key: cord-0858443-6s1k3kit
authors: Heldman, Madeleine R.; Kates, Olivia S.; Safa, Kassem; Kotton, Camille N.; Georgia, Sarah J.; Steinbrink, Julie M.; Alexander, Barbara D.; Hemmersbach‐Miller, Marion; Blumberg, Emily A.; Multani, Ashrit; Haydel, Brandy; La Hoz, Ricardo M.; Moni, Lisset; Condor, Yesabeli; Flores, Sandra; Munoz, Carlos G.; Guitierrez, Juan; Diaz, Esther I.; Diaz, Daniela; Vianna, Rodrigo; Guerra, Giselle; Loebe, Matthias; Rakita, Robert M.; Malinis, Maricar; Azar, Marwan M.; Hemmige, Vagish; McCort, Margaret E.; Chaudhry, Zohra S.; Singh, Pooja P.; Hughes Kramer, Kailey; Velioglu, Arzu; Yabu, Julie M.; Morillis, Jose A.; Mehta, Sapna A.; Tanna, Sajal D.; Ison, Michael G.; Derenge, Ariella C.; van Duin, David; Maximin, Adrienne; Gilbert, Carlene; Goldman, Jason D.; Lease, Erika D.; Fisher, Cynthia E.; Limaye, Ajit P.
title: Changing trends in mortality among solid organ transplant recipients hospitalized for COVID‐19 during the course of the pandemic
date: 2021-10-07
journal: Am J Transplant
DOI: 10.1111/ajt.16840
sha: 35ed5baa13ff12b89584d2a51d97a809c6300d06
doc_id: 858443
cord_uid: 6s1k3kit

Mortality among patients hospitalized for COVID‐19 has declined over the course of the pandemic. Mortality trends specifically in solid organ transplant recipients (SOTR) are unknown. Using data from a multicenter registry of SOTR hospitalized for COVID‐19, we compared 28‐day mortality between early 2020 (March 1, 2020–June 19, 2020) and late 2020 (June 20, 2020–December 31, 2020). Multivariable logistic regression was used to assess comorbidity‐adjusted mortality. Time period of diagnosis was available for 1435/1616 (88.8%) SOTR and 971/1435 (67.7%) were hospitalized: 571/753 (75.8%) in early 2020 and 402/682 (58.9%) in late 2020 (p < .001). Crude 28‐day mortality decreased between the early and late periods (112/571 [19.6%] vs. 55/402 [13.7%]) and remained lower in the late period even after adjusting for baseline comorbidities (aOR 0.67, 95% CI 0.46–0.98, p = .016). Between the early and late periods, the use of corticosteroids (≥6 mg dexamethasone/day) and remdesivir increased (62/571 [10.9%] vs. 243/402 [61.5%], p < .001 and 50/571 [8.8%] vs. 213/402 [52.2%], p < .001, respectively), and the use of hydroxychloroquine and IL‐6/IL‐6 receptor inhibitor decreased (329/571 [60.0%] vs. 4/492 [1.0%], p < .001 and 73/571 [12.8%] vs. 5/402 [1.2%], p < .001, respectively). Mortality among SOTR hospitalized for COVID‐19 declined between early and late 2020, consistent with trends reported in the general population. The mechanism(s) underlying improved survival require further study.

During the early portion of 2020, short-term mortality among solid organ transplant recipients (SOTR) hospitalized for COVID-19 was high, with estimates ranging from approximately 18%-30%. [1] [2] [3] Multiple recent studies of hospitalized adults (general population) with COVID-19 have reported that mortality has declined substantially since the start of the pandemic in the United States and Europe, from 20% to 25% during March and April 2020 to less than 10% during July through November 2020. [4] [5] [6] [7] The overall decline in mortality has been attributed to various factors including earlier diagnosis due to greater access of testing, improvements in the supportive management, and the potential impact of therapies such as corticosteroids and remdesivir. 4 Whether similar decreases in mortality have occurred in SOTR has not been reported.

We previously described the 28-day outcomes of SOTR hospitalized for COVID-19 who were enrolled in a multicenter registry between March 1 and April 15, 2020. 1 This registry accrued additional cases diagnosed between April 15 and December 31, 2020.

Here, we compare outcomes by 28 days among SOTR hospitalized for COVID-19 during the first half of 2020 to those diagnosed during the second half of 2020, to determine whether reductions in mortality reported among the general population have similarly occurred among SOTR.

We performed a multicenter observational cohort study of SOTR with laboratory-confirmed SARS-CoV-2 infection, as described previously. 1 This study was approved by the institutional review board (IRB) at the University of Washington with a waiver of informed Mortality among patients hospitalized for COVID-19 has declined over the course of the pandemic. Mortality trends specifically in solid organ transplant recipients (SOTR) are unknown. Using data from a multicenter registry of SOTR hospitalized for COVID-19, we compared 28-day mortality between early 2020 (March 1, 2020-June 19, 2020) and late 2020 (June 20, 2020-December 31, 2020). Multivariable logistic regression was used to assess comorbidity-adjusted mortality. 

