Coronavirus disease 2019 in solid organ transplant recipients in the setting of proactive screening and contact tracing of Qatar

Background: Clinical data on Coronavirus Disease 2019 (COVID-19) in solid organ transplant (SOT) recipients are limited. We herein report the initial clinical experience with COVID-19 in SOT recipients in Qatar. Methods: All SOT recipients with laboratory-confirmed COVID-19 up to May 23, 2020 were included. Demographic and clinical data were extracted retrospectively from the hospital’s electronic health records. Categorical data are presented as frequency and percentages, while continuous variables are summarized as medians and ranges. Results: Twenty-four SOT recipients with COVID-19 were identified (kidney 16, liver 6, heart 1, and liver and kidney 1). Organ transplantation preceded COVID-19 by a median of 60 months (range 1.7–184). The median age was 57 years (range 24–72), and 9 (37.5%) transplant recipients were females. Five (21%) asymptomatic patients were diagnosed through proactive screening. For the rest, fever (15/19) and cough (13/19) were the most frequent presenting symptoms. Five (20.8%) patients required invasive mechanical ventilation in the intensive care unit (ICU). Eleven (46%) patients developed acute kidney injury, including three in association with drug-drug interactions involving investigational COVID-19 therapies. Maintenance immunosuppressive therapy was modified in 18 (75%) patients, but systemic corticosteroids were not discontinued in any. After a median follow-up of 226 days (26–272), 20 (83.3%) patients had been discharged home, 2 (8.3%) were still hospitalized, 1 (4.2%) was still in the ICU, and 1 (4.2%) had died. Conclusions: Our results suggest that asymptomatic COVID-19 is possible in SOT recipients and that overall outcomes are not uniformly worse than those in the general population. The results require confirmation in large, international cohorts.


INTRODUCTION
By January 2021, the global number of infections caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the cause of Coronavirus Disease 2019 (COVID- 19), was approaching 90 million, with nearly 2 million associated deaths. 1 Clinical outcomes associated with COVID-19 appear to be considerably worse in older individuals and in those with chronic medical conditions such as hypertension, diabetes mellitus, and chronic kidney disease. 2 In general, respiratory viral infections in solid organ transplant (SOT) recipients are associated with more rapidly progressive and severe disease, prolonged viral shedding, and a higher risk of mortality. 3 However, SOT recipients are under-represented in large COVID-19 cohorts, and the interaction between COVID-19 and SOT has not been fully elucidated. 4 While the immune-suppressed status of SOT recipients may increase their risk of severe COVID-19 and mortality, it is possible that chronic immune suppression may mitigate some of the severe inflammation-driven COVID-19 manifestations. 5 We herein report the clinical characteristics, management, and outcomes of SOT-associated COVID-19 in Qatar.

MATERIALS AND METHODS
Hamad Medical Corporation encompasses multiple hospital facilities and provides all COVID-19 medical care for the population of Qatar. SARS-CoV-2 infection was diagnosed on respiratory tract specimens by real-time polymerase chain reaction (RT-PCR) assays using the TaqPath COVID-19 Combo Kit (Thermo Fisher Scientific, Waltham, Massachusetts) or the Cobas SARS-CoV-2 Test (Roche Diagnostics, Rotkreuz, Switzerland). SARS-CoV-2 testing was offered to all individuals presenting with symptoms suggestive of COVID-19, known close contacts of confirmed cases including healthcare workers, and all returning travelers.
The Communicable Diseases Center's COVID- 19 database includes records of all RT-PCR-confirmed SARS-CoV-2 infections in Qatar. The database was used to identify all SOT recipients who had a laboratory-confirmed SARS-CoV-2 infection by May 23, 2020. Demographic and clinical data were extracted from the hospital's electronic health records (Cerner Millennium, Cerner Corporation, Kansas City, Missouri, United States of America) during the period from May 25 to June 21, 2020. Final disposition was based on the patients' status on December 20, 2020. The outcomes assessed included COVID-19 severity according to the World Health Organization. 2 Acute kidney injury (AKI) was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines. 6 COVID-19 diagnosis was confirmed using real-time polymerase chain reaction (RT-PCR) on airway specimens (Thermo Fisher Scientific, Waltham, Massachusetts). All patients received standard clinical care as per the local COVID-19 management guidelines. In addition to supportive care, individual patients received hydroxychloroquine, azithromycin, oseltamivir, lopinavir/ritonavir, darunavir/cobicistat, and/or tocilizumab. Specific regimens were selected by the treating physicians based on the disease severity and the presence of any organ dysfunction or potential drug-drug interactions. Decisions relating to immunosuppressive therapy were made by the attending transplant teams. Tacrolimus therapeutic drug levels were determined by an electro-chemiluminescence immunoassay (Roche Diagnostics, Rotkreuz, Switzerland) with a target reference range of 8.5 -17 ng/mL. Categorical data are presented as frequencies and percentages, while continuous variables are summarized as medians and ranges. Statistical analyses were performed using Microsoft Excel 2016 (Microsoft Corporation, Redmond, Washington, United States of America). The study protocol is consistent with the ethical guidelines of the 1975 Helsinki Declaration and was approved by the Institutional Review Board with a waiver of informed consent (MRC-01-20-191).
Baseline radiological abnormalities consistent with pneumonia were documented in 16 (66.7%) patients. Baseline characteristics of individual patients are summarized in Table S1 in the supplementary file. All patients received azithromycin. Other investigational therapies used are shown in Table 2. All but six patients had their maintenance immune suppressive therapy modified as part of their COVID-19 management. The most frequent changes were dose reduction or suspension of MMF (17/21, 81%) and tacrolimus (8/21, 38.1%). While systemic corticosteroids were not discontinued in any of the patients who were on maintenance prednisolone, the dose was increased in 12/19 (63.2%) patients, including all five who required invasive mechanical ventilation ( Table 2,  and Table S2 in the supplementary file).
The most frequently observed complication was AKI (11, 46%), involving eight kidney, two liver, and one heart transplant recipient. Three patients developed AKI in association with high tacrolimus levels (23.3 ng/mL, 30.5 ng/mL, and 18.8 ng/mL) following the initiation of protease inhibitor augmentation as an investigational COVID-19 therapy (Table S2 in the supplementary file). By the end of follow-up, renal function returned to baseline in all three of these patients. One incident of AKI occurred in a patient with congestive heart failure and a concomitant urinary tract infection, and another in a patient who received concomitant trimethoprim-sulfamethoxazole. Both patients had had pre-existing chronic kidney graft dysfunction with estimated glomerular filtration rates below 30 mL/min and were still in hospital at the end of follow-up (Table S2 in the supplementary file). Other complications included acute liver dysfunction (9, 37.5%), none of which occurred in a liver transplant recipient. Five (20.8%) patients required invasive mechanical ventilation for severe ARDS. Of these, two were successfully extubated and transferred to the medical floors after 24 and 33 days and were eventually discharged home, and one patient died after 26 days of admission. The remaining two patients had developed anoxic brain injury and were still in hospital at the end of follow-up (Table 2 and Table S2 in the supplementary file). After a median follow-up period of 226 days (26-272), 20 patients (83.3%) had been discharged home or to a community isolation facility, 2 (8.3%) were still hospitalized in non-ICU areas, 1 (4.2 %) was still in ICU, and 1 (4.2%) had died ( Table 2). By end of follow-up, negative SARS-CoV-2 RT-PCR tests on airway samples were documented in 19 (79.2%) patients. Viral clearance in those patients occurred within 5-55 days from the first positive results (Table S2 in the supplementary file).

