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ARTICLE
A Multicenter Cohort Study of Indian Centers on Reoccurring SARS-CoV-2 Infections in Kidney Transplant Recipients

Abstract

Objectives: There is scarcity of data on reoccurrence of SARS-CoV-2 infections in kidney transplant recipients.
Materials and Methods: We conducted a retrospective multicenter cohort study and identified 13 kidney transplant recipients (10 living and 3 deceased donors) with recurrent COVID-19, and here we report demographics, immunosuppression regimens, clinical profiles, treatments, and outcomes.
Results: COVID-19 second infection rate was 0.9% (13/1350) in kidney transplant recipients with a median age of 46 years; median time interval from transplant to first episode of COVID-19 diagnosis was 9.2 months (interquartile range, 2.2-46.5 months). The most common comorbidities were hypertension (84%) and diabetes (23%). Fever was significantly less common with recurrent COVID-19. COVID-19 severity ranged from asymptomatic (23%), mild (31%), and moderate (46%) during the first infection and asymptomatic (8%), mild (46%), and severe (46%) in the second infection. All 6 kidney transplant recipients with severe second infections died. The median interval between the 2 episodes based upon reverse transcriptase polymerase chain reaction COVID-19-positive tests was 135 days (interquartile range, 71-274 days) without symptoms. Statistically signi­ficant risk factors for mortality were dyspnea (P = .04), disease severity (P = .004), allograft dysfunction (P < .05), higher levels of neutrophil-to-lymphocyte ratio (P = .05), and intensive care unit/ventilator requirement (P = .004). Although our limited resources did not allow for molecular diagnostics and typing, we suggest that these second episodes were reinfections with SARS-CoV-2.
Conclusions: To our knowledge, this is the largest study of kidney transplant recipients with reoccurring SARS-CoV-2 infection, and we observed 46% mortality.


Key words : COVID-19, Immunosuppression, Infectious agents, Living kidney donor, Viral reinfection

Introduction

India is being ravaged by a second wave of the COVID-19 pandemic. India overtook Brazil as the country with the second highest number of recorded cases of COVID-19 after the United States. The health infrastructure in-country has collapsed, with acute shortages of hospital beds and oxygen supply.1 We recognize that many decisions are made based on the practical limitations that transplant programs face in settings of scarce resources, such as the highest daily COVID-19 cases in the world amid an oxygen shortage and health care shortage in India.2,3

The first cases of SARS-CoV-2 reinfection were confirmed by whole genome sequencing in the general population and in a liver transplant recipient by To and colleagues4 and Tomkins-Tinch and colleagues,5 respectively. Ye and colleagues reported a reactivation rate of 9% in adults with SARS-CoV-2 infection.6 Reactivation and reinfection of previously recovered COVID-19 patients may rarely occur but can result in devastating complications for transplant outcomes.5,7-11 Reinfections in patients recovered from COVID-19 could create a serious challenge in tackling the COVID-19 pandemic because these patients could be a source of virus spread in the community.10,12-18 In organ transplant recipients, risk of SARS-CoV-2 reactivation may be related to immunosuppression, age, sex, and underlying comorbidities, including diabetes, heart disease, obesity, cancer, and virologic factors. Immuno­compromised transplant recipients may be at higher risk for reactivation and reinfections with SARS-CoV-2. The degree of protective immunity conferred by infection with SARS-CoV-2 is currently unknown.

Reoccurring SARS-CoV-2 infections in transplant recipients are not well understood. To date, few reports of reoccurring COVID-19 infection in the posttransplant setting have been published.5,6,8-10 Reoccurring SARS-CoV-2 infections raise several unanswered questions. Can SARS-CoV-2 infection have a second episode in kidney transplant recipients (KTR) who had previously recovered from COVID-19? Is the mortality in immunosuppressed patients higher in the second episode of COVID-19? Clearly, there is a need to evaluate the clinical significance of reoccurring COVID-19 in KTR. Here, we have addressed these questions and have reported information gathered through a multicenter cohort study from India of reoccurring SARS-CoV-2 infections in 13 KTR.

