Mycobacterium tuberculosis in Solid Organ Transplant Recipients
* Corresponding author: Aruna Subramanian, email@example.com
The diagnosis and treatment of tuberculosis in organ transplant recipients presents several challenges. Impediments to rapid and accurate diagnosis may lead to treatment delay and include negative tuberculin skin tests (TSTs), negative sputum smear results in spite of active disease and atypical clinical presentations (1,2). Therapeutic challenges arise from drug-related toxicities, metabolic interactions between immunosuppressive and antituberculous drugs, and side effects from long courses of antituberculous medications (3). Increasing drug resistance and inadequate immune responses to Mycobacterium tuberculosis (MTB) due to exogenous immunosuppression increase the complexity of treating tuberculosis in this population (4).
Recommendations for the diagnosis and treatment of latent tuberculosis infection and active tuberculosis disease in organ transplant recipients are made based on consensus guidelines formulated by experts in the field (5–10). Only a few controlled studies of treatment of latent or active tuberculosis in organ transplant candidates or recipients are available (11–13). Case series and epidemiologic surveys of organ transplant patients with tuberculosis are often used for guidance in this area (14–24).
It should be noted that the rates of tuberculosis 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 tuberculosis disease among solid organ transplant (SOT) patients is estimated to be 20–74 times that of the general population (1). For active tuberculosis 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 15% (1). Also, the frequency of the disease appears to be different according to the transplanted organ, with higher frequency in lung recipients (9,10). About two-thirds of reported cases of active tuberculosis disease in transplant recipients occur in the first posttransplant year (2), with the median time to development of disease reported as 9 months. In most cases, infection is thought to arise by reactivation of old foci of infection, because primary infection has only been documented in a small number of cases. Acquisition of MTB from the donated organ has been documented in renal, lung and hepatic transplantation, but appears to account for less than 5% of all active TB cases in transplant recipients (2,25). Nosocomial acquisition of MTB has been documented during an outbreak on a renal transplant unit, but fortunately also appears to be uncommon (26). The rate of primary infection is likely to be greater in developing countries but this has not been carefully evaluated.
Few risk factors have been defined for the occurrence of active tuberculosis disease after transplantation (1,2,9,10). Surprisingly, only 20–25% of all cases of active tuberculosis disease occurring after transplantation are in patients who had positive TST reactions before transplantation. This may in part be due to anergy in patients with end stage organ failure. The precise frequency at which TST positive patients later develop active tuberculosis after transplantation has not been determined. Other reported risk factors for active tuberculosis disease include prior residence outside the United States and the presence of findings on chest radiographs suggestive of healed tuberculosis. Basiri et al. report a case-control study from Iran where subjects who were on hemodialysis for longer periods of time had greater risk of active tuberculosis disease and the odds of TB were higher with increasing episodes of allograft rejection (27). It is clear that certain immunosuppressive drugs (e.g., OKT3 and T-cell depleting antibodies) are associated with a greater risk of tuberculosis than others (1). Torre-Cisneros et al. reported recently (10) that recipient age is an independent risk factor for posttransplant TB, at least in Spain where TB in the general population has decreased significantly in recent years. This allows for speculation that older persons are more likely to have latent TB and the same might prove to occur in regions where TB control programs have been successful.
Clinical Manifestations and Diagnosis
The clinical manifestations of tuberculosis in transplant recipients can differ from those in normal hosts (1,2). Importantly, about one-third to one-half of all cases of active tuberculosis disease after transplantation are disseminated or occur at extra-pulmonary sites, compared to only about 15% of cases in normal hosts. A minority of transplant patients have classic cavitary changes on chest radiograph. For these reasons the diagnosis of active tuberculosis disease after transplantation requires a high index of suspicion, often involves a diagnostic invasive procedure (28) and in practice is often delayed. The mortality of tuberculosis after transplantation is increased in patients who have disseminated disease, have had prior rejection or received OKT3 or anti-T-cell antibodies (1,2).
A diagnosis of latent tuberculosis infection is usually made by documenting a positive TST (see further) in a person who has no signs, symptoms or chest radiographic evidence of active tuberculosis disease. Interferon-γ release assays, including QuantiFERON-Gold (QFT, Cellestis) and T-SPOT.TB (Oxford Immunotec Ltd) have emerged as alternatives to the TST in the general population. However, their performance has not been adequately studied in highly immunosuppressed persons including transplant recipients, and therefore their routine use for evaluation of latent TB infection in transplant recipients is not recommended at this time (29). That said, the QFT and T-SPOT.TB tests are highly specific, and a positive test should be interpreted as evidence of M. tuberculosis infection. As for the TST, the QFT and T-SPOT.TB cannot distinguish latent TB infection from active TB disease. Compared to QFT, T-SPOT.TB appears to have a slightly higher sensitivity for detecting M. tuberculosis (30,31).