Data were collected using an online data collection tool, REDCap (Research Electronic Data Capture), as described previously. 1, 8 A summary of all collected variables is shown in Table S1 . Only patients who were hospitalized within 28 days of diagnosis, and for whom 28-day follow-up forms were completed, were included in this analysis. Patients were excluded if they were hospitalized for another indication prior to or concurrent with their first positive SARS-CoV-2 test ( Figure S1) 

Demographic and baseline characteristics were assessed as counts and percentages for categorical values and as a mean (standard deviation) or median (interquartile range) for continuous variables. χ 2 and Fisher's exact tests were used to assess proportions of categorical variables. Continuous variables were assessed using Student's t-test or the Wilcoxon rank-sum test. Death by 28 days was the primary outcome, and admission to the intensive care unit (ICU), use of mechanical ventilation, initiation of renal replacement therapy, pathogen-proven bacterial and fungal pneumonia, bloodstream infection, acute cellular rejection, and duration of hospitalization were secondary outcomes. Age, sex, organ transplanted, geographic location, comorbidities, and features related to immunosuppression were evaluated as potential risk factors for mortality using univariable logistic regression (Table S2 ). These covariates were selected a priori based on hypotheses and/or prior studies showing a relationship with COVID-19 mortality. 10 Figure S1 ). Overall, the baseline characteristics of hospitalized patients excluded due to an unknown period of diagnosis were similar to those of the included population with an available time period of diagnosis (Table S3 ).

The mean age was similar in the early (57 ± 13 years) and late (58 ± 14 years) periods (p = .28). 

The use of hydroxychloroquine and monoclonal antibodies targeting interleukin 6 (IL-6) or the IL-6-receptor (IL-6R) declined between the early and late periods ( 

In this large multicenter observational cohort study, mortality among SOTR hospitalized for COVID-19 declined during the pandemic, even when controlled for baseline comorbidities, similar to trends reported in the general population.

We explored potential explanations for the observed reduction in mortality during the most recent study period. We noted key differences in patient characteristics between the study periods: the prevalence of heart and lung disease, high-risk comorbidities that are strongly associated with mortality in SOTR with COVID-19, 1 was significantly lower in the late, more recent period. However, mortality remained lower in the late period after adjusting for these confounding conditions, consistent with findings from the general population demonstrating decreased mortality among persons of all ages and in those with multiple medical comorbidities. 4,13 Thus, differences in underlying comorbidities between study periods are unlikely to fully explain the observed decrease in mortality and suggest that other factors were likely contributory.

We also assessed COVID-19 illness severity between time periods as a possible explanation for the observed decline in mortality. Based on our findings of decreased mortality despite unchanged surrogates of illness severity and controlling for baseline comorbidities between study periods, we speculate that general improvements in care and COVID-specific treatments may explain the improved survival in SOTR between the first and second portions of 2020.

The adoption of therapeutic corticosteroids, prone positioning to improve oxygenation without mechanical ventilation, and overall adaptation of health care systems to the pandemic have been cited as potential reasons for lower contemporary mortality in the general population. 4, 5, 7, 18 The decrease in use of renal replacement therapy observed in this cohort is consistent with findings from the general population and may reflect changes in the approach to volume management over the course of the pandemic. 19 We observed a decline in the use of mechanical ventilation, despite an increase in the proportion of patients requiring any form of supplemental oxygen. The observed decrease in mechanical ventilation likely reflects global changes in the approach to the management of COVID-19 over time, as early intubation at the onset of hypoxemia was a frequent practice early but became less common over time. 20 The current observational study design does not allow for definitive testing of these hypotheses and associations between specific interventions and outcomes should be interpreted with caution. Substantial confounding by indication, whereby sicker patients were more likely to receive therapeutic interventions, precludes meaningful assessment of the association between various treatments and outcomes on This study was restricted to de-identified patient information, a practical strategy that circumvented the need for local IRB approval at many participating institutions, facilitating prompt accumulation of data during a global pandemic. This practical study design did not allow for evaluation of month-by-month variations in mortality. However, we defined study periods using a logical cutoff time that corresponded with the timing of treatment paradigm shifts and data from the general population demonstrate stable mortality throughout our study's later period. 4 The voluntary nature of participation and reporting of cases makes it challenging to understand the extent to which the study cohort represents the entire SOT population. We minimized the potential impact of reporting biases by limiting the analysis to patients hospitalized for COVID-19, which created a more homogeneous study population. Although there were geographic differences between the two study periods, there was no difference in mortality across regions in the univariable analysis,

suggesting that any regional differences in care, including threshold for hospitalization, were unlikely to explain the observed mortality trends.

There were significant differences in the racial and ethnic composition of patients between time periods. Social determinants of health and structural racism have placed racial and ethnic minority groups at a higher risk for SARS-CoV-2 acquisition as well as the medical comorbidities that are associated with poor outcomes from COVID-19. 21 may be less likely to die than non-Hispanic White patients. 24, 26, 27 These observations support the definition of race and ethnicity as social constructs that reflect risk factors for COVID-19 exposure and underlying comorbidities without independent biological implications for disease progression following infection. 28 In our cohort of SOT recipients hospitalized for COVID-19, neither race nor ethnicity were associated with death. Therefore, it is unlikely that the temporal variation in the racial and ethnic composition of our cohort is related to the observed trends in mortality.

In conclusion, this large multicenter study demonstrates that 

Kassem Safa

Maricar Malinis

Arzu Velioglu

COVID-19 in solid organ transplant: a multi-center cohort study

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The REDCap consortium: building an international community of software platform partners

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COVID-19 mortality among kidney transplant candidates is strongly associated with social determinants of health

Assessment of racial/ethnic disparities in hospitalization and mortality in patients with COVID-19 in

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The impact of race and ethnicity on outcomes in 19,584 adults hospitalized with COVID-19

Association of race with mortality among patients hospitalized with coronavirus disease 2019 (COVID-19) at 92 US hospitals

Updated guidance on the reporting of race and ethnicity in medical and science journals

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Additional supporting information may be found in the online version of the article at the publisher's website.