Materials and Methods

We conducted a retrospective observational cohort study of 8 Indian transplant centers and identified 13 KTR (10 living and 3 deceased donor) with real-time reverse transcription polymerase chain reaction (RT-PCR)-confirmed reoccurring SARS-CoV-2 infections from April 2020 to May 2021. Ethical approval for this study was obtained from the Ethics Committee of Institute of Kidney Diseases and Research Center, Dr. H. L. Trivedi Institute of Transplantation Sciences. All transplants were performed according to local laws and regulations (Transplantation of Human Organs and Tissues Act, India) and the Declaration of Helsinki and Declaration of Istanbul. We recorded details of demographics, immunosuppression regimens, clinical profiles, treatments, and outcomes.

Definition of second episode of COVID-19
The diagnosis of COVID-19 was confirmed by SARS-CoV-2-positive RT-PCR from nasopharyngeal (nasal) and oropharyngeal (throat) swabs in the first and second infections. The COVID-19 severity was graded according to Government of India criteria as asymptomatic or mild, moderate, or severe disease.19 None of the patients was symptomatic at the time of discharge subsequent to the primary COVID-19 infection. Two successive SARS-CoV-2 RT-PCR tests >48 hours apart were negative before the second episode parallel with clinical convalescence. The methodology of swab collection was properly performed, hence excluding chances of false-negative results due to sampling errors.

Immunosuppression regimen for kidney transplant recipients with COVID-19
The mainstay of treatment consisted of reduction of immunosuppression therapy based on disease severity and a case-by-case evaluation. In patients who were asymptomatic or had mild disease, mycophenolate/azathioprine doses were reduced/­stopped and no change was made in steroids and calcineurin inhibitors. For patients with moderate or severe disease, mycophenolate/azathioprine were discontinued and calcineurin inhibitors were reduced or discontinued and steroids were increased. We have previously reported our treatment details.20,21

Institutional protocol for transplant surgery and COVID-19 treatment
COVID-19-specific treatment algorithms were created by a hospital-based multidisciplinary team, and treatment protocols were updated regularly with available evidence and resources. Patients in the intensive care unit (ICU) were managed by the same transplant teams, infectious disease consultants, and intensivists. However, there was no standard consensus on the treatment of COVID-19; therefore, treatments were applied according to guidelines for COVID-19 established by the National Organ and Tissue Transplant Organization (NOTTO), Government of India.20 The investigational therapies used for patients who were in this study included favipiravir (in mild and moderate cases), remdesivir, COVID-19 convalescent plasma, tocilizumab, and intravenous immunoglobin (in moderate to severe cases).

We prepared donors and recipients for transplant surgery according to transplant-specific guidelines from NOTTO.20 All transplant recipients and donors provided fully documented written informed consent. We ensured adequate availability of personal protective equipment and ensured that health care workers were properly trained regarding COVID-19 and “COVID free safe transplant pathways” (per NOTTO) to reduce the risk of transmission. We performed routine clinical and epidemiological screening for COVID-19 in donors, recipients, health care workers, and caretakers; routine laboratory screening with COVID-19 RT-PCR tests on nasopharyngeal and oropharyngeal swabs and chest computed tomography scans or chest radiography were performed 24 to 72 hours before surgery, for all living and deceased donors. We ensured social distancing and COVID-19 preventive measures before surgery for living donors, recipients, and health care workers. We used induction and other immunosuppressive drugs based on each recipient’s immune risk stratification as practiced before COVID-19.

Statistical analyses
Statistical analyses were performed with the SPSS software (version 17.0). Continuous data are presented as median values and interquartile ranges (IQR); t tests were used to compare 2 groups. Categorical data were compared with the chi-square test or the Fisher exact test. P < .05 was accepted as statistically significant.

Results

Study population
The second infections of 13 KTR with COVID-19 were included from (1) the Muljibhai Patel Urological Hospital, Nadiad (n = 3); (2) the Institute of Kidney Diseases and Research Center and Dr. H. L. Trivedi Institute of Transplantation Sciences, Ahmedabad (n = 2); (3) the Postgraduate Institute of Medical Education and Research, Chandigarh (n = 2); (4) the Rabindranath Tagore International Institute of Cardiac Sciences, Kolkata (n = 2); (5) the Jaslok Hospital and Research Centre, Mumbai (n = 1); (6) the Indraprastha Apollo Hospitals, New Delhi (n = 1); (7) the Primus Hospital, New Delhi (n = 1); and (8) the King Edward Memorial Hospital, Mumbai (n = 1).

