key: cord-0707223-fjz6qqrm
authors: Kates, Olivia S; Haydel, Brandy M; Florman, Sander S; Rana, Meenakshi M; Chaudhry, Zohra S; Ramesh, Mayur S; Safa, Kassem; Kotton, Camille Nelson; Blumberg, Emily A; Besharatian, Behdad D; Tanna, Sajal D; Ison, Michael G; Malinis, Maricar; Azar, Marwan M; Rakita, Robert M; Morillas, Jose A; Majeed, Aneela; Sait, Afrah S; Spaggiari, Mario; Hemmige, Vagish; Mehta, Sapna A; Neumann, Henry; Badami, Abbasali; Goldman, Jason D; Lala, Anuradha; Hemmersbach-Miller, Marion; McCort, Margaret E; Bajrovic, Valida; Ortiz-Bautista, Carlos; Friedman-Moraco, Rachel; Sehgal, Sameep; Lease, Erika D; Fisher, Cynthia E; Limaye, Ajit P
title: COVID-19 in solid organ transplant: A multi-center cohort study
date: 2020-08-07
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa1097
sha: ec80e9ec94c9a2dbd1d40aa1a2d9131f0a9d1ae4
doc_id: 707223
cord_uid: fjz6qqrm

BACKGROUND: The COVID-19 pandemic has led to significant reductions in transplantation, motivated in part by concerns of disproportionately more severe disease among solid organ transplant (SOT) recipients. However, clinical features, outcomes, and predictors of mortality in SOT recipients are not well-described. METHODS: We performed a multi-center cohort study of SOT recipients with laboratory-confirmed COVID-19. Data were collected using standardized intake and 28-day follow-up electronic case report forms. Multivariable logistic regression was used to identify risk factors for the primary endpoint, 28-day mortality, among hospitalized patients. RESULTS: Four hundred eighty-two SOT recipients from >50 transplant centers were included: 318 (66%) kidney or kidney/pancreas, 73 (15.1%) liver, 57 (11.8%) heart, and 30 (6.2%) lung. Median age was 58 (IQR 46-57), median time post-transplant was 5 years (IQR 2-10), 61% were male, and 92% had ≥1 underlying comorbidity. Among those hospitalized (376 [78%]), 117 (31%) required mechanical ventilation, and 77 (20.5%) died by 28 days after diagnosis. Specific underlying comorbidities (age >65 [aOR 3.0, 95%CI 1.7-5.5, p<0.001], congestive heart failure [aOR 3.2, 95%CI 1.4-7.0, p=0.004], chronic lung disease [aOR 2.5, 95%CI 1.2-5.2, p=0.018], obesity [aOR 1.9, 95% CI 1.0-3.4, p=0.039]) and presenting findings (lymphopenia [aOR 1.9, 95%CI 1.1-3.5, p=0.033], abnormal chest imaging [aOR 2.9, 95%CI 1.1-7.5, p=0.027]) were independently associated with mortality. Multiple measures of immunosuppression intensity were not associated with mortality. CONCLUSIONS: Mortality among SOT recipients hospitalized for COVID-19 was 20.5%. Age and underlying comorbidities rather than immunosuppression intensity-related measures were major drivers of mortality.

The COVID-19 pandemic has affected over 10 million people, with over 500,000 deaths worldwide.

Estimated mortality rates among those hospitalized with COVID-19 vary widely and have been associated with advanced age and comorbidities in the general population; however, less is known about outcomes of COVID-19 in solid organ transplant (SOT) recipients. [1] [2] [3] Based on experience with other respiratory viruses in immunocompromised populations, there has been concern about a disproportionately severe impact of COVID-19 in SOT recipients related to immunosuppression. 4, 5 However, because of the unique contribution of a dysregulated and exaggerated immune response in COVID-19 morbidity and mortality, there has also been discussion of a possible favorable effect of immunosuppression in SOT recipients who develop COVID-19. 6 Concerns about unfavorable outcomes, along with other issues such as infection control and resource availability, have led to changes in immunosuppression management and a substantial decrease or even temporary discontinuation of transplants at many centers around the world. As of 11 April 2020, the overall rate of deceased donor organ transplantation had fallen by 51% in the United States, by 87% in Spain, and by 91% in France. 7 The clinical aspects and impact of COVID-19 in SOT recipients remain uncertain. Early results have varied, with mortality rates ranging from 7.1% to as high as 53% in one small series. 8, 9 These studies had important limitations including small size, single-center or limited geographic locale, or limited follow-up. [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] More precise estimates of morbidity and mortality of COVID-19 in SOT, identification of risk factors for mortality, and comparison to general populations are critical for two main purposes: 1) to better understand the impact of transplant-related immunosuppression on outcomes of COVID-19, and 2) to inform transplant program practices in the COVID-19 era and in the event of resurgence of the epidemic.

