key: cord-254464-6l7fwylu
authors: Shingare, Ashay; Bahadur, Madan M.; Raina, Shailesh
title: COVID‐19 in recent kidney transplant recipients
date: 2020-06-08
journal: Am J Transplant
DOI: 10.1111/ajt.16120
sha: 
doc_id: 254464
cord_uid: 6l7fwylu

As coronavirus disease 2019 (COVID‐19) pandemic spread across the globe, transplant programs suffered a setback. We report the first experience of COVID‐19 infection within 1 month of living donor kidney transplant (LDKT). We describe 2 LDKT recipients who were detected positive for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection at day 19 and day 7 post‐transplant. They had minimal symptoms at diagnosis and did not develop any respiratory complications or allograft dysfunction. Immunosuppression was de‐escalated; however, nasopharyngeal swab real‐time reverse transcription polymerase chain reaction (rRT‐PCR) remained positive for SARS‐CoV‐2 for a prolonged time. Younger age, absence of other comorbidities and lower dose of anti‐thymocyte globulin (ATG) used as induction possibly contributed to good outcome in our recent LDKT recipients compared with earlier published cases of recent deceased donor kidney transplant recipients with COVID‐19.

Worldwide 

Sooner or later we would need to restart transplant programs, both LDKT & deceased donor kidney transplant (DDKT), as dust settles on the acute era to a post-COVID-19 new normal, where severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection will be a possibility. Nationwide lockdown was announced in India on March 24, 2020. As of May 23, 2020 

At Jaslok Hospital and Research Centre, Mumbai, India, 7 kidney transplants were performed from March 01 to March 25, 2020. Of these, 5 were LDKT and 2 were DDKT. Last transplant was performed on March 25, 2020, almost 2 weeks after the first reported case of COVID-19 in the state. Following this, transplant activity was suspended and patients already on dialysis were continued on same modality, whereas patients awaiting preemptive LDKT were managed conservatively. During the further follow-up over next 2 months, 2 of these 7 patients tested positive for SARS-CoV-2 by nasopharyngeal swab real-time reverse transcription polymerase chain reaction (rRT-PCR), 3 tested negative and 2 were not tested as they were asymptomatic.

First patient was a 35 years old man who underwent LDKT on March 20, 2020 with ABO compatible spousal donor. His previous medical history included chronic kidney disease of unknown etiology and hypertension for past 2 years. He had been on hemodialysis since 12 months. Triple immunosuppression consisting of prednisolone, tacrolimus and mycophenolate mofetil was started 2 days prior to the transplant and 1 mg/kg of induction agent anti-thymocyte globulin (ATG) was given on the day of surgery. His serum creatinine reached a nadir of 1 mg/dL by day 3 and he was discharged on day 10 post-transplant.

He developed dry cough on day 19 post-transplant; however, he was afebrile with no shortness of breath. On evaluation, oxygen saturation was 99% in ambient air, blood pressure 134/80 mmHg and respiratory rate 20 breaths per minute. Nasopharyngeal swab rRT-PCR was ordered in view of his symptoms and it was positive for SARS-CoV-2. He was readmitted to the hospital as prevalent local government protocol required hospital Accepted Article based isolation of COVID-19 positive cases. There were no abnormalities on chest X-ray. Laboratory evaluation revealed total leucocyte count 5.1 x 10 9 /L, absolute lymphocyte count 0.4 x 10 9 /L, C-reactive protein 10.8 mg/L, procalcitonin < 0.05 ng/mL and no growth on blood culture.

He was started on hydroxychloroquine and azithromycin as per prevalent institutional protocol.

Immunosuppression dose reduction included rapid tapering of prednisolone to 15 mg/day and tacrolimus dose adjustment to maintain trough level 4-6 ng/mL. Mycophenolate mofetil was stopped in view of lymphopenia. Prophylactic valganciclovir 450 mg/day was continued but cotrimoxazole 80/400 mg was reduced to alternate days. He remained afebrile throughout the course. After change in local government protocol allowing for home isolation of COVID-19 positive cases, he was discharged after 28 days from admission. His serum creatinine at discharge was 1.05 mg/dL and nasopharyngeal swab rRT-PCR was still positive for SARS-CoV-2.

Second patient was a 45 years old man with hepatitis B and chronic kidney disease due to At diagnosis, chest X-ray revealed no abnormalities and total leucocyte count was 10.9 x 10 9 /L with absolute lymphocyte count 0.9 x 10 9 /L. Serum procalcitonin was 0.06 ng/mL and blood culture was negative. He was shifted to the COVID-19 ward and was started on hydroxychloroquine and azithromycin. Mycophenolate mofetil was reduced to 250 mg/day; prophylactic valganciclovir 450 mg/day was continued and cotrimoxazole 80/400 mg was reduced to alternate days. He too underwent rapid tapering of prednisolone dose to 15 mg/day and tacrolimus dose adjustment to maintain trough level 4-6 ng/mL. His nasopharyngeal swab rRT-PCR turned negative after 48 days from exposure and subsequently he was discharged after 52 days form admission. His serum creatinine at discharge was 0.9 mg/dL.

