key: cord-0747131-gunhn1ru authors: Santos, Carlos A. Q.; Rhee, Yoona; Hollinger, Edward F.; Olaitan, Oyedolamu K.; Schadde, Erik; Peev, Vasil; Saltzberg, Samuel N.; Hertl, Martin title: Comparative incidence and outcomes of COVID‐19 in kidney or kidney‐pancreas transplant recipients versus kidney or kidney‐pancreas waitlisted patients: A single‐center study date: 2021-05-28 journal: Clin Transplant DOI: 10.1111/ctr.14362 sha: 74add67588f92f0d2eb28d4cacc510fe99541a48 doc_id: 747131 cord_uid: gunhn1ru BACKGROUND: COVID‐19 epidemiologic studies comparing immunosuppressed and immunocompetent patients may provide insight into the impact of immunosuppressants on outcomes. METHODS: In this retrospective cohort study, we assembled kidney or kidney‐pancreas transplant recipients who underwent transplant from January 1, 2010, to June 30, 2020, and kidney or kidney‐pancreas waitlisted patients who were ever on the waitlist from January 1, 2019, to June 30, 2020. We identified laboratory‐confirmed COVID‐19 until January 31, 2021, and tracked its outcomes by leveraging informatics infrastructure developed for an outcomes research network. RESULTS: COVID‐19 was identified in 62 of 887 kidney or kidney‐pancreas transplant recipients and 20 of 434 kidney or kidney‐pancreas waitlisted patients (7.0% vs. 4.6%, p = .092). Of these patients with COVID‐19, hospitalization occurred in 48 of 62 transplant recipients and 8 of 20 waitlisted patients (77% vs. 40%, p = .002); intensive care unit admission occurred in 18 of 62 transplant recipients and 2 of 20 waitlisted patients (29% vs. 10%, p = .085); and 7 transplant recipients were mechanically ventilated and died, whereas no waitlisted patients were mechanically ventilated or died (11% vs. 0%, p = .116). CONCLUSIONS: Our study provides single‐center data and an informatics approach that can be used to inform the design of multicenter studies. immune response may prevent severe cytokine storm that ensues in a subset of patients with COVID-19-induced acute respiratory distress syndrome. 7, 8 However, chronic immunosuppression is known to worsen the disease courses of most infections, including but not limited to cytomegalovirus, influenza, Streptococcus pneumoniae, and invasive fungal infections. [9] [10] [11] [12] In this retrospective cohort single-center study, we determined the incidence and outcomes of COVID-19 in kidney or kidneypancreas transplant recipients and kidney or kidney-pancreas waitlisted patients at Rush University Medical Center in Chicago. We hypothesize that these patients have an incidence proportion of COVID-19 similar to the general population, but that transplant recipients have greater occurrences of hospitalization, intensive care unit admission, mechanical ventilation, and death compared to waitlisted patients due to chronic immunosuppression. Epidemiologic studies examining disease courses of COVID-19 between comparable immunosuppressed and immunocompetent patients may provide insight regarding the impact of chronic immunosuppressive therapy on outcomes. We performed a retrospective cohort study of kidney and kidneypancreas transplant recipients who underwent transplantation from January 1, 2010, to June 30, 2020 (total n = 981), and kidney and kidney-pancreas waitlisted patients who were ever on the waitlist from January 1, 2019, to June 30, 2020 (total n = 687). We excluded transplant recipients who died before November 1, 2019 (n = 94), since they could not have had the opportunity to develop COVID-19. We excluded waitlisted patients with a previous transplant since they had already been exposed to immunosuppression (n = 125), waitlisted patients who underwent transplant on or before June 30, 2020, since they would be in the transplant cohort (n = 121), and waitlisted patients who died before November To facilitate obtaining data from the electronic health record in our center, we leveraged existing informatics infrastructure developed for the Chicago Area Patient-Centered Outcomes Research Network (CAPriCORN), 13 a clinical data research network that is part of the Patient-Centered Outcomes Research Network (PCORnet), and adapted it to populate normalized datasets with a monthly refresh from November 1, 2019, to capture conditions and events during the COVID-19 pandemic. 