EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Coronavirus disease (COVID-19) has engulfed the whole world, and India has been the second worst-hit nation. Organ transplant services were halted in both the public and private care sectors of India, with public care sectors more adversely affected. Deceased donations were disproportionately more affected, with unfavorable rates at the peak of the pandemic. Mortality outcomes of COVID-19 among different organ transplant recipients in India have been lower compared with the Western world, with younger age and less comorbidities among Indian populations partly responsible for the lower mortality. Mortality and graft loss were mostly associated with older age and those with chronic graft dysfunction. During the pandemic, invasive fungal infections, like mucormycosis, have been reported, illustrating the need for multidisciplinary management. The Indian transplant societies have formulated and timely revised guidelines for transplantation in the COVID-19 era. Living donor transplants (both liver and kidney) after recovery from COVID-19 were both first described in India, providing a guiding tool for the world. Follow-up reports of recovered solid-organ transplant recipients have also been reported in Indian studies, showing reassuring long-term outcomes. Data of breakthrough COVID-19 cases after vaccination among both transplant recipients and waitlist candidates and research in vaccine efficacy for solid-organ transplant recipients is still underway. We suggest continuing and intensifying research activities for a better plan and strategy in case of a future pandemic.

Key words : Coronavirus 2019, Severe acute respiratory syndrome novel coronavirus, Solid-organ transplant

Severe acute respiratory syndrome novel coronavirus (SARS-CoV-2) infection globally impacted all aspects of health care and society on a massive and irreparable scale. Globally, as of October 1, 2021, there have been 233 503 524 confirmed cases of COVID-19 (coronavirus disease), including 4 777 503 deaths, as reported by the World Health Organization. Transplant communities have been at increased risk of COVID-19-associated morbidity and mortality, requiring special attention to minimize the damage. The impact on solid-organ transplant (SOT) trends and COVID-19 mortality among transplant recipients have shown considerable variation with different geographic regions and even in different parts of the nation. This demonstrates the uneven COVID-19 burden and diversity in approach to the pandemic by various parts of the world.1 Overall, India has been the second-worst affected nation. However, in the pandemic’s second wave during April to June 2021, the daily peaks in the Indian subcontinent have reached the highest in the world. Recently, as of October 3, 2021, the number of active COVID-19 cases in India was 270 557 (0.80%), the number of discharged patients was 33 094 529 (97.87%), and reported mortality was 448 817 (1.33%).² Judging from the lower mortality rates in Indian settings, it is evident that India has tackled the pandemic relatively well, considering the health care resource limitations and the population density. Strict and early quarantine measures, early isolation, contact tracing, and testing were the prime reasons for the success of India in its fight against COVID-19. Another important aspect in handling this pandemic was propagating the right knowledge and awareness about the virus and vaccination. Since the beginning of the pandemic, both an “Infodemic” and the F (fear) virus were more pandemic than COVID-19 itself.³

The applauding efforts by all the Indian transplant societies, which have timely published and updated their guidelines for helping transplant professionals and patients amid this pandemic, were the cornerstone for care of SOT recipients during this pandemic. The Liver Transplantation Society of India has provided timely updated guidelines for liver transplant (LT) and has classified LT procedures as urgent or semi-urgent. They have also amended guidelines for testing of the donor and the recipient for LT.⁴ Authorities in India have also provided protocol guidelines for pediatric LT.⁵ The Indian Society of Heart and Lung Transplantation has also recommended guidance for patients and professionals concerning heart and lung transplantation. For example, they mandated normal high-resolution computed tomography of the thorax before lung donation, which was an important step.^6,7 The National Organ and Tissue Transplantation Organization (NOTTO),⁸ which is the apex body for SOT in India, issued a position statement and guiding tool for management and treatment of COVID-19 in SOT patients.

There is an unmet need to regularly enrich and update our practices and policies for transplantation in the pandemic and to grasp learning points for the pandemic’s next waves. Hence, we aimed to accumulate evidence from Indian studies in understanding COVID-19 in the context of SOT. We performed a comprehensive literature search with the MeSH terms coronavirus, transplantation, India, and SARS-CoV-2 in PubMed, Google Scholar, MEDLINE, and Embase, with no language or date restrictions through October 3, 2021. This evidence will help illustrate the COVID-19 management principles and policies of Indian transplant centers, which will serve as a tremendous learning tool for emerging transplant centers across the world.

