EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Worldwide, India ranks number 2 and 3 for COVID-19 burden and absolute transplant numbers, respectively. Here, we summarized our single and multicenter Indian studies on solid-organ transplant during the COVID-19 pandemic. During the pandemic, solid-organ transplants declined 40% to 50%. The mortality rate in COVID-19-positive kidney transplant recipients (11.6%) was lower in India compared with the developed world during the first wave and lower compared with maintenance hemodialysis patients (13% to 38%) but significantly higher compared with the nonimmunosuppressed general population (1% to 3%) in India. We contributed to National Organ and Tissue Transplant Organization transplant-related guidelines to increase safety and access to solid-organ transplant. We reported the safety and feasibility of remdesivir (n = 57) and convalescent plasma therapy (n = 10) in kidney transplant recipients. We reported 100% patient and graft survival without any complications related to COVID-19 in a large cohort of kidney transplant recipients who recovered from COVID-19 (n = 372) and a large cohort of kidney transplant recipients of living donors (n = 31) who recovered from COVID-19 without any change in induction and maintenance immunosuppression. COVID-19 disease severity and mortality in the second episode (reoccurring infection) was higher (46%) compared with the first episode (11.6%). There was 4.4% incidence of COVID-19-associated mucormycosis in kidney transplant recipients with mortality of 46% in the second wave. We reported COVID-19 vaccine safety with suboptimal efficacy in kidney transplant recipients and dialysis patients compared with the general population. Our report suggested that transplant with carefully selected COVID-19-recovered donors and patients may be feasible and safe, at least over the short term. Continued research is needed on vaccine efficacy, booster doses, and long-term followup sequelae.

Key words : Immunosuppression, Impact, Kidney transplant recipients, Pandemic

Globally, as of April 14, 2022, there have been 500 186 525 confirmed cases of coronavirus disease (COVID-19), including 6 190 349 deaths, reported to the World Health Organization. In addition, as of April 13, 2022, a total of 11 294 502 059 SARS?CoV?2 vaccine doses have been administered worldwide. Solid-organ transplant (SOT) is an established risk factor for COVID-19-associated morbidity and mortality. Worldwide data¹ have shown that the impact of COVID-19 on transplant volume has been unequal in various regions of the globe. Some nations have shown a marked decline in transplant numbers even with low-level impacts of the pandemic, and some nations have had a negligible impact compared with the higher overall mortality in their region. Developing nations had more struggles, as the level of health care workers and medical supplies emptied faster compared with the slow augmentation of medical facilities and recovery of cases. The pandemic led to a high diversion of medical services, and many transplant centers were transformed into dedicated COVID-19 centers.

The Indian subcontinent was the second worst-hit nation in the COVID-19 pandemic overall. Per the Ministry of Health and Family Welfare (MOHF),² as of April 16, 2022, India has 11 366 (0.03%) active cases, 42 507 834 (98.76%) recovered cases, and 521 747 (1.21%) deaths. In addition, the total COVID-19 vaccination numbers reached 1 863 831 723. India posted nationwide, statelevel, and regional lockdowns at different times over the pandemic period. During the lockdown period, a survey of liver transplant centers³ demonstrated medical, social, and psychosocial impacts among the liver transplant recipients. Another survey⁴ of parents of pediatric liver transplant recipients showed knowledge gaps and areas of concern to be targeted during the pandemic. Accessing the real-world situation by survey in the pandemic assists in understanding both deficits in knowledge and requirements needed to change health policies for better management of the targeted population. Western literature on the effects of COVID-19 on transplant services and clinical outcomes are exclusive, and there are comparatively fewer reports from the Indian subcontinent, especially for heart and lung transplantation. The primary purpose of this review article is to summarize the data published from Indian transplant centers, which would allow an excellent learning resource that describes the overview of the research and lagging areas in India. This would help in filling the knowledge gap and help in forming a focused approach in case of future waves of the pandemic.

