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Outcomes of COVID‐19 in solid organ transplant recipients: A matched cohort study

Abstract Whether solid organ transplant (SOT) recipients are at increased risk of poor outcomes due to COVID‐19 in comparison to the general population remains uncertain. In this study, we compared outcomes of SOT recipients and non‐SOT patients hospitalized with COVID‐19 in a propensity score matched analysis based on age, race, ethnicity, BMI, diabetes, and hypertension. After propensity matching, 117 SOT recipients and 350 non‐SOT patients were evaluated. The median age of SOT recipients was 61 years, with a median time from transplant of 5.68 years. The most common transplanted organs were kidney (48%), followed by lung (21%), heart (19%), and liver (10%). Overall, SOT recipients were more likely to receive COVID‐19 specific therapies and to require ICU admission. However, mortality (23.08% in SOT recipients vs. 23.14% in controls, P = .21) and highest level of supplemental oxygen (P = .32) required during hospitalization did not significantly differ between groups. In this propensity matched cohort study, SOT recipients hospitalized with COVID‐19 had similar overall outcomes as non‐SOT recipients, suggesting that chronic immunosuppression may not be an independent risk factor for poor outcomes in COVID‐19.


| Therapeutic approach
The overall therapeutic approach for SOT recipients and non-SOT recipients in this period was the same. Investigational agents, including remdesivir, in either clinical trials or the expanded access program were considered in all patients with COVID-19 at our center. Early in the pandemic, off label hydroxychloroquine with or without azithromycin was also considered. Beginning April 10, 2020, intravenous methylprednisolone 1 mg/kg/d for at least 5 days was also given to those patients with severe COVID-19, defined as having an oxygen saturation below 94% on ambient air or requiring supplemental oxygenation. One or more doses of intravenous tocilizumab 4-8 mg/kg (maximum 800 mg) were also considered for patients with at least 7 days of symptoms, progressive respiratory distress, and rising levels of inflammatory markers such as C-reactive protein, ferritin, or interleukin-6 (IL-6). Among SOT recipients, baseline immunosuppression was moderately decreased upon diagnosis, with a particular emphasis on decreasing or discontinuing antimetabolite drugs such as mycophenolate or azathioprine.

| Analytic approach
All SOT recipients hospitalized and RT-PCR positive for SARS-CoV-2 were included as cases. We used the nearest-neighbor propensity-score matching method in this analysis. The propensityscore model includes age categories (below 55, between 55 and 70, and above 70 years of age), gender (M/F), BMI (above or below 30 kg/m 2 ), race (white, black, and other), ethnicity (Hispanic and non-Hispanic), hypertension, and diabetes. For each case, three control patients were matched except for one case, who matched only two controls samples. The covariates in propensity score models were presented before and after propensity score matching in Table 1.
Mean and standard deviation, number, and percent were used to summarize clinical characteristics and outcomes including death and hospital discharge. Chi-square and two-sample t test were used to compare categorical or continuous variables between these groups. Inpatient mortality was analyzed by Kaplan-Meier survival analysis.
Finally, outcomes on intubation and hospital discharge were also summarized. All analyses were conducted by using SAS statistical software (version 9.4, SAS Institute, Cary, NC).
Due to these differences in major COVID-19 risk factors, patients in the control group were subsequently selected for propensity score matching based on age categories (<55, 55-70, and >70 years of age), gender, race, ethnicity, BMI (above or below 30 kg/m 2 ), diabetes, and hypertension. A total of 350 patients were selected for the matched control group, for a 3:1 ratio comparison with the SOT recipients. After matching, there were no significant differences in any of these demographic and medical morbidities between the SOT recipient and non-transplant groups (Table 1).

| Transplant-related characteristics
The transplant-related characteristics of the 117 SOT recipients included in this cohort are displayed in Table

| COVID-19 clinical course, disease severity, and mortality
Laboratory values, antiviral treatment, and disease severity are displayed in Table 3. There were no significant differences in peak white blood cell count, liver enzymes, total bilirubin, or nadir albumin levels between groups. Both initial and peak serum creatinine levels were significantly higher among SOT recipients compared to controls (P < .01). While some inflammatory markers including initial and peak CRP, procalcitonin, D-Dimer, and IL-6 were not significantly different, both initial and peak ferritin were significantly higher among SOT recipients compared to controls (P < .01 and 0.09, respectively).
SOT recipients were significantly more likely to receive COVID-19 treatments including hydroxychloroquine, remdesivir, tocilizumab, and high-dose corticosteroids (all P < .01, Table 3). In terms of disease severity, SOT recipients were more likely to have been admitted to the intensive care unit (32.5% vs. 27.7%, P = .04) although highest level of oxygen support was not different between the groups. There were no differences in median length of stay between the control and SOT groups either before ( Figure 1).
In addition, there was no significant difference in 28-day mortality between different solid organ transplant types (P = .69).

| D ISCUSS I ON
Understanding patient characteristics associated with poor outcomes related to COVID-19 remains a high priority, particularly in distinct groups such as those on chronic immunosuppression.
Among SOT recipients, there is ongoing debate as to whether TA B L E 1 Baseline characteristics and 28-day mortality of SOT recipients and control group before and after propensity score matching Before propensity score matching After propensity score matching course-factors that might confound interpretation of the overall risk for immunosuppressed patients. 14 As extensively described by now, SARS-CoV-2 infection seems to trigger a dysregulated hyperinflammatory cascade that is associated with high mortality in a small but significant proportion of individuals. Termed COVID-19 associated hyperinflammation (COVID-HI), the exact mechanism remains undefined but appears to overlap with several known inflammatory syndromes such as cytokine release syndrome (CRS), macrophage activation syndrome, hemophagocytic lymphohistiocytosis (HLH), and involving multiple pathways including T cell and macrophage activation as well as complement fixation. 26

TA B L E 3 (Continued)
F I G U R E 1 Twenty-eight-day survival probability in solid organ transplant recipients and matched controls