Impact of COVID-19 in Activities of Transplant Centers
COVID-19 has hit the world in an unprecedented way, and the divergence of transplant facilities for the care of general COVID-19 patients has become a universal priority. The primary goal has been to maintain a balance between maintaining quality of life among waitlist patients and the risk of acquiring or transmitting COVID-19 during transplant. At the peak of the pandemic, nonemergent and elective transplants were at a complete halt with space for emergency transplants only. Across the world, many transplant centers were temporarily converted to dedicated COVID-19 centers to compensate for the overflow of patients from the saturated centers assigned to COVID-19 care.

Declines in transplant rates have been different for living donation and deceased donation procedures and have also been different with respect to the specific organ. Per the Global Observatory on Donation and Transplantation data,⁹ globally, living donor kidney transplant (LDKT) has been the most affected, with a reported 31.3% decline. This is dissimilar to the Indian subcontinent where it was less affected (25.3%). The global decline in deceased donations was reported as 49%, whereas India reported a higher decline in deceased donations (50.9%) during the pandemic. In the Indian subcontinent, the steepest decline was seen in deceased donor kidney transplant (54.7%), with deceased donor LT also quite high.¹⁰ However, this was an expected decline for India. In a resource-limited nation like India, with deceased donor procedures at their infancy, reallocation of health services to tackle COVID-19 during the high surge was prioritized, as this was a national health emergency.¹¹

Throughout the pandemic, Indian centers have reported on their landscape of COVID-19 in SOT. During the initial wave of the pandemic in India, the immediate and gross diminution of kidney transplant procedures and patients was reported from a single center.¹² In a multicenter (n = 18) national analyses, transplant rates were shown to decline more in public sectors, with patients on wait lists being more adversely affected. This report depicted the state of transplant in the most vulnerable areas of a developing nation like India.¹³

In another multicenter report from India on transplant recipients, the incidence of early COVID-19 (defined as COVID-19 within 1 month of surgery) was 2.6% for 838 transplants performed during the pandemic. In the study, 1049 kidney transplant recipients (KTRs) were diagnosed with COVID-19, with 2% of those having early COVID-19. Mortality rate for early COVID-19 was similar to that shown in KTRs overall (4.5% vs 8.5%; P = 1).¹⁴ The report implied that early COVID-19 showed no adverse outcome in KTRs and that ceasing transplant in fear of adverse outcomes in KTR owing to higher immunosuppression should not be practiced. A recent multicenter study on the impact of living donor LT described the impact of the pandemic and difficulty in restructuring of transplant activities.¹⁵

Another salient task for transplant professionals was safeguarding patients on waitlists and assessing their chances of receiving transplants amidst the pandemic. There is an option of maintenance hemodialysis (MHD) for patients with renal failure who can thence thrive and survive; however, there is no alternative therapy for liver failure. In a multicenter report, the COVID-19 severity (23.9% vs 15.7%; P < .01) and mortality (15.5% vs 8.5%; P < .01) rates among patients on waitlists (n = 1703) were higher compared with KTRs (n = 1049).¹² In another multicenter (n = 18) retrospective analysis,¹⁶ patients on MHD and on waitlists were adversely affected during the lockdown period of the pandemic. Finally, in a nationwide (n = 11) report,¹⁷ in which 263 patients on MHD were analyzed, mortality was reported as 13.3%, with old age and twice per week dialysis (instead of 3 times/week) and use of a temporary catheter being associated with higher mortality. These reports highlighted the adverse impact of COVID-19 in waitlisted patients, pointing to a favoring for transplant with calculated risks and logistics based on transmission rate. A major issue was an asymptomatic presentation among patients on MHD, with these patients being more prone to COVID-19 as they have an unavoidable hospital visit for a dialysis session. In an Indian report,¹⁸ patients on MHD who underwent SARS-CoV-2 testing every 2 weeks during routine visits were analyzed for 3 months. The approach detected 80% of patients as asymptomatic, helping in further prevention of the spread of the virus. Such strategies can be applied in other dialysis centers as an effective measure for curbing transmission rates during potential future waves.