A c c e p t e d M a n u s c r i p t 7 We report the results of a large, prospective, multi-center study of SOT recipients with COVID-19, all of whom were followed for 28 days, using standardized data collection tools, to assess patient characteristics, clinical presentation, outcomes, and risk factors for mortality.

The study was approved by the University of Washington Institutional Review Board with waiver of informed consent. The Institutional Review Board issued a "not human subjects research" designation for contributors reporting de-identified data accessed during routine clinical care. Study sites underwent review by local institutional review boards if needed to access data outside of routine care, or to maintain a key to identify patient records, at their discretion.

This multi-site prospective cohort study included recipients of any SOT with laboratoryconfirmed COVID-19 by polymerase chain reaction of an upper or lower respiratory sample.

Study data were collected using the secure, web-based data capture software program REDCap (Research Electronic Data Capture), hosted at the University of Washington. 22, 23 The standardized electronic case report form included only de-identified patient data. 

Results are presented descriptively in pre-specified subpopulations, including in patients stratified by death by 28 days, hospitalized patients only, and by organ(s) transplanted. The primary outcome was 28-day mortality in the subset of patients hospitalized after COVID diagnosis. We summarized published studies of COVID-19 in hospitalized SOT and general populations as of June 19, 2020, and calculated pooled weighted estimates of mortality and baseline comorbidities. Studies of SOT recipients that included >10 patients and outcomes of patients hospitalized with COVID-19 were considered for inclusion. The association between baseline covariates and death was assessed in univariate and multivariable analyses using logistic regression for both the subset hospitalized after COVID diagnosis and among the full cohort. We assessed all collected variables, and those that either had a p<0.1 in univariate analysis or that were considered important based on results of previous studies, and for which there were adequate events to allow for meaningful analysis, were considered for the multivariable model. Stepwise regression was used to inform the final model and potential interactions among covariates were assessed. Complete data were available for the majority of variables; missing data were handled via multiple imputation using the multivariate by chained equations method. 23 The final multivariable logistic regression model included age; gender; mTOR-containing maintenance immunosuppression regimen, baseline comorbidities (congestive heart failure [CHF], chronic lung disease, diabetes mellitus, obesity) individually or in combination; initial absolute lymphocyte count; and evidence of pneumonia on initial chest imaging. Both age and absolute lymphocyte count were assessed as dichotomous variables (age <=65 vs > 65 years, lymphocytes <0.5 vs >=0.5 x 10 9 /L), based on clinical relevance and previously published studies, and A c c e p t e d M a n u s c r i p t 9 after analyzing the effects as continuous variables and as multiple discrete strata. Although there are no defined well-validated measures of immunosuppression intensity, we assessed the following as potential surrogates, in accordance with prior studies: earlier time post-transplant, thoracic (lung or heart) compared to non-thoracic organ transplant, receipt of augmented immunosuppression within three months of COVID-19 diagnosis, or a higher number of baseline maintenance immunosuppressive agents. 10, 11, 16, 25 Number of maintenance immunosuppressive agents was assessed by comparing those on 2 immunosuppressants and those on 3 or more immunosuppressants to those receiving 0 or 1 immunosuppressants at baseline as a reference, considering all immunosuppressants and separately considering only the most commonly used immunosuppressants (calcineurin inhibitors, anti-metabolites, and steroids). All analyses were performed using Stata version 13.1 (Stata Corporation, College Station, Texas).

A total of 538 cases were submitted between March 7 and May 14 2020; 56 were excluded, leaving 482 in the final study population. Reasons for exclusion were: No confirmed COVID-19 diagnosis (n=6), duplicate reports (n=6), reports missing >10% of requested data (n=4), reports submitted with less than 28 days of follow-up (n=18), and cases previously published as of the date of data extraction (n=21). One report was withdrawn by the contributor. (Consort diagram; Supplemental Table 1 . The overall study population included patients with mostly community-acquired infection (83%), from a range of geographic locales, and included a small proportion of lung transplant recipients (~6%) and recent transplant recipients (~6%). Most were receiving calcineurin inhibitor-based maintenance immunosuppression (91%). A high proportion had at least one of the underlying comorbidities listed in Table 1 (445 [92.3%] overall, and 97% of kidney, 78% of liver, 87% of heart, and 86.7% of lung recipients).