14 Demographics, healthcare encounters, vital signs, laboratory results, medications administered in the inpatient setting, and death were electronically collected according to CAPriCORN common data model specifications and augmented with ancillary datasets on bed information to capture patient movement within hospital stays, and mechanical ventilation, to capture intubation and duration of ventilator use. Information outside of these domains was gathered by manual chart review of free text notes in the electronic health record using a standardized data collection tool by one physicianepidemiologist author (YR) and validated for accuracy by another physician-epidemiologist author (CS). COVID-19 was identified by querying the electronic datasets for detection of SARS-CoV-2 RNA by RT-PCR or nucleic acid amplification from nasal or nasopharyngeal swab specimens from November 1, 2019, to January 31, 2021. Demographic data, vital signs (temperature and body mass index), laboratory results, hospitalization, intensive care unit admission, mechanical ventilation, and death were captured from the electronic datasets, whereas comorbidities, organ type, cause of renal disease, induction, and maintenance immunosuppression, presenting symptoms for COVID-19, oxygen supplementation, chest radiographic findings, and treatments tried for COVID-19 were collected by manual chart review. Demographics, comorbidities, and maintenance immunosuppression were determined at the time of COVID-19 identification, whereas cause of | 3 of 8 SANTOS eT Al. Descriptive statistics were used to describe the demographic and clinical characteristics of the study populations, the incidence pro- The median ages of transplant recipients and waitlisted patients with COVID-19 were 58 (range 28-78) and 52 (range 22-73) years, respectively (p = .14) ( Common presenting symptoms of COVID-19 in transplant recipients and waitlisted patients were fever (55% vs. 55%), cough (47% vs. 50%), and dyspnea (39% vs. 30%) ( Of 62 kidney or kidney-pancreas transplant recipients with COVID-19, acute kidney injury defined as increase in serum creatinine ≥1.5 times baseline occurred in 15 patients (24%), and new renal replacement therapy defined as acute need for dialysis occurred in 4 patients (6%) ( Table 2 ). Acute kidney injury was attributed to acute tubular necrosis in 11 patients, tacrolimus toxicity in two patients, dehydration in one patient, and osmotic diuresis secondary to hyperglycemia in one patient. There were no instances of clinically suspected or biopsy-proven kidney allograft rejection. One kidneypancreas transplant recipient with COVID-19 had lipase elevation that peaked at 152 U/L. Biopsy of the transplanted pancreas showed mild acute cellular rejection that was managed with increased tacrolimus and oral steroid dosing. Lipase normalized after two weeks. Hospitalization occurred in 48 of 62 transplant recipients, and 8 of 20 waitlisted patients with COVID-19 (77% vs. 40%, p = .002) ( We performed a subset analysis wherein we examined the incidence We found in this retrospective cohort single-center study that the incidence proportion of laboratory-confirmed COVID-19 in kidney TA B L E 2 Clinical features and outcomes of COVID-19 in kidney or kidney-pancreas transplant recipients and kidney or kidney-pancreas waitlisted patients (24) New renal replacement therapy-no./total no. (%) e 4/62 (6) Clinically suspected or biopsy-proven kidney allograft rejection 0 Lipase >60 u/L a , f 1/5 (20) Outcomes Abbreviation: CAPriCORN, chicago area patient-centered outcomes research network. a Temperature, laboratory values and outcomes (hospitalization, intensive care unit admission, mechanical ventilation and death) were derived from electronically generated datasets mapped to CAPriCORN common data model specifications; outcomes were subsequently validated with manual chart review; presenting symptoms, oxygen requirement, chest radiographic findings and treatment were identified by manual chart review. b Body temperature and laboratory tests taken from one day prior through 30 days after COVID-19 identification; some patients did not have laboratory tests performed. c Antimetabolite includes mycophenolate or azathioprine; calcineurin inhibitors include tacrolimus and cyclosporine; mTOR inhibitors include sirolimus and everolimus. d Acute kidney injury defined as increase in serum creatinine ≥1.5 times baseline which is known or presumed to have occurred within the prior seven days. e Acute renal replacement therapy during hospital admission. f Elevated lipase in kidney-pancreas transplant recipients. g Hospitalization, intensive care unit admission and mechanical ventilation were first electronically identified from three days prior through 30 days after COVID-19 identification and then validated with manual chart review. our study are more similar to the national cohort study in England, because our approach to cohort inception was more congruent and adhered to guidelines for reporting observational studies. 19 However, our study differs from the national cohort study in England in that it includes transplant recipients from a more current era and excludes waitlisted patients with a previous solidorgan transplant since they had already been exposed to chronic immunosuppression. Our study also differs from the national cohort study in terms of locale and demographic characteristics of the study population. The clinical features of COVID-19 in kidney transplanted and waitlisted patients were comparable and similar to what has already been reported in the literature. [1] [2] [3] [4] [5] 16 Fever and cough were common presenting symptoms, but less common symptoms such as myalgias and diarrhea were also identified. Leukopenia, lymphopenia, and thrombocytopenia were frequently found among patients in whom a complete blood count was done, and elevations reporting that remdesivir administration had no effect with regard to duration of hospital stay, initiation of mechanical ventilation, or overall mortality. 