Evaluation of Transplantation Candidates and Donors
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) (7,32). Further inquiry about possible institutional exposure and travel to areas highly endemic for tuberculosis is also helpful. Any history of active tuberculosis should be documented, as well as details on 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 tuberculosis. All transplant candidates, including those with a history of BCG vaccination, should undergo evaluation for latent TB infection (III). Conventional tuberculin skin testing 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 tuberculin skin testing, and should be interpreted according to manufacturers’ guidelines. 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 (33). 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 (II). For living donors with latent TB infection, treatment for latent TB infection should be considered prior to organ donation, especially for recent seroconverters. 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 (9). It is not possible to perform tuberculin skin tests on deceased donors, but a history should be obtained from the donor's family or relatives of previous active tuberculosis 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.
Treatment of Latent Tuberculosis
Public health authorities recommend treatment of latent tuberculosis in persons who are actively immunosuppressed (6). The standard recommended treatment dose is isoniazid 5 mg/kg (maximum of 300 mg) daily for 9 months for adults and 10–15 mg/kg (up to 300 mg) daily for children (I) (see Table 1 for dose adjustment with renal insufficency). Alternative treatments are isoniazid given twice weekly by directly observed therapy (DOT) for 9 months (adult dose 15 mg/kg with maximum of 900 mg/dose; pediatric dose 20–25 mg/kg with maximum of 900 mg/dose); isoniazid daily for 6 months, or rifampin daily for 4 months (II). 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. The daily doses of rifampin are 10 mg/kg (maximum of 600 mg) for adults and 10–20 mg/kg (maximum of 600 mg) for children. Despite this public health recommendation, the use of isoniazid to treat latent tuberculosis infection in transplant recipients is controversial due largely to a high rate of hepatotoxicity reported in some studies (34–36). Recent data, however, show a low risk of hepatotoxicity due to isoniazid in renal transplant recipients without serious underlying liver disease (37) and in patients with compensated liver disease awaiting liver transplantation (38,39).
Table 1. Antituberculous medications1
|First line drugs|
| Isoniazid||5 mg/kg PO or IV (maximum 300 mg)||10–15 mg/kg (maximum 300 mg)||Minimal|
| Rifampin||10 mg/kg PO or IV (maximum 600 mg)||10–20 mg/kg (maximum 600 mg)||None|
| Pyrazinamide||25–30 mg/kg PO (maximum 2.0 g)||20–30 mg/kg PO (maximum 2.0 g)||Minimal|
| Ethambutol||15–25 mg/kg PO (maximum 1.6 g)||15–20 mg/kg PO (maximum 1.0 g)||Mild|
| Streptomycin||15 mg/kg (max 1 g) IM or IV4||20–30 mg/kg IM or IV (max 1 g)||Major|
|Second line drugs|
| Kanamycin||15 mg/kg (maximum 1.0 g) IM or IV4||15–30 mg/kg (maximum 1.0 g) IM or IV4||Major|
| Amikacin||15 mg/kg (maximum 1.0 g) IM or IV4||15–30 mg/kg (maximum 1.0 g) IM or IV4||Major|
| Rifabutin||5 mg/kg PO (maximum 300 mg)||Appropriate dosing for children is unknown||None|
| Levofloxacin||1000 mg/day PO or IV||N/A||Moderate|
| Ethionamide||15–20 mg/kg (maximum 1.0 g; usual daily dose 500–750 mg)||15–20 mg/kg (maximum 1.0 g)||Mild|
| Cycloserine||10–15 mg/kg (maximum 1.0 g/day in two doses; usual dose 500–750 mg/day in two doses)||15–20 mg/kg (maximum 1.0 g/day in two doses)||Moderate|
| Capreomycin||15 mg/kg (maximum 1.0 g) IM or IV4||15–30 mg/kg (maximum 1.0 g) IM or IV4||Major|
The rationale for latent TB treatment in this setting is supported by the fact that active TB disease is difficult to diagnose in transplant recipients, the cause of appreciable morbidity and mortality and a potential public health risk. With this in mind, the following recommendations are made
- 1Isoniazid preventive treatment for 9 months—given daily, or given twice weekly by DOT—should be considered for all transplant patients who have a positive tuberculin skin test (III), unless they have received a prior adequate course of treatment for latent tuberculosis infection or active tuberculosis disease. The alternative regimens that employ 6 months of isoniazid are not recommended for routine use in transplant recipients (III) because 9 months of treatment confers additional protection over 6 months. Pyridoxine (Vitamin B6) 25–50 mg daily should be administered concomitantly with isoniazid to all transplant recipients as they are already at increased risk of neurotoxicity from other transplant medications (III). Regimens that employ rifampin for 6 or 4 months are not preferred due to limited data on efficacy and are to be avoided after transplantation due to drug interactions. If standard treatment is not tolerated, alternative regimens such as ethambutol plus either levofloxacin or moxifloxacin could be considered for high-risk individuals (9). If no alternative treatment is possible, then careful clinical follow-up with prompt diagnostic attention to protracted fever or pulmonary symptoms is likely the best course.