Clinical Spectrum of COVID-19 in Transplant Patients
At the initial phase of the pandemic, our understanding of the clinical spectrum of COVID-19 in SOT was naïve; over time, our knowledge has now widened exponentially. In general, SOT recipients do not have many differences in presentation of SARS-CoV-2 compared with the general population, although mortality and morbidity rates in SOT recipients are higher.¹⁹

A recent multicenter study documented a 13% incidence of COVID-19 in KTRs, with 14% mortality in the pandemic 2020 year.²⁰ In a recent large single-center study from India²¹ that compared outcomes of KTRs in different pandemic waves, no differences in mortality were shown but comorbidity numbers dramatically decreased in the second wave. In a large cohort (n = 250) study of COVID-19 in KTRs from regions in southeast Asia, which included multiple centers in India,²² in-hospital mortality was around 10%, which was lower than the reported fatality from the Western world. The relatively younger age and fewer comorbidities in Indian patients were the primary plausible reasons for this discrepancy. In a single-center case series of pediatric renal transplant recipients, successful management of COVID-19 was reported.²³

There have also been published Indian reports on LT recipients. A case series24 (n = 6) on LT recipients showed favorable outcomes. In another case series (n = 12) of LT recipients from North India, the outcome was also favorable.²⁵ Outcomes of LT procedures performed during the pandemic were similar to those shown in general patients in a single-center study conducted in Western India.²⁶ A multicenter study²⁷ later found similar conclusions. A report incorporated a list of major changes for LT practices during the pandemic.²⁸ Telemedicine, which has been an integral part of the health system, now was a feasible option for pediatric LT units.²⁹

There has been apprehension on the use of new investigational therapies in SOT, as pharmacokinetics and pharmacodynamics along with drug-drug interactions in SOT recipients make them at high risk for adverse reactions. In a novel single-center study, the feasibility of remdesivir for COVID-19 was shown in KTRs,³⁰ where no liver abnormalities or worsening of renal functions was reported. These results had large implications, as remdesivir became one of the first-line drugs for the treatment of COVID-19, despite the lack of a definite efficacy in randomized clinical trials. Another experimental therapy that was initially in the limelight as an effective anti-COVID-19 therapy was plasma therapy. Plasma therapy was found to be safe in KTRs in preliminary data from an Indian report, which was among the first such report published.³¹ However, a large Indian trial (PLACID)³² that tested plasma therapy showed no mortality benefit for COVID-19.

During the pandemic, invasive fungal infections have emerged as a major threat, prolonging hospital stays and increasing mortality rates. The number of mucormycosis cases following COVID-19 exploded in the country. Indian transplant centers³³ were among the first to report COVID-19-associated mucormycosis in transplant patients. The first case report of disseminated mucormycosis post-COVID-19 in KTRs was also reported from Northern India.³⁴ A recent multicenter study reported 61 cases of mucormycosis in KTRs, with 26% mortality.³⁵

Because vaccine development and definite COVID-19 therapy were far from reach during the initial pandemic, a concerning point for transplant centers was the chances and outcomes of reinfection/reactivation. In various studies, COVID-19 neutralizing antibodies are expected to decline over a few months of infection, hence increasing the susceptibility of reinfection. However, data among SOT recipients have been less reported. In this context, an Indian study reported excessively high mortality with repeat SARS-CoV-2 infection,³⁶ although the low incidence of such reinfection/reactivation decreases the magnitude of this problem.³⁷ On an encouraging note, in a report of 47 COVID-19 cases in KTRs that assessed for seroconversion and durability of response, the results were reassuring.³⁸

As reports of sequelae following recovery from COVID-19 emerged, transplant professionals become more reluctant and meticulous in the follow-up of post-COVID-19 cases. Although there are scarce follow-up studies of recovery from COVID-19 in SOT recipients, a single-center analysis³⁹ on concomitant BK virus infections during COVID-19 did not show poor outcomes in follow-up. In another report,⁴⁰ the quality of life, along with graft outcomes, of recovered KTRs showed marked improvement. In 2 published reports from India,^40,41 graft loss in follow-up after COVID-19 recovery was associated with baseline allograft dysfunction. An Indian center reported a case of graft thrombosis leading to graft loss in a KTR with early post-COVID-19.⁴² This report called for thorough surveillance for chances of thrombosis in follow-up and hence early intervention.

Overall, observational studies from Indian centers have provided deeper insight into understanding the diversified clinical spectrum of COVID-19 in SOT recipients.

