The potential liver donor with tuberculosis: A fresh look at international recommendations based on a survey of practice in Indian liver transplant centres

INTRODUCTION

Liver transplant recipients (LTRs) are at increased risk of developing tuberculosis (TB) compared to the general population.^1–5 Although mainly due to reactivation or de novo infection,^1,5 it is estimated that 4% of TB in LTR is donor-driven.^3,5 Most patients are diagnosed within 6 months of transplant.¹ The symptoms of post-transplant TB are often atypical, diagnosis is often delayed and the risk of disseminated or extrapulmonary disease is high, resulting in high disease-associated mortality.^1–6 Treatment with anti-TB medication may be prolonged and associated with adverse drug reactions.^7,8

The approach to the organ donor with TB in western countries is determined in the setting of low disease burden and high cadaveric organ donation rates.^1,5,9–11 Europe, North America and Australia together host approximately 6% of the worlds burden of TB.¹² Organ donation rates in these countries range from 6 to 47 per million population.¹³ In this context, the recommendation to decline organs from donors with inadequately treated TB seems appropriate.

In contrast, India hosts 27% of the approximately 10 million individuals in the world with TB.¹² Approximately 3% of these patients have multidrug-resistant TB.¹⁴ The organ donation rate in India is only 0.3 per million population and liver transplant programmes are largely living donor-based.¹⁵ Tuberculin skin tests or interferon gamma release assay to diagnose latent TB infections are of dubious value in this clinical scenario and are not routinely performed on either organ donors or recipients in India.¹⁶ Nor is prophylaxis with isonicotinic acid hydrazide (INH) commonly used for LTR.¹⁶ This scenario may be common to other low infrastructure countries in which liver transplant programmes are likely to develop in the next decade. Are the recommendations from western expert consensus statements applicable, or should they be modified to suit the different environment?

We have attempted to determine the current practice in liver transplant centres in India and compared this to international recommendations.

METHODS

A list of all recognized liver transplant centres in India were obtained from the website of Multi-Organ Harvesting Aid Network Foundation.¹⁷ Centres at which a visiting transplant team from a larger centre performed the liver transplant were excluded from the study, as were centres where the programme had been discontinued. A questionnaire (Tables Ia and b) was sent to the lead surgeon or hepatologist at each active and independent liver transplant centre through email. The answers to the questions were collated and analysed. The following definitions were used:

Sputum-positive pulmonary TB. Acid-fast bacilli seen on either a tracheal aspirate or broncho-alveolar lavage specimen.

Sputum-negative pulmonary TB. Radiological abnormality on chest X-ray or computed tomography scan highly suspicious for TB but acid-fast bacilli not seen on tracheal aspirate or bronchoalveolar lavage specimen.

Lymph node TB. Cervical lymph node or cold abscess confirmed to be TB on the evaluation of aspirated pus or on biopsy.

Abdominal TB. Ileocaecal, ileal or peritoneal TB confirmed on histology.

Disseminated TB. Tuberculous infection diagnosed by radiology and/or microbiology and pathology at two or more non-contiguous sites.

RESULTS

Of the 113 centres across India certified to perform liver transplantation, 52 had active, independent liver transplant programmes. Responses were obtained from 49 (94%) of these centres. Sixteen (30%) centres performed more than 50 liver transplants annually. The three non-responders were low-volume centres.

Deceased donors

Many responders would accept organs from deceased donors with untreated TB. This ranged from 7 (14.3%) for donors with disseminated TB to 31 (63.3%) for those with cervical lymphadenopathy/cold abscess for recipients with decompensated chronic liver disease. Fifty-five per cent respondents accepted such donors only for recipients with MELD (model for end-stage liver disease) scores above 25. The proportion increased by a factor of 1.25 (range 1.15–1.35) for recipients with acute-on-chronic liver failure and 1.5 (range 1.3–1.7) for those with acute liver failure.

Two-thirds of respondents treated recipients of organs from deceased donors with untreated TB with antitubercular therapy (ATT). Most started ATT after postoperative transaminases had normalized. Three respondents started treatment with ethambutol and levofloxacin immediately postoperatively and added other drugs after transaminases returned to normal. Nearly all the remaining one-third responders gave recipients of these organs INH prophylaxis. A small minority (3%–5%) preferred to observe recipients and start ATT once the disease became clinically apparent (Fig. 1a-c).

Close

FIG 1.

Liver transplant centre acceptance for deceased donors with tuberculosis (TB): (a) recipient with decompensated chronic liver disease; (b) recipient with acute liver failure; (c) recipient with acute-on-chronic liver failure. Horizontal axis (left to right): Deceased donors with sputum +ve pulmonary TB, sputum –ve pulmonary TB, lymph node TB, abdominal TB and miliary TB. Vertical axis: Number of transplant centre respondents (total=49). Bar height: Number and percentage acceptance by transplant centre respondents for deceased donors with TB. Bar colour: Proportion of transplant centres recommending observation (OBS), INH prophylaxis (INH) or anti-TB treatment for recipients following deceased donor liver transplantation from donors with TB

Export to PPT

Living donors

Very few centres would accept organs from untreated living donors with TB irrespective of the recipients’ condition. Cervical lymph node TB was an exception with 7 (14.3%) and 12 (24.5%) respondents willing to accept them in the elective and acute liver failure scenario, respectively. There were varying opinions regarding how best to treat LTR from living donors with untreated TB, with the consensus being approximately two-thirds to one-third in favour of ATT as against INH prophylaxis.