Seventy-eight percent of the cohort was hospitalized for COVID-19. A small number were already hospitalized for another indication at the time of diagnosis (6.4%), and the remainder (16%) were managed on an outpatient basis. Of patients hospitalized due to COVID-19, 147 (39%) required ICU care and 117 (31%) required mechanical ventilation. The mortality rate by day 28 after COVID-19 diagnosis among the overall cohort was 90 of 482 (18.7%), and 77 of 376 (20.5%) among those hospitalized. A summary of clinical outcomes is shown in Table 2 for the entire cohort and for the subset hospitalized due to COVID-19. Table S2 shows the baseline characteristics and outcomes stratified by organ type transplanted.

Unadjusted Kaplan Meier analyses of mortality by day 28 after diagnosis, separately for all patients and the hospitalized subset, by specific organ transplant type, and by thoracic (heart or lung) versus non-thoracic organ transplant, are shown in Figure 1 . For the majority of subsets assessed, mortality appeared to stabilize by the end of the 28-day follow-up.

A c c e p t e d M a n u s c r i p t 11

Risk factors for mortality were analyzed among the subset of patients hospitalized with COVID-19, since mortality occurred primarily in this group and because comparator studies in general populations focus on this subset (Table 3) . Age >65, CHF, chronic lung disease, and obesity, rather than all comorbidities assessed, were the baseline factors independently associated with mortality by 28 days. These comorbidities were common: the proportions with 1, or >2 were 200 (42.3%) and 84 (17.8%), respectively. Rates of these baseline comorbidities were similar among the different organ transplant groups except for lung recipients, in whom 9 (32%) had 2 or more of these comorbidities. When these specific comorbidities were assessed in combination in multivariable analysis (omitting the individual components), the strength of the association with mortality was higher with a greater number of comorbidities: 1 vs 0, aOR 3.0 (95%CI: 1.4-6.3), >2 vs. 0, aOR 11.0 (95%CI: 5.0-24.0), suggesting a cumulative effect of baseline comorbidities on mortality. Race, ethnicity, and male gender were not associated with mortality. Presence of pneumonia at baseline (assessed by abnormal chest imaging) and lymphopenia (<0.5 thousand/mL) were independently associated with mortality. Qualitatively and quantitatively similar results were seen in the overall cohort for all of these analyses (data not shown).

We explored multiple potential surrogates of immunosuppression intensity (earlier time posttransplant, thoracic [lung, heart] compared to non-thoracic organ transplant, or receipt of augmented immunosuppression within three months), and did not find an association of any of these factors with mortality. Results of the analysis between thoracic vs. non-thoracic organs and mortality were similar when thoracic organ was restricted to lung transplant only. We also assessed the association between a higher number of maintenance immunosuppressive agents (0-1 vs 2 and A c c e p t e d M a n u s c r i p t 12 0-1 vs 3 or more immunosuppressants at baseline) and death in univariate analysis and similarly found no association either when considering all types of maintenance immunosuppression or when restricting analysis to calcineurin inhibitors, antimetabolites, and steroids only. (Table 3) Interventions and treatments.

The most commonly used intervention was immunosuppression modification in 337 (70%) patients.

( Figure 2 ) In 56% the antimetabolite (mycophenolate or azathioprine) was discontinued, 10% had the antimetabolite reduced, and <1% had all immunosuppression discontinued. The most commonly used treatment was chloroquine or hydroxychloroquine, in 296 (61%) patients. QTc prolongation was reported in 13/296 (4.4%). One patient experienced ventricular fibrillation with Torsade de pointes, and one patient developed a junctional arrhythmia. Fourteen (2.9%) patients were treated with remdesivir, 49 (10%) received corticosteroids, and 63 (13%) received an anti-IL6-receptor monoclonal antibody, either tocilizumab (57) or sarilumab (5).

In this multicenter cohort study of SOT recipients with COVID-19, the 28-day mortality rate among hospitalized patients was 20.5%. Older age, CHF, chronic lung disease, obesity, lymphopenia, and radiographic abnormalities at presentation were associated with mortality, but transplant-related measures of immunosuppression intensity were not.