Recovery of COVID-19 in Transplant Candidates and Potential Donors
Since the advent of the pandemic, there has always been a dilemma with regard to transplant among donors and recipients who have recovered from COVID-19. The basic problem is the unknown sequalae in donors and recipients, which could complicate outcomes. The ideal induction therapy, maintenance immunosuppression, and waiting time are other factors for consideration. Studies from India have been among the first worldwide to comprehensively report such transplants for living donations. In a multicenter report,⁴³ LDKT from 31 COVID-19-recovered donors was studied, and its safety was confirmed. There was 100% graft and patient survival and no complications in donors. In another multicenter study, LDKT in 75 COVID-19-recovered candidates resulted in successful short-term outcomes.⁴⁴ These 2 reports remain the largest cohort of donors or recipients who underwent kidney transplant after COVID-19 recovery. On the background of these safety data, many transplant centers have conducted transplant procedures in recovered donors and recipients. The basic protocol derived from the studies, for donors and recipients after COVID-19 recovery, was a clinical asymptomatic period of 28 days, 2 consecutive negative reverse transcriptase polymerase chain reaction tests, with the last one just before transplant, social distancing of 14 days for donors and recipients before surgery, and normal chest radiology results. Because deceased donation procedures are less prominent in India, such findings have been less documented in our subcontinent. However, the worldwide first case report of a COVID-19-linked death followed by organ procurement was reported in India.⁴⁵

Transplant in patients who have recovered from COVID-19 has also been reported in LT, where 9 patients who underwent living donor hepatectomy had good outcomes. In this multicenter study from India, the findings reported were among the first study of its kind.⁴⁶ The learning point was that LT should be continued with safe practices, as it is an emergency in many cases.⁴⁷ A single case report of LT after recovery from COVID-19 in Western India has also been described⁴⁸ as well as a first report⁴⁹ of intestinal transplant in a 9-year-old child after small bowel gangrene due to COVID-19 in Western India. In a multinational report of 12 lung transplant procedures as a result of severe COVID-19, early outcomes were promising. Lung transplant has been reported to be technically more demanding in COVID-19 cases; however, outcomes of lung transplant were similar to outcomes shown in non-COVID-19 patients. In summary, SOT in recovered donors and recipients is feasible and safe, with equivalent outcomes and no changes in immunosuppression compared with routine practice. However, further long-term outcome data will give a more definitive conclusion.

Data on Vaccination of Solid-Organ Transplant Recipients and Patients on Waitlists
Challenges of vaccination to one of the highest populations in the world remain enormous. Unfortunately, the surge of the pandemic’s second wave has overburdened health resources and has led to hampering of vaccination implementation. As of October 3, 2021, the COVID-19 vaccination number was 905 175 348 for India.² Data on vaccinations for SOT recipients in India are scarce, apart from a handful of single-center experiences. In a single center study, 5 KTR recipients developed breakthrough COVID-19, following the Oxford AstraZeneca vaccine,⁵⁰ with 3 patients who died. In another description of 11 breakthrough cases among patients with chronic kidney disease, including 4 on waitlists, no mortality was reported.⁵¹ Overall, there are no safety issues for SOT recipients who received the vaccines approved in India. Cases on vaccine-induced thrombocytopenia in SOT recipients from India are yet to be reported. In previously formulated guidelines for vaccination, NOTTO focused on the prioritization of patients on waitlists and transplant recipients for vaccination.⁵² Recently, NOTTO and the apex Indian government’s authoritative bodies for organ transplantation have updated existing guidelines for SOT, where they enlisted guidelines based on recent evidence, which can be a learning tool for transplant professionals across the globe.⁵³

A Way Forward
The limitations of studies from India are that the research methodology is largely retrospective and observational. Randomized controlled trials are scarce; in addition, there is a lack of studies on responses to the COVID-19 vaccine in SOT recipients, which is the need of the hour. Their scarcity is explained by logistic issues and financial constraints in the public domains, where patient load remains high. Still, India seems to be stepping toward improving the quality of its research work; during the pandemic, nationwide collaborations have allowed many multicenter studies. It is important to continue to be on guard and to continue developing awareness and educating SOT patients as they are at a highly vulnerable state for COVID-19.⁵⁴ Until efficacy data for patients on waitlists and SOT recipients are not reassuring, COVID-19 appropriate behaviors should be followed.

Conclusions
COVID-19 has resulted in a national emergency around the world. The low-economy nations have recovered more slowly, and high-income nations, like those within the United Nations, have shown excellent responses to the pandemic, despite having maximum cases. Indian transplant societies have done a tremendous job by formulating and amending guidelines that helped to pave the path for safe practices across Indian transplant centers. India has vastly contributed to the existing literature by defining optimal protocols for transplant from recovered donors and living donor transplant recipients. In addition, other studies, such as those describing clinical profiles, breakthrough COVID-19 cases, and long-term follow-up data, have been useful for transplant physicians across the world. Research on vaccine efficacy remains in development.

Volume: 20 Issue: 3 March 2022 - Supplement - 1

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