23 High-dose glucocorticoids were given to over a quarter of transplant recipients. A randomized controlled trial comparing dexamethasone to usual care conducted by the RECOVERY Collaborative Group showed that dexamethasone was associated with lower 28-day mortality among those who were on mechanical ventilation or oxygen alone at randomization, but not among those receiving no respiratory support. 24 The case fatality rates we found for transplanted and waitlisted patients with COVID-19 were 11% and 0%, respectively, which is similar to reported rates in other studies of kidney transplant recipients 1-5 and patients on hemodialysis. 16 In summary, we found that the incidence proportion of COVID-19 in kidney or kidney-pancreas transplant recipients was similar to that of kidney or kidney-pancreas waitlisted patients and that transplant recipients had numerically higher occurrences of hospitalization, intensive care unit admission, mechanical ventilation, or death compared to waitlisted patients. This study provides single-center data that can be used for power calculations, as well as an informatics approach that can enable the conduct of multicenter studies. The authors would like to acknowledge Ronda Billerbeck, Sandra Delgado, Ekta Kishen and Karthikeyan Swaminathan for their help with database management. The authors would also like to acknowledge Graeme Forrest for his critical review. The authors declare no conflicts of interest. Carlos A. Q. Santos -participated in research design, writing of the paper, performance of the research and data analysis. Yoona Rhee -participated in research design, writing of the paper and performance of the research. Edward F. Hollinger -participated in research design and writing of the paper. Oyedolamu K. Olaitan -participated in research design and writing of the paper. Erik Schadde -participated in research design and writing of the paper. Vasil Peev -participated in research design and writing of the paper. Samuel N. Saltzberg -participated in research design and writing of the paper. Martin Hertl -participated in research design, writing of the paper and performance of the research. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Carlos A. Q. Santos https://orcid.org/0000-0002-6224-0371 COVID-19 infection in kidney transplant recipients A single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia Early description of coronavirus 2019 disease in kidney transplant recipients in New York Covid-19 and kidney transplantation COVID-19 in kidney transplant recipients Clinical characteristics of Covid-19 in New York city Coronaviruses and immunosuppressed patients: the facts during the third epidemic Immunosuppression drug-related and clinical manifestation of Coronavirus disease 2019: a therapeutical hypothesis Delayed-onset cytomegalovirus disease coded during hospital readmission after kidney transplantation Comparative epidemiology and outcomes of human immunodeficiency virus (HIV), non-HIV non-transplant, and solid organ transplant associated Cryptococcosis: a population-based study Invasive pneumococcal disease in solid organ transplant recipients-10-year prospective population surveillance Influenza and other respiratory virus infections in solid organ transplant recipients Chicago area patient-centered outcomes research network Evaluating foundational data quality in the national patient-centered clinical research network A case of novel coronavirus disease 19 in a chronic hemodialysis patient presenting with gastroenteritis and developing severe pulmonary disease COVID-19 in hemodialysis patients: a report of 5 cases SARS-CoV-2 infection and early mortality of waitlisted and solid organ transplant recipients in England: a national cohort study COVID-19 outcomes in patients waitlisted for kidney transplantation and kidney transplant recipients The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies Cytomegalovirus: a guide for the perplexed Polyomavirus reactivation and immune responses to kidney-specific self-antigens in transplantation Remdesivir for the treatment of Covid-19 -preliminary report Repurposed antiviral drugs for Covid-19 -Interim WHO solidarity trial results Dexamethasone in hospitalized patients with Covid-19 -preliminary report Identifying scenarios of benefit or harm from kidney transplantation during the COVID-19 pandemic: a stochastic simulation and machine learning study Comparative incidence and outcomes of COVID-19 in kidney or kidney-pancreas transplant recipients versus kidney or kidney-pancreas waitlisted patients: A singlecenter study