We conducted a literature search through the search engines of EMBASE, MEDLINE, PubMed, Google Scholar, Scopus, and WHO portal for COVID-19. We used the following MeSH terms: COVID-19, SARS-CoV-2, solidorgan transplantation, kidney, pancreas, liver, heart, India. We included no filter for time of publication. There was no restriction on languages. For publication types, we excluded systematic reviews, meta-analyses, and editorials. We included relevant published research items, including guidelines, reviews, original articles, brief communication, commentaries, letter to editors, case reports, and case series. If full text was not available or not reported, that study was excluded from our review. Any research data coming from Indian centers that pertained to SOT were eligible for inclusion. Inclusion criteria involved all SOT data associated with COVID-19 from Indian centers, irrespective of the age of the SOT recipient or organ transplanted. Exclusion criteria involved studies on hemopoietic stem cell transplant or eye or tissue transplant. The authors HSM and VBK performed the literature search, and SC checked the authenticity and validity of the articles. Any confusion or discordance in the articles was resolved by group discussion among these authors.

Development of Transplant-Specific Guidelines During the COVID-19 Pandemic

False assumptions, knowledge gaps, diversified virus strains, diverse health care systems, resource limitations, and dilemmas on decision making were some of the reasons for worsening the situation in the first wave of the pandemic⁵; hence, consensus statements and evidencebased regularly upgraded guidelines were necessary to increase safety in patients care. During the first wave, the “Infodemic” was more pandemic than COVID-19. The National Organ and Tissue Transplant Organization (NOTTO), a national-level organization governing Indian activities of coordination and networking for procurement and distribution of organs and tissues and the registry of organs and tissues for donation and transplant, made a tremendous effort to publish guidelines⁶ for transplant professionals on COVID-19, starting from the first wave of the pandemic.⁷ The organization published vaccine guidelines for transplant professionals that stressed equity and priority of vaccines for SOT and patients on wait lists.⁸ The updated NOTTO guidelines for vaccination in SOT⁹ calls for prioritizing the SOT population for vaccination. Vaccination was not mandatory and is a voluntary process in India, and no patient can be removed from the waitlist if he or she is unvaccinated. However, those on the waitlist are counseled compulsorily for at least 1 dose before surgery. Similarly, for living donors, presurgery vaccination of both the donor and recipient is ideal, but failure for the same does not predispose them to delayed surgery. In Indian settings, currently, antibody response measurements are only for research purposes, and the booster dose is not specific to the SOT population. The vaccine-induced thrombotic thrombocytopenia (VITT)-specific NOTTO guidelines¹⁰ for vaccination for India urged on having a multispecialty collaboration for decision making in accepting or discarding a VITT donor. The Indian Society of Organ Transplantation¹¹ has provided guidelines for transplant for living donors and potential recipients who are recovering from COVID-19. The introductory goal of the recommendations was to ensure a COVID-19-free safe pathway for transplant, without compromising the outcomes of the donor or recipient who is recovering or has recovered from COVID-19. The Liver Transplant Society of India (LTSI)¹² issued timely guidelines for safeguarding patients on waitlists and liver transplant recipients who are at high risk for mortality. They also published guidelines on emergent surgeries, minimally invasive strategies, hepatectomy, and isolation strategies. The LTSI also issued protocol guidelines for conducting pediatric liver transplant.¹³ The Indian Society of Heart and Lung Transplantation (ISHLT),¹⁴ which is the governing body for heart and lung transplant, has also published recommendations for patients and professionals involved in care in this area of transplantation. The key element of the ISHLT guidelines was normal highresolution computed tomography of the thorax before lung donation, which remained a prerequisite for the major part of the pandemic for SOT. The Indian Society of Organ Transplantation, the LTSI, and the ISHLT together formulated guidelines for continuing deceased organ donation during the COVID-19 pandemic.¹⁵ Discarding or accepting an organ has ethical, moral, medical, and psycho-social aspects. These guidelines have given a solid framework for the basis of decisionmaking in all of these complex judgments and served as a guiding tool for the initial management and approach to the pandemic for transplant centers across the nation. In brief, guidelines can only steer the path, but it becomes a pledging responsibility for the transplant programs¹⁶ to educate, support, and remain accessible to SOT groups of patients in pandemic times. The COVID-19 Working Group of Indian Society of Nephrology has reported guidance to improve safety during maintenance dialysis.¹⁷

Decline in Transplant Capacity and Volume During the Pandemic: An Unavoidable Situation

