, Sunnyvale, CA, USA), an automated molecular test for MTB and resistance to rifampin (RIF), can increase the sensitivity and decrease the time to diagnosis. However, such tests may be falsely negative when low levels of mycobacteria are present. A diagnosis of latent TB infection may be made by documenting a positive TST or IGRA in a person without signs, symptoms, or chest radiographic evidence of active TB. IGRAs, including QuantiFERON-Gold (QFT, Cellestis) and T-SPOT TB (Oxford Immunotec Ltd, Abingdon, UK) have emerged as alternatives to the TST in the general population 38, 39. The use of these tests in transplant candidates and donors is discussed later. It should be noted that neither the TST nor IGRA assays can distinguish latent TB infection from active disease. Both IGRA and TST should be interpreted with caution in patients receiving high levels of immunosuppressive drugs as they may yield falsely negative or indeterminate results 40, 41. Therefore screening for LTBI should be done prior to administration of immunosuppressives. That said, the QFT and T-SPOT TB tests are highly specific, and a positive test should be interpreted as evidence of MTB infection. Compared to QFT, T-SPOT TB appears to have a slightly higher sensitivity for detecting MTB infection 42, 43. A careful history of previous exposure to MTB should be taken from all transplant candidates, including details about previous TST results and exposure to individuals with active TB in the household or workplace (III) 8, 44. Further inquiry about possible institutional exposure and travel to areas highly endemic for TB is also helpful. Any history of active TB should be documented, as well as details regarding the length and type of treatment. It is also important to document previous treatment for latent TB and obtain relevant records. A chest radiograph should be examined for evidence of old healed TB. All transplant candidates, including those with a history of BCG vaccination, should undergo evaluation for latent TB infection (III). Conventional TST can be used in all situations, with a test being considered positive if there is ≥5 mm of induration at 48–72 h (III). If feasible, patients with negative reactions should have a second skin test performed 2 weeks later, as the TST can convert from being falsely negative to positive due to “boosting” in some individuals with remote MTB exposure. For individuals not highly immunosuppressed, the QFT and T-SPOT TB are alternatives to TST, and should be interpreted according to manufacturers’ guidelines. IGRA testing may be preferred to TST in transplant candidates with a prior history of BCG vaccination, as IGRA results will not be impacted by prior receipt of BCG. Studies of the performance of the QFT in liver transplant candidates indicate their utility in patients with advanced liver disease, with indeterminate results more common in candidates with higher MELD scores 43, 45, 46. The T-SPOT TB test may be more sensitive than TST in detecting LTBI in kidney transplant candidates 47. A Korean study of kidney transplant recipients revealed T-SPOT TB to be helpful in predicting risk for post transplant active TB in patients who were TST negative prior to transplant 10, 48. In transplant candidates with epidemiologic evidence of high risk for latent or asymptomatic active TB, careful radiographic assessment with CXR and thoracic CT may be helpful if results of TST and IGRA are negative or indeterminate 3, 49. Unfortunately, none of the available screening tests are infallible in diagnosing latent or active infection with MTB; therefore treatment decisions must be individualized based on the clinical likelihood of infection and a careful review of the available data. The management of discordant TST and IGRA test results also requires a thorough assessment of the candidate's individual TB risk 50. Since the sensitivities of TST and IGRA do not overlap fully, both modalities can be employed in screening, with appropriate timing to avoid the potential induction of false positive IGRA results 51. This should only be considered in transplant candidates with high pretest probability of LTBI in whom a single positive test result might change clinical management. Patients with a prior history of positive TST or IGRA testing may be screened for active TB and then treated as appropriate without retesting. A current negative screening test, especially in patients with organ failure awaiting transplantation, does not negate a prior positive test result. Individuals having a reliable prior history of treated latent TB infection or treated TB disease need not undergo TST, QFT or T-SPOT TB. However, these individuals should have a symptom review and chest X-ray, as well as additional testing if indicated, to screen for active TB. Living donors should undergo an evaluation similar to that described for transplant recipient candidates (III). For living donors, the TST should be interpreted as positive or negative according to CDC guidelines