The mortality rate of hospitalized patients in the cohort was similar to pooled weighted estimates derived from prior studies (Table S3a) [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] although these studies were small and heterogeneous. A small proportion of patients (33 [8.7%] ) in this cohort remained hospitalized by day 28, so it is A c c e p t e d M a n u s c r i p t 13 possible that the eventual mortality rate may have been slightly higher. Among the underlying comorbidities assessed, CHF, chronic lung disease, and obesity were independently associated with increased mortality. The prevalence of these baseline comorbidities was high, and the magnitude of the association of these comorbidities with mortality was greater with increasing numbers of comorbidities, suggesting cumulative impact. Several previously described comorbidities associated with mortality in general populations (DM, CKD, HTN) 2,3,26 were not independently associated with mortality in this SOT cohort. Reason(s) for this difference remain uncertain, but might be related to definitions utilized or other differences in populations. Pneumonia at the time of diagnosis, as defined by chest imaging abnormalities, was also associated with mortality among hospitalized patients, as similarly reported in general population studies. 27, 28 Collectively, these findings are compatible with underlying comorbidities and illness severity at presentation as the major determinants of mortality in SOT recipients. Although there have been concerns about geographic variability in outcomes, an independent association of mortality with geographic location was not identified in this study. Although black and Hispanic patients comprised a higher proportion of this cohort relative to Organ Procurement and Transplantation Network data as of June 4, 2020, we did not observe an association of these factors with mortality. The observational study design precluded assessment of the relationship between various treatments utilized and mortality. Table S3b ). 2,27-31 Mortality estimates ranged from 8-33% in these studies (pooled weighted average, 19 .3% [933 of 4831]), and were generally comparable to the mortality among the SOT cohort in the current study. Among general population cohort studies, the prevalence of baseline comorbidities and median age were also similar to those in the current SOT cohort. Additionally, there was a consistent association of age and underlying comorbidities with increased mortality across general population studies, similar to that found in the present SOT cohort, highlighting the impact of these factors on mortality across different populations. Similarly, in a large population of patients with cancer, age and comorbidities were associated with mortality, but not stage of malignancy or recent treatments including chemotherapy or immunotherapy. 32 However, future comparisons between general and immunocompromised populations should include careful adjustment for comorbidities and the use of well-validated mortality risk scores in this setting.

There are several implications of our findings. First, we identified specific factors (age >65 years, CHF, chronic lung disease, obesity) for COVID-19 mortality in hospitalized SOT recipients, that should facilitate targeting of future studies of prevention or treatment to high-risk SOT populations. SOT is a life-saving and quality of life-improving intervention, and immunosuppression-related factors in this setting did not appear to independently impact mortality. These findings support current Center for A c c e p t e d M a n u s c r i p t 15 Medicare and Medicaid Services recommendations that SOT be considered a grade 3b procedure (i.e. do not delay), even in the setting of widespread COVID-19 activity, 33 as long as other necessary resources to safely perform transplantation and associated care are available. Although similar to the general population, mortality among SOT recipients hospitalized with COVID-19 is very high, and prevention of new infections using evidence-based individual and institutional strategies such as those put forth by the AST will be essential to mitigate the negative effects of this pandemic. 34 The strengths of the study include the flexible design, broad multi-center participation, standardized data collection, and standardized 28-day duration of follow-up. We demonstrate the feasibility and importance of a broadly collaborative, multidisciplinary approach to rapidly develop a dataset to inform on an emerging infectious challenge. We also acknowledge potential limitations. We relied on clinician-reported cases, which may be subject to reporting bias; however, contributors attested that cases were reported consecutively and not selectively. As for all reported prior studies, diagnosis of COVID-19 and subsequent inclusion may be subject to testing bias. We focused on hospitalized patients, and thus these conclusions may not be broadly generalizable to all patients diagnosed and managed in the outpatient setting, particularly as testing practices evolve. The pragmatic study design precluded the collection of extensive laboratory parameters as well as complex clinical risk scores. Future studies should consider the predictive value of clinical risk scores such as the Sequential Organ Failure Assessment (SOFA) in COVID-19 outcomes. Independent verification of all submitted data also was not feasible. Despite follow-up of all patients for 28 days, 33 (8.7%) were still hospitalized, so the total mortality rate might eventually be slightly higher than that reported, and longer-term outcomes were not assessed. The numbers of patients with nonkidney organ transplants and those who were early in the post-transplant period was small, and even though these factors were not associated with mortality in multivariable analysis, this may have been limited by power. Thus, additional studies are needed in non-kidney organ transplant A c c e p t e d M a n u s c r i p t 16 recipients and those who are recently transplanted. The sample size, while substantially larger than previously reported, might not have been large enough to identify less frequent covariates or those with lesser association with mortality.

In summary, among hospitalized SOT recipients with COVID-19 with high rates of underlying medical comorbidities, mortality was similar to that described in the general population and was driven largely by underlying medical comorbidities and certain clinical features at presentation, rather than surrogate measures of immunosuppression intensity. Future studies to better define the attributable effect of immunosuppression on outcomes in SOT recipients are warranted. A c c e p t e d M a n u s c r i p t 23 A c c e p t e d M a n u s c r i p t 26 A c c e p t e d M a n u s c r i p t 28 

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We are grateful for critical review and comments by Siddhartha Kapnadak MD, and for the assistance of Emma Honeyman BS with manuscript preparation.