The overall COVID-19 burden was highest in the United States and India. In an analysis from the global observatory on organ donation and transplantation,¹⁸ transplant volume decreased in all regions of the world but more so in the developing than in the developed world. Developed nations like the United States were able to rebuild during the second wave after an initial drop in transplant volume during the first wave; this allowed their cumulative transplant numbers per year to remain less affected. However, nations like India suffered more, especially for less well-organized deceased donation programs.^19,20 Because deceased donation is in the preliminary stages in India and continuation of elective transplant surgery would shrink the medical capacity and intensive care unit beds, which could be utilized during the pandemic, the temporary ceasing of elective transplant surgeries was expected in Indian settings.²¹ The impact on liver transplant volume was described in a trinational study,²² which included South Indian liver transplant centers. The study showed a significant decline in volume that was influenced by logistics, local and national regulatory policies, COVID-19 transmission state, and health care capacity. A single-center study that involved the largest public sector transplant hospital in India²³ described the landscape of changing transplant volumes amid the pandemic during the first and second waves. In a multicenter study²⁴ (n = 18) on the cumulative impact on kidney donation and nephrology practices, public sector hospitals were reported to be more affected than private transplant hospitals. Most (70% to 90%) of transplant services are available in private sector hospitals in India. The study also reported no increase in allograft biopsies or non-COVID-19 admissions, which subtly showed no longterm impact of COVID-19 infection in the context of graft function. Pediatric liver transplant programs were shown to effectively continue in the absence of alternative medical therapies such as dialysis in patients with end-stage kidney disease, without many diversions of health care resources by using minimal medical capacity.²⁵ Although living donor liver transplant (LDLT) procedures were reduced, a study showed that the pattern of referred patients shifted to those who were sicker.²⁶ This shows that the logistics of a pandemic can be avoided by a better referral policy, as we make them stricter, with triaging of urgent procedures. In a South Indian report, health policy changes to minimize COVID-19 infection had a potential added benefit of reducing other infections, leading to better outcomes²⁷ This is important in developing nations like India, where infectious etiologies are responsible for mortality in posttransplant settings. This early report described that, after restructuring a COVID-19-free pathway, liver transplant outcomes were not affected by the pandemic per se. Another similar multicenter experience²⁸ echoed the findings in liver transplant practices. Patients with decompensated liver failure and those with high Model for End-Stage Liver Disease scores were more likely to have irreversible outcomes if transplant services remain at a standstill. The selective recognition and surgery of such patients were shown in a report,²⁹ which are the practiced recommendations from the LTSI. In a study from North India,³⁰ the incidence and outcomes of LDLT recipients and waitlisted patients were reported to be similar to the general population, and favorable outcomes of LDLT performed amid the pandemic were also reported. Another study from North India³¹ stressed the continuation of LDLT practices despite hurdles caused by the pandemic. An Indian report³² observed good outcomes of living donor kidney transplant (LDKT) conducted during the pandemic. A multicenter project³³ reported less mortality in an early period of transplant and higher mortality in waitlisted patients with COVID-19. These evidences support continuing transplant in the COVID-19 pandemic with all safety measures if health care capacity is not overwhelmed.

Outcomes of SARS-CoV-2 infection in Solid-Organ Transplant in India Versus Other Areas of the World