for the general population 52. QFT and T-SPOT TB are alternatives and should be interpreted according to manufacturers’ specifications. If a test reveals evidence of MTB infection, then active disease should be ruled out, starting with a symptom review and chest x-ray (III). For living donors with latent TB infection, treatment for latent TB infection should be considered prior to organ donation, especially for recent TST or IGRA converters. Organs from potential donors, whether living or deceased, with active TB disease should not be used. Also, a well-founded suspicion of active TB should contraindicate donation, and residual pulmonary lesions should contraindicate lung donation 10. It is not possible to accurately perform TST or IGRA on deceased donors, but a history should be obtained from the donor's family or relatives of previous active TB and any associated treatment. Ideally, it would also be desirable to know if the donor had exposure to active TB within the last 2 years. Public health authorities recommend treatment of latent TB in persons who are actively immunosuppressed 7. In highly endemic areas where TB transmission is common, some transplant experts recommend universal isoniazid prophylaxis for the first year posttransplant during the period of maximum immunosuppression 14. Treatment options for latent TB are listed in Table 1. The data supporting various treatment options for latent TB are extensive, with a paucity of information devoted to the management of transplant candidates 53-55. The mainstay of latent TB treatment is isoniazid, but its use in transplant recipients was controversial in the past due to a high rate of hepatotoxicity reported in older studies 56-58. More recent data, however, show a low risk of hepatotoxicity due to isoniazid in renal transplant recipients without serious underlying liver disease 59, and in patients with compensated liver disease awaiting liver transplantation 60, 61. A 4-month course of rifampin monotherapy can be used for the treatment of latent TB 62, but is limited by drug–drug interactions that preclude continuation of treatment posttransplant, thus it is preferable to complete the course of rifampin prior to transplantation. A previously recommended regimen of pyrazinamide and rifampin daily for 2 months has been associated with a high rate of hepatotoxicity and is no longer recommended. A promising new regimen for treatment of LTBI is a 12-week course of isoniazid and rifapentine 63. It is recommended weekly as directly observed therapy in otherwise healthy individuals ≥12 years of age who have a risk factor for developing active TB 64. However, it has not been studied in patients with organ failure, such as those awaiting transplantation. Use of this regimen after transplantation is limited by severe drug interactions between rifamycins and immunosuppressive agents. Because of the challenges of treating active TB disease after transplant, every effort must be made to diagnose and treat active TB pretransplant. A major challenge when screening transplant candidates is distinguishing latent TB from clinically asymptomatic active TB. Should asymptomatic candidates not receive a diagnosis of active TB until after transplant, successful treatment is still possible with early aggressive management 66. Drugs commonly used to treat active TB disease are listed in Table 2. Also noted are their standard adult and pediatric doses, the degree of dose adjustment required for renal dysfunction, and common side effects 6, 7. Drug interactions are addressed in Chapter 32. The standard treatment recommendation for active TB disease in the general population is to administer a four-drug regimen of isoniazid, rifampin, pyrazinamide and ethambutol for the first 2 months (“intensive phase”) followed by isoniazid and rifampin alone for an additional 4 months (“continuation phase”) (I). Ethambutol can be discontinued if the MTB isolate is susceptible to isoniazid, rifampin and pyrazinamide. Fluoroquinolones including moxifloxacin and levofloxacin have potent activity against MTB, and while not recommended for use as “first-line” therapy, they can be useful components of multidrug regimens in individuals who have hepatotoxicity on standard TB therapy or who have poor liver function. With respect to dosing interval, daily TB therapy is recommended. Twice- or thrice-weekly administration of TB therapy is not recommended due to the increased risk of relapse associated with intermittent dosing (II-2) 67 and the potential for wide fluctuations in immunosuppressive drug levels due to drug–drug interactions with rifamycins. With respect to treatment duration, published data in renal transplant recipients indicate that 6 months of treatment should be adequate; however, some experts disagree 10, 17. A longer duration of therapy is recommended for the treatment of bone and joint disease (6–9 months) (I), central nervous system disease (9–12 months) (II-2), and should be considered in individuals with