Demographics
We identified 13 KTR (10 living related donors and 3 deceased donors) with second COVID-19 infections in our analysis. The second infection rate was 0.9% (13/1350 KTR with first episode of COVID-19) in our study. Eleven patients had both (first and second) COVID-19 episodes after transplant; 2 KTR had their first COVID-19 episode before transplant while on dialysis and a second episode after transplant. The overall median age of our cohort was 46 years (IQR, 28-50 years); most of the patients were men (62%, n = 8). None of the recipients was obese, and all underwent ABO-compatible transplants without desensitization. We divided patients into subgroups by age, including 21 to 30 years (4 patients), 31 to 40 years (2 patients), 41 to 50 years (4 patients), 51 to 60 years (2 patients), and 61 to 70 years (1 patient). Patients had a median time interval from transplant to first episode of COVID-19 diagnosis of 9.2 months (IQR, 2.2-46 months). In detail, the time after transplant surgery was <12 months in 8 patients (62%), from 1 to 5 years after transplant in 3 patients (23%), and more than 5 years after transplant in 2 patients (15%). None of the KTR had received COVID-19 vaccination before or after transplant.

For living donors, recipients were close relatives (mother, 38.5%; sister, 15.4%; wife, 15.4%; husband, 7.7%); 23% of recipients had a graft from a deceased donor. Median human leukocyte antigen matching (HLA A, B, and DR) was 1.5 (IQR, 0-3). All donors who donated kidneys after March 2020 had a SARS-CoV-2-negative RT-PCR test at time of surgery. Baseline demographics, clinical symptoms, and laboratory results of COVID-19 second infections in KTR are summarized in Table 1. Clinical symptoms and laboratory results during first and second COVID-19 infections are summarized in Table 2.

Comorbidities
Comorbidities were present in 11 patients (84.6%) and included arterial hypertension (84.6%; n = 11), diabetes (23%; n = 3), allograft dysfunction (84.6%; n = 11 episodes), hypothyroid (15.4%; n = 2), heart disease (15.4%; n = 2), hepatitis C virus (7.7%, n = 1), and retransplant (15.4%; n = 2). Multiple comorbidities were present in 8 patients (61.5%), with hypertension and diabetes being the most common. Two patients (15.3%) were on an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker at the time of COVID-19 diagnosis, and 8 patients (61.5%) had received pneumococcal vaccine before transplant. No KTR had received COVID-19 vaccine before the first or second COVID-19 infection.

Immunosuppression regimens
Induction regimen consisted of antithymocyte globulin (median dose of 3 mg/kg; IQR, 1.5-3 mg/kg; Sanofi-Aventis) for 8 patients (61.5%), basiliximab (Simulect, Novartis) for 1 patient (7.7%), and Grafalon (6 mg/kg rabbit anti-human T-lymphocyte globulin [previously marketed as ATG-Fresenius], Neovii) for 1 patient (7.7%); 3 patients (23%) did not receive an induction treatment. The most common maintenance immunosuppression regimen included a triple regimen consisting of prednisolone, tacrolimus, and mycophenolate. Forty-six percent of patients (n = 6) had a history of rejection treatments, including steroid pulse (n = 6), antithymocyte globulin (n = 3), and rituximab (n = 1).

Clinical presentation
Table 2 shows clinical symptoms and laboratory parameters for the first and second COVID-19 episodes. The most common symptoms included fever (84%), cough (69%), and dyspnea (38%) during the first episode of COVID-19. Fever was significantly less common with the second episode of COVID-19 (84% vs 30% in the first vs second episode; P = .01). Clinical severity during the first episode of COVID-19 ranged from asymptomatic in 3 patients (23%), mild in 4 patients (31%), and moderate in 6 patients (46%); during the second episode, 1 patient was asymptomatic (8%), 6 patients had mild COVID-19 symptoms (46%), and 6 patients had severe symptoms (46%).