Respondents were approximately equally divided between those who would accept living donors upon completion of the intensive phase of ATT versus a full course of ATT. Among the former, 25%, 33% and 42% advised INH prophylaxis, ATT and observation for recipients from these donors, respectively. No treatment was advised by any of the respondents for recipients of organs from donors who had completed a full course of ATT (Fig. 2a-c).

Close

FIG 2.

Liver transplant centre acceptance for living donors with tuberculosis (TB): (a) recipient with decompensated chronic liver disease; (b) recipient with acute liver failure; (c) recipient with acute-on-chronic liver failure. Horizontal axis (left to right): Deceased donors with sputum +ve pulmonary TB, sputum –ve pulmonary TB, lymph node TB, abdominal TB and miliary TB. Bar colour: Proportion of transplant centres accepting only fully treated living donors, living donors on completion of the 2month intensive phase of treatment (Intensive) or untreated donors (Untreated)

Export to PPT

DISCUSSION

Strict restrictions are put on the use of potential organ donors with TB in western countries where the burden of TB is low and the cadaveric organ donation rate high^1,5,9–13 translating to a low incidence of donor-derived TB.⁵ In contrast, TB is highly prevalent in India¹² while cadaveric organ donation rates remain low.¹³ Adoption of western recommendations may limit availability of organs further. The Indian liver transplant community has responded by relaxing selection criteria for potential organ donors with TB. This survey shows that up to 80% of liver transplant centres would accept deceased donors, and surprisingly 15% would accept living donors with TB in selected LTR.

It is unclear whether this policy is acceptable. Three Indian reports suggest the incidence of new-onset TB after liver transplant between 0.5% and 2.3%^6,18 (Subramanaian S, personal communication; Table II). About 30%–80% of these patients presented with disseminated or extrapulmonary TB and 40% died from TB-related complications.^6,18 These results are similar to the western reports with respect to incidence, disease presentation and mortality, despite the different approach to donor selection. Varghese et al.¹⁹ report an incidence of TB of 9% among 67 LTRs but include patients diagnosed during transplant evaluation. Earlier reports in Indian live donor kidney transplant recipients placed the risk of TB at 13%.²⁰ This has not been noted in LTRs perhaps because of the lower doses of immunosuppression used. Only Bhangui et al. report the incidence of TB in potential living donors¹⁸ (Table II).

Consensus conference reports and national guidelines from the West strongly advise against accepting organs from donors with untreated or partially treated TB except in dire circumstances^1,5,9–11 (Table III). One could argue that patients with high MELD scores or acute liver failure might constitute ‘dire circumstances’ in an Indian environment. However, they also recommend that should such an organ be accepted, the recipient receive ATT postoperatively.^1,5,9–11 Two-thirds of centres in India recommend ATT as per these international guidelines. Most of the remaining third advised INH prophylaxis to avoid the 19%–23% risk of acute rejection reported with rifampicin/rifabutin.⁷ The risk of hepatotoxicity does not differ significantly between modified ATT (7%–8%) and INH prophylaxis (6%),⁷ and the use of this agent in the background of increasing multidrug-resistant TB in India is questionable. There is ample literature showing the safety of ATT, as well as its efficacy in treating TB in LTRs undergoing LT for ATT-induced liver injury.⁸ Although the risk of transmission of TB is likely to be prohibitively high in donors with abdominal or miliary TB, transmission from isolated pulmonary or cervical lymph node TB, remote from the liver may not be. INH prophylaxis may be unnecessary in the latter situation, if biopsy of the graft and hilar lymph nodes do not show granulomas.

The use of living donors with untreated or partially treated TB is controversial, and is not recommended in any consensus statement,^1,5,9–11 and should be actively discouraged (Table III). Although very few centres stated that they would accept such donors, approximately half accepted them after completion of the intensive phase of ATT. Concerns with this strategy, although unproven, include the potential risk to the donor from restarting ATT on a regenerating liver, the consequences of interruption of ATT during the immediate postoperative period in partially treated donors,²¹ and the possibility of transmitting multidrug-resistant TB which constitutes 3% of all cases in India.¹⁴ Living donors and their recipients ought not to be subjected to these risks.

Nunn et al.²² in a review of 15 trials of short-course chemotherapy for TB in Africa and Asia determined that 78% of 574 relapses occurred within 6 months and 91% within 12 months of completion of treatment, respectively, usually at the site of the initial infection. Their report²² forms the basis of international recommendations that recipients of organs from donors completing ATT within the past 2 years receive INH prophylaxis. However, whether liver transplantation constitutes a significant risk for donor-derived TB when the initial TB infection occurred in a remote organ is unclear. No Indian centre recommended INH prophylaxis in LTRs from donors who had completed 6 months of ATT.

This study has a number of deficiencies. The impact of this relaxed policy for donor selection cannot be determined without clear knowledge of the number of potential donors with active TB and the number of recipients with donor-derived TB. One centre stated that they had not been faced with the clinical situations outlined in the questionnaire. They felt it was not possible to adequately assess the deceased donor for TB prior to harvest. The risk of transmission of TB to medical personnel when donors with open pulmonary TB are accepted for organ harvest exists and is unknown. Finally, this is an assessment of current practice rather than correct practice and highlights the need for the Indian transplant community to evaluate outcomes in light of the policy in use at their centre.

In conclusion, this survey shows that most transplant centres in India would accept untreated deceased donors with TB, nearly half would accept living donors with TB after completion of the intensive phase of ATT for high-risk LTRs in the absence of an alternative. Post-transplant treatment for recipients of organs from such donors is often inadequate according to the international recommendations. However, this strategy does not appear to negatively impact LTR according to the available Indian literature. We have suggested alternative recommendations for an Indian scenario (Table III).