- 2Most of the patients who develop active tuberculosis disease after transplantation have negative tuberculin skin tests before transplantation. For this reason, some authorities recommend the use of isoniazid preventive therapy in selected tuberculin skin test negative patients including: (a) those with radiographic evidence of previous tuberculosis and no history of adequate treatment, (b) those who have received an organ from a donor who is tuberculin skin test positive or (c) those patients who have had close and prolonged contact with a case of active tuberculosis, a circumstance in which the risk of de novo infection may be 50% or higher (III).
- 3If either the recipient or donor has recently converted their tuberculin skin test from negative to positive, then prompt recipient evaluation and treatment for latent TB infection (if no evidence of active TB disease) is indicated (III).
- 4Underlying liver disease limits use of isoniazid preventive therapy in transplant recipients (III). Latent TB therapy should still be strongly considered in patients with liver disease if they are known to be recent tuberculin skin test converters (III) because the risk of progression to active TB disease is high in this setting. The interaction between isoniazid and calcineurin inhibitors is not clinically significant enough to preclude the use of isoniazid.
- 5The timing of isoniazid administration requires balancing risks and benefits for individual patients. Factors that require consideration include the current medical condition, transplant urgency, risk of progression to active TB and anticipated timing of transplantation (if not yet performed). Individuals with recent TB exposure and/or recent TST conversion should receive evaluation and latent TB treatment as soon as medically practicable, due to heightened risk for progression to active TB. Renal transplant candidates who are awaiting deceased donor transplantation should be treated before transplantation, as they may face long waiting times and renal failure is itself a risk factor for active tuberculosis disease. Treatment should be considered before lung transplantation in TST positive individuals, because active tuberculosis may be difficult to diagnose in the presence of chronic lung disease. In some transplant candidates it may be preferable to delay the administration of isoniazid until after transplantation, at which time the risk for active tuberculosis is higher and the patient may be more stable medically. The administration of isoniazid to liver transplant recipients is somewhat controversial. In this population, it may be prudent to delay the initiation of isoniazid until liver function is relatively stable (III). In liver transplant recipients who are taking isoniazid, rises in serum transaminase levels should not be automatically ascribed to isoniazid. A specific diagnosis should be sought, with liver biopsy, if necessary.
- 6Transplant recipients receiving isoniazid should routinely be monitored for hepatotoxicity. A suggested approach is to monitor at 2 week intervals for 6 weeks and then monthly. A single blood test (ALT) should suffice. Low grade elevations of hepatic transaminases to 1.5–3 times normal are relatively common during the first months isoniazid use and may not require immediate discontinuation of isoniazid, but should prompt more frequent laboratory monitoring (III).
- 7Organ transplantation may be performed in patients that are receiving treatment for latent TB. After transplantation, latent TB treatment should be continued until completion.
- 8If treatment of latent TB has been delayed until after transplantation, then the selected regimen should be initiated as soon as medically possible after the recipient is stabilized.
Treatment of Active Tuberculosis
Drugs commonly used to treat active tuberculosis disease are listed in Table 1. Also noted are their standard adult and pediatric doses and the degree of dose adjustment required for renal dysfunction (5,6).
The standard treatment recommendation for active tuberculosis 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 four 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 (40) 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 (9,16). A longer duration of therapy is recommended for the treatment of bone and joint disease (6–9 months), central nervous system disease (9–12 months), and should be considered in individuals with severe disseminated disease (6–9 months). In addition, 9 months of treatment is recommended for individuals with cavitary pulmonary tuberculosis in whom sputum at completion of 2 months of treatment is still culture-positive for MTB. 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 2 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). 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, 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 and tacrolimus usually have to be increased at least two- to five-fold (II). 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 (41). 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 may be required) and when it is stopped (as the dose may then need to be reduced).
The hepatotoxicity of rifampin and isoniazid used in combination is greater than isoniazid alone and noted to be particularly severe in liver recipients (35). Liver function tests should be closely monitored.
Future Directions and Research
Transplant physicians can derive valuable information about the management of TB after transplantation from ongoing research in nontransplant populations. Because immunosuppression may eliminate tuberculin skin test responses, development of diagnostic tests for latent TB that do not rely on an intact T-cell response would greatly aid clinical management. 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. Fortunately, new treatment regimens are on the horizon, including potent drugs that may have the potential to shorten and simplify anti-TB therapy (3).
Subramanian. AK.: Grant/Research Support, Pfizer, Chimerix, Adamas; Consultant/Scientific Advisor, Viropharma. Dorman S.: The author has nothing to disclose.