severe disseminated disease (6–9 months) (II-1). In addition, 9 months of treatment is recommended for individuals with cavitary pulmonary TB in whom sputum at completion of 2 months of treatment is still culture-positive for MTB (I). Longer treatment duration should always be considered if the response to treatment is slow. Longer treatment courses are mandated if second line drugs are used to replace first line drugs, or if there is resistance to rifampin ± other drugs (III). For drug susceptible TB, when treatment is extended beyond 6 months, the intensive phase remains two months in duration and the duration of the continuation phase is extended. DOT programs have been shown to improve adherence and outcome in TB patients and are recommended for transplant recipients (II-2). If a transplant recipient receives antituberculous medication in a public health clinic, close communication with the health clinic is necessary to ensure that clinic personnel are aware of transplant specific issues. Consultation with a TB expert is recommended for any patient with active TB, and is imperative for patients whose TB is complicated by drug resistance or drug intolerance, as well as those who require nonstandard treatment for whatever reason. The major difficulty in administering antituberculous therapy to transplant patients is drug–drug interactions involving rifampin. Nevertheless, a rifamycin-containing regimen is strongly preferred due to the potent MTB sterilizing activity of this drug class. Rifampin is a strong inducer of the microsomal enzymes that metabolize cyclosporine, tacrolimus, sirolimus, and everolimus. To some extent rifampin may also interfere with corticosteroid metabolism. It may be difficult to maintain adequate levels of immunosuppressive drugs while using rifampin, and rejection episodes occurring in conjunction with rifampin use have been widely reported. Successful use of rifampin has been reported in transplant recipients, but doses of cyclosporine, tacrolimus and sirolimus will have to be increased at least two- to fivefold (II-3). An option is to replace rifampin with rifabutin (another rifamycin) (I). Rifabutin has activity against MTB that is similar to rifampin, but rifabutin is a much less potent inducer of cytochrome P3A4, and therefore immunosuppressant levels may be easier to maintain 68. There is relatively little published clinical experience using rifabutin after transplantation, since active TB is relatively uncommon in transplant recipients in the United States and rifabutin is generally not available in parts of the world in which TB is more common. However, in HIV-infected individuals, the effectiveness of rifabutin-containing regimens appears no different than that of rifampin-containing regimens. Rifabutin dose is 5 mg/kg (maximum 300 mg) given once daily. With either rifampin or rifabutin, immunosuppressant levels should be monitored closely when the rifamycin is started (as higher doses of the immunosuppressant will be required) and when it is stopped (as the dose may then need to be reduced). Management of posttransplant TB with nonrifamycin regimens has been successful in countries where rifabutin is not available 69, 70. When prescribing medications for treatment of latent or active TB a careful review of all drug-drug interactions is recommended. Refer to Chapter 32 in the guidelines for further information. The hepatotoxicity of isoniazid, rifampin and pyrazinamide used in combination is greater than isoniazid alone and noted to be particularly severe in liver recipients 57. Liver function tests should be closely monitored. Isoniazid use may be associated with peripheral neuropathy and other neurotoxicity. Ethambutol use can impair visual acuity; early detection with periodic ophthalmologic monitoring for toxicity is recommended. Transplant physicians can derive valuable information about the management of TB after transplantation from ongoing research in nontransplant populations. Since immunosuppression may eliminate TST and IGRA responses, development of diagnostic tests for LTBI that do not rely on an intact T cell response would greatly improve diagnosis and clinical management, especially in the case of donor derived infections. Another important advance would be the development and/or clinical validation of antituberculous drugs that are free of significant organ toxicities and drug–drug interactions. New treatment regimens are on the horizon, including potent drugs that may have the potential to shorten and simplify anti-TB therapy 4. Evaluation of these in transplant candidates and recipients may provide useful treatment alternatives for this population in the future. This manuscript was modified from a previous guideline written by Aruna Subramanian and Susan Dorman published in American Journal of Transplantation 2009;9 (Suppl 4): S57–S62 and endorsed by the American Society of Transplantation/Canadian Society of Transplantation. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.