Mortality rates among COVID-19-positive kidney transplant recipients (KTRs) were lower in India (11.6%) compared with the developed world, especially during the first wave, and lower compared with maintenance hemodialysis patients (13% to 38%), but significantly higher compared with the nonimmunosuppressed general population (1% to 3%) in India.^34-36 The young age of SOT recipients might have contributed to less mortality in India compared with the developed world. The pandemic had affected all domains of health, as evidenced by a crosssectional study³⁷ of 109 liver transplant recipients in India. The outcomes of liver transplant recipients were favorable in an Indian study.³⁸ Outcomes of LDLT recipients with COVID-19 infection were reported in another North Indian study,³⁹ with outcomes in patients who had recent kidney transplant shown to be favorable in a case series from Western India.⁴⁰ This was one of the first few case series in world literature. A small case series of 9 KTRs from Eastern India⁴¹ reported recovery in 100% of patients who acquired COVID-19. In a single-center study⁴² from North India of 20 cases, a large mortality rate of 25% was reported. Other reports from North India of 67 KTRs with COVID-19 showed 27% mortality overall with 100% mortality in ventilated patients⁴³ and a mortality rate higher than the general population in 62 KTRs with COVID-19.⁴⁴ A multicenter Indian study⁴⁵ that compared COVID-19 KTRs versus nonimmunosuppressed patients during the first wave reported higher overall patient mortality rates (11.6%) in 250 KTRs than in nonimmunosuppressed patients (1%). This rate was less than that of the Western world during the first wave. A single-center study from a large Indian transplant center of 259 KTRs with COVID-19 demonstrated the changing clinical spectrum of COVID-19 with similar mortality between the 2 waves.⁴⁶ In a report of the second wave from a South Indian center, 20 KTRs had good outcomes.⁴⁷ A propensity-matched study⁴⁸ of 1627 COVID-19 cases in which 179 were KTRs reported no difference in mortality among SOT recipients versus the general population. This was the first Indian report that conducted a head-to-head comparison in Indian ethnicity. We reported for the first time in India the safety and feasibility of remdesivir⁴⁹ and convalescent plasma component therapy⁵⁰ for SOT patients with moderate to severe COVID-19. Because remdesivir was in the forefront as an anti-COVID-19 medicine, this work was an important one for widespread use of the drug, especially in India. Convalescent plasma component therapy was another potential anti-COVID-19 agent. Eventually, remdesivir and convalescent plasma component therapy⁵¹ showed no association with improved morbidity or mortality. Cytomegalovirus coinfection⁵² with COVID-19 was found to increase morbidity and mortality, showing the need for a holistic approach in the management of SOT. Rare coinfections in a liver transplant recipient with pulmonary aspergillosis, tuberculosis, and hemophagocytic lymphohistiocytosis was also reported.⁵³ We reported the successful use of telemedicine for management of KTRs and donors in a single center.⁵⁴ The use of telemedicine during the COVID-19 national lockdown and travel restrictions was useful in limiting the virus spread and in speeding the delivery of life-saving drugs such as immunosuppressives and could be a useful approach for future pandemics.⁵⁵ Another report showed that use of telemedicine among pediatric nephrologists⁵⁶ effectively managed care during the pandemic. Data on pediatric SOTs from India remain scarce. In an Indian report⁵⁷ of 7 pediatric SOT recipients with COVID-19, mortality was 10%. Another report⁵⁸ showed complete recovery of a pediatric KTRs with COVID-19. In a pediatric liver transplant recipient,⁵⁹ COVID-19 presented as hypoxia of unknown origin in the immediate transplant period.

Long-Term Status of COVID-19 in Solid-Organ Transplant Recipients

Long-term health issues of COVID-19 are an emerging issue in the world. There are limited reports on post- COVID-19 long-term follow-up in SOT recipients. A single-center report recorded favorable graft survival in KTRs with BK polyomavirus virus coinfections.⁶⁰ The same center⁶¹ reported 1-year follow-up outcomes in KTRs with COVID-19, showing good clinical and psychosocial recovery results. A single-center report from Eastern India reported favorable follow-up of COVID-19 in KTRs. A subsequent report⁶² from a center in Western India, however, reported remarkable numbers of unrecovered or incompletely recovered acute kidney injuries in post-COVID-19 KTRs. In a follow-up study⁶³ from Eastern India, similar results in 104 KTRs with COVID-19 were reported, with those with severe COVID-19 having high rates of residual abnormality, allograft dysfunction, and death. A study from Western India⁶⁴ first reported the antibody dynamics following COVID-19 infection in KTRs with Indian ethnicity. In a first study of reinfection of COVID-19 among SOT recipients in India,⁶⁵ reinfection resulted in mortality. A multicenter study⁶⁶ reported that reoccurring SARS-CoV-2 infections resulted in 46% mortality, which was 4 times higher than the mortality rate during the first wave of the COVID-19 pandemic in SOT recipients (11%). Although our limited resources did not allow for molecular diagnostics and typing, there was an anecdotal report⁶⁷ of graft artery thrombosis in a KTR. Briefly, the COVID-19 long-term sequelae have been seen as a rare entity in SOT recipients, and transplant professionals have not postulated as much with these occurrences during the first wave versus during the second and third waves because of knowledge obtained from the first wave.