Outcomes
The median cycle threshold (Ct) value for the SARS-CoV-2 RT-PCR tests was 24 (IQR, 24-25) in the first episode and 24 (IQR, 20-27) in the second episode. The median time interval between the first episode and the second episode based on COVID-19-positive RT-PCR tests was 135 days (IQR, 71-274 days) without symptoms. The median time interval from RT-PCR-confirmed COVID-19-positive results to negative results for surviving patients during the first episode was 20 days (IQR, 15-25 days) and for the second episode was 9 days (IQR, 8-13.5 days). There were 7 patients (54%) who survived, but 6 patients (46%) with severe disease died. One patient lost his graft function, and 1 patient died while on dialysis for acute kidney injury. Median time from RT-PCR-confirmed COVID-19-positive test results to death was 10 days (IQR, 8-21 days). The median follow-up duration was 64 days (IQR, 47-133 days) with reoccurring COVID-19 infection in KTR who survived. Overall patient mortality was 46% (6/13) but was 100% (6/6) for patients who required ICU treatment and mechanical ventilation. In 6 KTR with asymptomatic, mild, or moderate symptoms during the first COVID-19 episode, disease severity advanced to death during reinfection. In 7 of the 13 KTR, the second COVID-19 infection was severe. Statistically significant risk factors for mortality in the second episode were dyspnea (P = .04), disease severity (P = .004), allograft dysfunction (P < .015), higher levels of neutrophil-to-lymphocyte ratio (P = .05), and ICU/ventilator requirement (P = .004).

Discussion

We present 13 KTR with 2 distinct episodes of SARS-CoV-2 infections, separated by a median of 135 days (IQR, 71-274 days) of clinical quiescence and 2 negative RT-PCR test results for SARS-CoV-2 infection between the first and the second episodes. Our results showed that the second episode of COVID-19 was more severe. Our careful clinical assessment indicated a second, new COVID-19 infection. The published literature suggests that reactivation of an RNA virus as a consequence of immunosuppression is unlikely. Therefore, such a case is most likely a reinfection, but unfortunately our resources were restricted and we were unable to apply molecular testing and typing; we were also not able to provide binding antibodies to mitigate convalescence. Hence, alternative scenarios may explain the outcomes, such as (1) a false-positive initial SARS-CoV-2 RT-PCR test, (2) a false-negative RT-PCR result at discharge subsequent to the primary infection, (3) intermittent/prolonged viral shedding, known to occur among chronic hemodialysis and transplant patients, (4) nosocomial transmission of infection, (5) false-positive RT-PCR retests, and (6) reactivation/reinfection. Most of our KTR in the first COVID-19 episode were symptomatic (77%), and RT-PCR tests with low Ct values were consistent with active primary infection, which ruled out the possibility of an initial false-positive test. Two negative nasopharyngeal RT-PCR results before the second COVID-19 infection with clinical convalescence ruled out the possibility of a previous false-negative RT-PCR result at discharge. Moreover, we observed increased disease severity and higher mortality during the second episode; therefore, the possibility of prolonged viral shedding was unlikely.

Notably, reoccurring COVID-19 infections in KTR demonstrated an increased disease severity with an augmented oxygen requirement. A history of COVID-19 exposure, increased inflammatory markers, abnormal chest imaging, and the subsequent low-Ct RT-PCR tests were all consistent with active infection; therefore, residual effects from the first infection were unlikely. In this scenario, a false-positive RT-PCR test result for SARS-CoV-2 during the reoccurring episode is unlikely. Positive follow-up RT-PCR test results may derive from remnant virus material transferred from the lower respiratory tract to the throat and nose with coughing. In COVID-19-positive RT-PCR retests, before reinfection/reactivation is suggested, it is necessary to consider (1) the possibility of prolonged viral shedding during the convalescence period, (2) the methods of specimen collection, and (3) possible sampling/technical errors associated with each component of the swab testing procedure, including details related to potential operator technical error, the method for discharging patients, and possibility of infection by other variants of SARS-CoV-2. Thus, with a careful clinical assessment, characteristic symptoms, a RT-PCR-confirmed COVID-19-positive test after a long period of clinical remission, and 2 negative tests of nasopharyngeal swabs in 13 KTR cases, it is reasonable to conclude that the second episode is the result of a SARS-CoV-2 reinfection that is different from the original infection.