DISCUSSION
We herein report the clinical presentation, management, and outcomes of SOT-associated COVID-19 in Qatar. To control the epidemic, local authorities implemented several measures, including travel restrictions, social distancing interventions, and proactive screening of repatriated travelers and contacts of confirmed COVID-19 cases. A notable finding in this report is the proportion of SOT recipients with asymptomatic SARS-CoV-2 infections, which were only detected because of intensive case identification efforts. Asymptomatic COVID-19  cases are very well documented in general, and their role in sustaining the pandemic is becoming increasingly appreciated. 7 However, to the best of our knowledge, this is the first time that asymptomatic SARS-CoV-2 infections are reported in SOT recipients.  (Table S1 and Table S2 in the supplementary file). Unlike a recent report of severe COVID-19 in a patient who presented shortly after liver transplantation, 10 one patient in this study received a liver graft from a deceased donor only seven weeks prior to her diagnosis with asymptomatic SARS-CoV-2 infection (Patient 4 in Table S1 and Table S2). Rather  Hospital discharge than a simple association between the type of graft and severity of COVID-19, the overall health status of the individual may be the most relevant factor. Large, preferably multi-center, cohort studies are urgently required to inform the risk assessment of SOT recipients with COVID-19 and to guide their medical management.
Despite widespread off-label use of hydroxychloroquine, azithromycin, and lopinavir/ritonavir for COVID-19, none of these agents has been proven clinically effective. 11,12 In addition to significant potential adverse events, such as cardiac arrhythmias and liver toxicity, these investigational agents could have detrimental interactions with immunosuppressants. 11 -13 As seen in this study and others, those interactions can result in toxicities that outweigh any potential benefits. 14, 15 Moreover, it is not yet known if the immune-suppressed status of SOT recipients may ameliorate the inflammatory manifestations of COVID-19. Notably, dexamethasone use is associated with significantly reduced mortality in COVID-19 patients who require oxygen support. 16 It is not yet clear if such a benefit is likely in SOT recipients who are already on a maintenance immune suppression regimen with or without corticosteroids. 4 Current recommendations for the management of severe COVID-19 in SOT recipients suggest that calcineurin inhibitors and MMF may be reduced or, if necessary, withheld, but the risk of graft dysfunction and rejection should be weighed very carefully against the risk of progressive COVID-19. 17,18 In this series, corticosteroids were either maintained or increased; MMF was continued the same, reduced or stopped; and tacrolimus doses were mostly changed only when potential interactions with investigational agents necessitated doing so. None of our patients experienced any evidence of acute rejection. It appears that a reasonable strategy in SOT recipients with COVID-19 is to maintain safe levels of immunosuppression while avoiding unproven investigational agents. 18 Clinical studies are urgently required to examine the role of investigational COVID-19 therapies in SOT settings and to help determine the most appropriate immunosuppressive therapy modification to minimize the risk of both severe infection and graft rejection. 17 Patients in this study who cleared SARS-CoV-2 from their airways did so within as short a time span as 5 days and up to as long as 55 days or more. This is consistent with known variability in SARS-CoV-2 shedding, especially in patients with severe COVID-19. 19

CONCLUSION
In conclusion, we report our experience thus far with COVID-19 in SOT recipients in Qatar. Proactive screening allowed the identification of asymptomatic SARS-CoV-2 infections. While some patients developed severe disease and required ICU support, the majority recovered without long-term complications. One patient died during follow-up. Our findings suggest that SOT-associated COVID-19 is not necessarily associated with a uniformly poor clinical outlook. Large clinical studies are required to better understand the clinical course of COVID-19 in SOT recipients, identify risk factors for severe disease, and determine the most appropriate management strategies.