This article is protected by copyright. All rights reserved Intensive care unit (ICU) monitoring and supplemental oxygen were not required, and kidney allograft function remained stable throughout the course of COVID-19 in both recipients. They had lymphopenia which could however be attributed to recent use of ATG. No anticoagulation was given to either patient and there were no episodes of thrombosis.

At the time of these transplants, epidemiological screening and clinical screening was done for all the donors and recipients. However, prevalent local government protocol only allowed laboratory testing of symptomatic individuals, close contacts of laboratory-confirmed positive cases of COVID-19 and those with history of international travel. Hence, protocol based pretransplant laboratory testing for SARS-CoV-2 was not done. All patients were educated about hand hygiene and coughing etiquette, and were provided with a face mask.

Pretransplant hemodialysis was done in the dialysis unit with contact and droplet precautions, environmental disinfection, spatial separation of beds, no attendant policy and informed consent. Post-transplant, these patients were isolated in kidney transplant unit which is separate from the intensive care unit.

Both patients on contact tracing could be attributed to pretransplant close contact with a hemodialysis patient in nonisolation ward, who later tested positive for SARS-CoV-2. Figure 1 illustrates probable moments of exposure and diagnosis of SARS-CoV-2 with nasopharyngeal swab rRT-PCR in these patients. First patient was asymptomatic during his post-transplant stay in the kidney transplant unit and was not tested prior to discharge. When he developed minimal symptoms after discharge, he was tested as number of testing facilities had increased by then. It is possible that he had presumed exposure during his pretransplant inpatient stay similar to the second patient, but remained asymptomatic and hence was not diagnosed earlier. Considering the 2-14 days incubation period of COVID-19 6 , exposure after discharge also remains an alternative possibility.

Due to intensive immunosuppression, recent transplant recipients (< 3 months post-transplant) are at increased risk of developing severe disease due to COVID-19. They are also likely to have superadded or coinfections due to other pathogens during this early post-transplant phase. In our observation, viral rRT-PCR positivity for SARS-CoV-2 can persist for long duration in transplant recipients which may impact their duration of stay indoors or in isolation centres. In an earlier report in a non-transplant setting, longest viral Accepted Article shedding was observed for 37 days. 7 In our second patient, nasopharyngeal swab rRT-PCR turned negative after 48 days from exposure.

We describe the clinical course of first reported COVID-19 cases in recent LDKT. Published studies have reported 5 cases of COVID-19 in recent DDKT. A report from New York describes poor outcome in 2 recent DDKT recipients (2/2 deaths). 8 In another report from London, 1 recent DDKT recipient required ventilator support and continuous renal replacement therapy, whereas other required brief ICU stay. 9 One recent DDKT recipient in a report from China was discharged at day 31 and did not require ICU stay. 10 Differences in COVID-19 mortality and complications between our experience with LDKT and above reports could possibly be due to higher dose of ATG used during immediate post-transplant period in DDKT where there are more chances of delayed graft function. Severe lymphopenia has been described in nonsurvivors of COVID-19. 7, 11 Preexisting lymphocyte depletion due to recent use of ATG may possibly contribute to severity of illness in transplant recipients who develop SARS-CoV-2 infection. Use of nonlymphocyte depleting agent basiliximab, or in case of living-related donor transplant with low immunological risk, no induction could be alternative strategies. Favorable outcome in our patients could also be attributed to younger age and absence of other comorbidities.

Worldwide mortality due to COVID-19 is variable. As of May 23, 2020, COVID-19 mortality per 100,000 population has been lower in China (0.33) and India (0.28) than European countries (Spain 61.27, Italy 53.97

and United Kingdom 54.86) and United States (29.34). 3 Mortality differences could be attributed to genetic variation and hence differential immune response in these populations. These differences could also be due to different strains of SARS-CoV-2 prevailing in these geographical locations. 12 Viral strains isolated from Indian patients have shown 99.97% homology to the original strains isolated form Wuhan, China. 13 Other plausible explanations for these mortality differences include age distribution of the population, prevalence of comorbidities, access to testing, overloading of health care system and lockdown strategies.

Our recent LDKT recipients had minimal symptoms and no allograft dysfunction after developing COVID-19.

Mortality and complications in recent transplant recipients with COVID-19 may be low in Asian populations, but more data is required to say so. In the new normal post-COVID-19 era, as transplant centres look forward to restart their program, our experience may be helpful. Transplant programs will require screening and laboratory testing of prospective donors and recipients to rule out COVID-19 and a pretransplant in-centre or

Early impact of COVID-19 on transplant center practices and policies in the United States

Kidney transplantation and the lock-down effect

Municipal Corporation of Greater Mumbai. COVID-19 daily update

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Covid-19 and Kidney Transplantation

COVID-19 infection in kidney transplant recipients

Identification of Kidney Transplant Recipients with Coronavirus Disease