The median duration of the first episode after kidney transplant was 9.2 months, which suggested that KTR patients were vulnerable in the early period after transplant. On the other hand, the KTR patients with COVID-19 second infections who were not admitted to a transplant center may be overlooked because such patients are more often admitted to transplant centers in the early period after transplant rather than at later periods.

Notably, second episodes of COVID-19 occurred in 8 patients (62%) during the first year of transplant. Thus, a higher immunosuppressive load including lymphocyte-depleting and antibody-depleting therapy during the first year after transplant may be associated with a higher risk of a second COVID-19 episode. Certainly, more detailed studies are required to document whether COVID-19 reoccurrence is associated with certain immunosuppression doses. Whether we should use immunosuppression with lower doses after COVID-19 recovery and shorter duration of the immunosuppression regimen remains an open question. With the exception of fever, no other clinical symptom distinguished the first episode from a second episode. The absence of fever might indicate a more immunocompromised state induced by the previous episode of COVID-19 infection. Mild to moderate disease courses might predict future severity of COVID-19 episodes. This association rules out the possibility of virus persistence after discharge.

The immune response of transplant patients to COVID-19 compared with the response of the general population is expected to be different, and hence the incidence of reoccurring infection is expected to be higher, although data are still evolving.7 Moreover, evidence that antibody response to COVID-19 vaccine in transplant patients is much lower compared with the general population has been recently published.22-24

Recent studies have reported that some patients have tested positive for COVID?19 by RT?PCR days or even weeks after disease recovery, even after previous negative results.25,26 A COVID-19-positive RT?PCR result does not prove SARS-CoV-2 viability with certainty, even if genome sequencing is performed.27 In fact, RT?PCR is not able to differentiate infectious virus from noninfectious RNA.28 Li and colleagues reported that 36 of 378 patients had COVID-19 RNA shedding longer than 30 days.29 However, in our study, COVID?19-positive tests combined with recurrent clinical symptoms and death in 46% of patients (6/13) suggest a viable infection is in play. For example, the virus may persist in a latent state in the lysogenic stage (viral reproduction), inactive or hidden in cells, without causing disease symptoms for a substantial period of time and then reactivate to cause the second episode.9-18 A recent study reported COVID-19 reinfections in 2 liver transplant recipients in Africa and the Middle East, 96 and 55 days after the primary infection, respectively, without patient death or graft loss.8 Another study reported a case of a liver transplant recipient with 2 distinct episodes of SARS-CoV-2 infections, separated by 111 days without symptoms and 2 negative test results for SARS-CoV-2 infection.5 Our recent study reported the first case of a KTR with some confirmatory features of a lethal COVID-19 reinfection.9

In our previous study on COVID-19 in 250 KTR from India, mortality was 14.5% in hospitalized patients.21 In the first episode in our present study, none of the patients had severe disease. However, in the second episode, 46% of patients developed severe COVID-19 that led to death, similar to findings of a recent study from Ecuador.30 An increase in disease severity and mortality during the second episode could be related to a different strain of the SARS-CoV-2. The SARS-CoV-2 B.1.617.2 (Delta) variant, designated as a Variant of Concern by the World Health Organization, has been described as the main variant in some parts of India during the second wave and may demonstrate resistance to previously formed antibodies.31,32 The Indian SARS-CoV-2 Genomics Consortium has so far processed more than 13 000 samples for genome sequencing. The RT-PCR tests in use in India do not miss the UK (Alpha, B.1.1.7), South Africa (Beta, B.1.351), Brazil (Gamma, P.1), and so-called double mutation India (Delta, B.1.617.2) variants, because the tests in use in India do target more than 2 genes. Sensitivity and specificity of the present RT-PCR tests remain as rigorous as earlier tests.33 Other possible causes of severe disease in the second COVID-19 episode are residual lung function abnormalities due to previous SARS-CoV-2 infection, as well as host susceptibility with recent use of antirejection treatment. Surveillance of pulmonary testing can be done after discharge to detect patients who are at higher risk for an adverse outcome in case of reinfection.