Evidence to Support Transplant With Donors With History of or With Ongoing COVID-19 Infection

Because living donation practices have been the mainstay of SOT in India, it was imperative to conclude the definitive evidence for safety of living donors who donated after recovery from COVID-19. In a multicenter study⁶⁸ of a large cohort of LDKT recipients who had COVID-19- recovered donors (n = 31), although the follow-up was relatively short, an absence of any occult complications and 100% patient and graft survival showed the safety of such transplants. In a case report from India⁶⁹ of a deceased donor with COVID-19 who died after terminal lung damage from COVID-19, lung transplant was avoided but kidney transplant was performed. The successful outcomes with both kidneys were encouraging, showing that donors who have recently died from COVID-19 can be potential deceased donors with careful selection. A multicenter report from South India⁷⁰ documented 9 living donor hepatectomies after COVID-19 illness, and a comprehensive review⁷¹ identified 25 such reports, showing that SOT performed in COVID-19-recovered donors was safe. Interestingly, some donors showed positivity in their real-time polymerase chain reaction tests at the time of donation; however, outcomes were not inferior. The shortterm follow-up of living donors after donation was mostly uneventful. Still, further long-term data on such donations are needed.

Complications of Recipients With COVID-19 After Transplant: Answering the Puzzle With Precision

An anecdotal study⁷² reported recurrent hepatic thrombosis after liver transplant in a patient with mild COVID-19 infection, raising concerns about the risks with a postulated hypercoagulability state after COVID-19 infections. A small bowel transplant following gangrene after COVID-19 in a child was first reported from India.⁷³ An initial report of successful LDKT from India marked the safety of LDKT following COVID-19 illness.⁷⁴ A South Indian center⁷⁵ reported the first case of liver transplant after COVID-19 illness. A liver transplant⁷⁶ was performed successfully in which the candidate recently recovered from COVID-19, breaking the threshold of a minimum 28-day asymptomatic period before surgery. To investigate the ideal strategy, we conducted a nationwide report⁷⁷ in which data from 75 KTRs who underwent LDKT were analyzed. The encouraging report showed 100% patient and graft survival. Prerequisites reported involved an asymptomatic period of at least 28 days, social distancing between donor and recipient for 14 days, no residual radiological abnormality, and at least 2 negative polymerase chain reaction SARS-CoV-2 tests. Because of shorter follow-up and a smaller number of severe COVID-19 cases, we confirmed the conclusions and safety of the report with another nationwide collaboration. A study of 372 COVID-19-recovered transplant candidates and the largest cohort of post-COVID-19 kidney donors who underwent LDKT,⁷⁸ with the largest median followup time of 241 days, reported on the safety of high-risk kidney transplant, where both the donor and recipient had COVID-19 history or were ABO-incompatible or sensitized. An important observation was no tailoring of induction or maintenance immunosuppression irrespective of the time gap from infection to transplant or severity of COVID-19 infection. Other data on excellent outcomes of liver transplant in COVID-19-recovered patients have been reported from India.⁷⁹ A recent South Indian study reported acceptable outcomes in 51 living donor liver transplant recipients who had recovered from COVID-19.⁷⁹ Another study reported favorable outcomes in the largest cohort of deceased donor liver transplant of COVID-19-recovered candidates.⁸⁰ A recent review⁸¹ concluded that patient and graft survival rates in COVID-19-recovered or even positive patients who underwent SOT were acceptable. Clinical symptoms at the time of surgery, cycle threshold value, radiological abnormalities, time from a positive to negative COVID-19 test, and the immune response of the recipient at the time of infection are parameters that decide the appropriate timing of transplant. Lung transplant as a rescue after COVID-19 pulmonary sequelae remains an important issue. One such report was published by an Indian center⁸²; in multinational data,⁸³ with contributions from a South Indian center, early excellent outcomes of lung transplant following pulmonary sequelae were reported. A daunting question in this scenario was the optimal timing at which the decision to proceed with lung transplant. This report was streamlined by the protocol and timing, which guided many transplant centers across the world. In a recent report⁸⁴ of a large cohort of lung transplant recipients following COVID-19, there was 100% patient survival.