Implications for further work
We have witnessed an interesting panorama of COVID-19 before vaccinations were fully imp­lemented in India, which has the second largest population in the world after China. There is a need for caution for KTR in future surges of COVID-19 in India, as the mortality rate in the second infection was high (46%). Our study suggests that a second episode of SARS-CoV-2 with a high morbidity and mortality can occur in KTR. Thus, previous exposure to SARS-CoV-2 might not result in a sufficient immunity in all KTR. This observation may be of relevance not only for vaccine development and application but all also for immunosuppression in transplant recipients recovering from COVID-19.34 All KTR, regardless of previous infection, must take identical precautions to prevent infection with SARS-CoV-2. The new SARS-CoV-2 B.1.617.2 (Delta) variant is associated with immune-escape properties, which may render the pathogen partially or fully resistant to the body’s immune response and antibody therapies.

Limitations
The lack of the molecular confirmation is the primary limitation to our study, as it has been stated that solid-organ transplant recipients can maintain positivity for months and in an intermittent fashion.12,14,16 In some of the patients, the interval between infections was as short as 37 to 44 days. Thus, these details raise some concern of whether these are examples of true reinfection or are simply cases of positive test results attributable to the previous (first) infection. However, we suggest that these infections are second episodes of COVID-19. After the first episode, frequent RT-PCR tests were performed, but we did not follow the patients after a subsequent COVID-19-negative RT-PCR test; therefore, we could not exclude the possibility that a new (second) episode was a true reinfection or simply the result of intermittent persistence of the original (first) infection episode. There was no dedicated database to include and follow up all KTR with COVID-19 after the first infection, and we chose only those recipients who tested positive for COVID-19 at a certain point in time. Patient populations are not homogeneous. In fact, 2 recipients did develop the first episode of COVID-9 infection before transplant.

Conclusions

We report results from 13 KTR with a mortality rate of 46% subsequent to reoccurrence of SARS-CoV-2 infection. Our results showed that recurrent episodes of COVID-19 were symptomatically more severe than the first episode. These cases stress that caution should be exercised during follow-up of patients previously infected with COVID-19, especially in vulnerable KTR, even after they appear to have overcome the first infection. Physicians and patients should be apprised of the possibility of reoccurring SARS-CoV-2 infections in KTR. Close monitoring on an outpatient basis is crucial. Further research into the possibility of reoccurring SARS-CoV-2 infection in KTR is required. Moreover, research from different transplant centers worldwide will provide more evidence to understand the true burden of reoccurring SARS-CoV-2 infections in the KTR setting and the clinical spectrum and outcomes of these cases.


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DOI : 10.6002/ect.2021.0284


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From the 1Department of Nephrology, Institute of Kidney Diseases and Research Center,
Dr. H. L. Trivedi Institute of Transplantation Sciences, Ahmedabad; the 2Department of Nephrology, Muljibhai Patel Urological Hospital, Nadiad; the 3Department of Nephrology, Rabindranath Tagore International Institute of Cardiac Sciences, Kolkata; the 4Department of Nephrology, Jaslok Hospital and Research Centre, Mumbai; the 5Department of Renal Transplant Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh; the 6Department of Transplantation Surgery, Indraprastha Apollo Hospitals, New Delhi; the 7Department of Nephrology, Primus Hospital, New Delhi; and the 8Department of Nephrology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
Acknowledgements: The authors are grateful for editing support received from Professor Stefan G. Tullius (Harvard Medical School, Boston, USA) and Professor Mehmet Haberal (Baskent University, Ankara, Turkey). The authors are thankful for valuable contributions from Dr. Deepesh Kenwar, PGIMER, Chandigarh, and Ashay Singhare, Jaslok Hospitals, Mumbai. The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Author contributions: All authors have equal contribution to the concept and design of the work, the acquisition, analysis, and interpretation of data, the drafting/revision of the work, and final approval.
Corresponding author: Vivek B. Kute, Department of Nephrology, Institute of Kidney Diseases and Research Centre, Dr. H. L. Trivedi Institute of Transplantation Sciences, Ahmedabad, India
Phone: +91 9099927543
E-mail: drvivekkute@rediffmail.com