COVID-19-Associated Mucormycosis in Solid-Organ Transplant: A Double Whammy Amid the Pandemic

During the second wave of the pandemic in India, the emergence of COVID-19-associated mucormycosis (CAM) broke the backbone of medical services, and India became the hub of CAM, as the bulk of the reports came from India. The definition, risk factors, diagnosis, and treatment were initially skeptical, but a consensus was soon formed.⁸⁵ From a historical point of view, patients with SOT remain at high risk of fungal infections, and CAM was also a threat to SOT. One of the first such reports in the world literature was from India.⁸⁶ Another report⁸⁷ of disseminated CAM in KTR, which ended in mortality, was also published. In a large single-center case series of 11 cases of CAM in 157 KTRs with COVID-19, 27% mortality was reported,⁸⁸ with diabetes, high neutrophil-to-lymphocyte ratio, and lymphopenia being risk factors for acquiring CAM. A study from a North Indian transplant center⁸⁹ reported similar mortality with a similar phenotype. In a multicenter study (n = 18),⁹⁰ representing the largest cohort of CAM in KTRs, the incidence was 4.4% (61 of 1382 COVID-19 KTRs) and the mortality rate was 26.2%, with obesity and high-flow oxygen requirement being risk factors for mortality. Mortality is high in pulmonary mucormycosis when compared with other infections. This shows the added damage done by COVID-19 pneumonia, as well as issues with late diagnosis and the difficulty in implementation of multidisciplinary management during the pandemic. An isolated case of allograft mucormycosis in a KTR who succumbed to death was also reported.⁹¹ Allograft CAM with bacterial pyelonephritis (E. coli) resulted in death in another KTR,⁹² and CAM with mycotic aneurysm was reported in a separate KTR.⁹³ The emergence of opportunistic infections should be suspected, and timely management should be implemented during pandemics. Uncontrolled diabetes, overuse of steroids, iron therapy, broad-spectrum antibiotics, zinc in multivitamins, and reuse of masks were possible contributing factors for mucormycosis epidemics within the COVID-19 pandemic during the second wave in India.⁹⁴

Indian Ethnicity Data for COVID-19 Vaccination in Solid-Organ Transplant

The first case series⁹⁵ of breakthrough COVID-19 infections following the COVISHEILD vaccine in SOT recipients was reported from India. Breakthrough infections among patients on the waitlist with the Oxford vaccine were also reported first by an Indian center.⁹⁶ Breakthrough infections were also reported among patients on the waitlist and liver transplant recipients from India.⁹⁷ These reports all underscored the need for continued COVID-19 vigilance even after vaccination in these highrisk patients, especially in high transmission states. Few data are available on vaccine immunogenicity in SOT. In a North Indian study,⁹⁸ COVISHIELD and COVAXIN together were studied in KTRs, and it was reported that, although the humoral response was developed in patients, the magnitude of response was lesser than the seroresponse following COVID-19 infection. In a meta-analysis of 112 studies, the humoral response rate after the primary series of vaccinations was recorded as 40%. Currently, a booster dose is in practice, and the Western world has moved up to the fourth or fifth dose. However, in Indian centers, booster dosing in SOT is not mandatory, and these practices are for research purposes. The presence of VITT was a relatively newer entity in the pandemic, which was mostly associated with the Oxford vaccine, and a report on organs from VITT donors was published recently.⁹⁹ There are numerous ethical aspects of vaccination,¹⁰⁰ which extend from vaccination of health care workers to family members of transplant candidates. In an international survey,¹⁰¹ which reported the real-world practices on organ donation, most nations are less keen to accept organs from unvaccinated donors and also from donors with COVID-19 infection who are asymptomatic. Most transplant centers are in favor of vaccinating candidates before they receive an organ but do not withhold from the list if not vaccinated. This is true in India, where there is no withdrawal from the waitlist if the candidate is not vaccinated. Research investigations on COVID-19 vaccines are still needed.¹⁰²

There is a global spectrum of outcomes of SOT and COVID-19, with lesser mortality due to younger age of SOT recipients or higher risk when there are opportunistic or secondary infections. The higher mortality rate in SOT recipients who require ventilation shows the important need for precision medicine, the need for higher advanced medical facilities, and the need for improved care in many regions of India. Our report suggested that transplant from carefully selected COVID-19-recovered donors and patients may be feasible and safe, at least in the short-term follow-up. However, data on vaccines are sparse and still accumulating, with further research needed. Continued research is needed on vaccine efficacy, booster doses, and long term follow-up sequelae.

Volume: 20 Issue: 8 August 2022 - Supplement - 4

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