Summary
Background
Many individuals take long-term immunosuppressive medications. We evaluated whether these individuals have worse outcomes when hospitalised with COVID-19 compared with non-immunosuppressed individuals.
Methods
We conducted a retrospective cohort study using data from the National COVID Cohort Collaborative (N3C), the largest longitudinal electronic health record repository of patients in hospital with confirmed or suspected COVID-19 in the USA, between Jan 1, 2020, and June 11, 2021, within 42 health systems. We compared adults with immunosuppressive medications used before admission to adults without long-term immunosuppression. We considered immunosuppression overall, as well as by 15 classes of medication and three broad indications for immunosuppressive medicines. We used Fine and Gray’s proportional subdistribution hazards models to estimate the hazard ratio (HR) for the risk of invasive mechanical ventilation, with the competing risk of death. We used Cox proportional hazards models to estimate HRs for in-hospital death. Models were adjusted using doubly robust propensity score methodology.
Findings
Among 231 830 potentially eligible adults in the N3C repository who were admitted to hospital with confirmed or suspected COVID-19 during the study period, 222 575 met the inclusion criteria (mean age 59 years [SD 19]; 111 269 [50%] male). The most common comorbidities were diabetes (23%), pulmonary disease (17%), and renal disease (13%). 16 494 (7%) patients had long-term immunosuppression with medications for diverse conditions, including rheumatological disease (33%), solid organ transplant (26%), or cancer (22%). In the propensity score matched cohort (including 12 841 immunosuppressed patients and 29 386 non-immunosuppressed patients), immunosuppression was associated with a reduced risk of invasive ventilation (HR 0·89, 95% CI 0·83–0·96) and there was no overall association between long-term immunosuppression and the risk of in-hospital death. None of the 15 medication classes examined were associated with an increased risk of invasive mechanical ventilation. Although there was no statistically significant association between most drugs and in-hospital death, increases were found with rituximab for rheumatological disease (1·72, 1·10–2·69) and for cancer (2·57, 1·86–3·56). Results were generally consistent across subgroup analyses that considered race and ethnicity or sex, as well as across sensitivity analyses that varied exposure, covariate, and outcome definitions.
Interpretation
Among this cohort, with the exception of rituximab, there was no increased risk of mechanical ventilation or in-hospital death for the rheumatological, antineoplastic, or antimetabolite therapies examined.
Funding
None.
Introduction
Although increasing vaccination uptake and other public health measures have reduced the burden of the pandemic, substantial morbidity and mortality continue to accrue in the unvaccinated and non-immune population.
and cancer, are risk factors for SARS-CoV-2 infection. However, previous studies have found that individuals with autoimmune diseases, such as rheumatoid arthritis or inflammatory bowel disease, have a greater incidence of COVID-19, but not of resultant invasive ventilation or death.
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Case series of patients with solid organ transplant with SARS-CoV-2 infection have compared the risk of severe COVID-19 outcomes to that of the general population and found higher hospitalisation and case fatality rates in the initial months of the pandemic (March to June, 2020).
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Despite the insights from these early studies, some questions remain unanswered, such as whether time trends in COVID-19 management could explain these apparent increased risks.
Evidence before this study
The evidence regarding the impact of immunosuppression and immunosuppressive medicines on COVID-19 outcomes is mixed, with previous studies finding that these individuals might have an increased risk of infection but not resultant invasive ventilation or death. It is unclear whether associations vary by medication class.
Added value of this study
This retrospective cohort study evaluated the risk of severe COVID-19 outcomes for individuals using 15 pharmacological classes that alter immune function, using electronic health information from 42 health systems in the USA. In this cohort, with the exception of rituximab, there was no increased risk of mechanical ventilation or in-hospital death for the rheumatological, antineoplastic, or antimetabolite therapies examined. Our sample size was large enough to consider separately a variety of drug classes with distinct molecular mechanisms of action, including the targeting of B-cell versus T-cell mediated immunity.
Implications of all the available evidence
Our results add to a growing body of evidence on the overall safety of most long-term immunosuppressive medications against the backdrop of continued COVID-19-related morbidity and mortality. These findings are important because of how commonly these medicines are used, and due to ongoing questions regarding the degree to which they increase the risks of poor outcomes among individuals who are hospitalised with COVID-19.
have reported no increased risk of severe COVID-19 among those taking long-term immunosuppressive medicines,
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and the theoretical possibility that such medicines might dampen the cytokine storm associated with severe COVID-19 has not been substantiated in the literature. Much of the previous long-term immunosuppressive medication literature has used small samples of patients, precluding the evaluation of specific medicine classes.
To address these research gaps, we performed a retrospective cohort study using data from the National COVID Cohort Collaborative (N3C), the largest US electronic health record repository, which captures COVID-19 care delivered between January, 2020, and June, 2021. In addition to evaluating overall risk, we also evaluated whether the therapeutic class of immunosuppressive medications alters the risk of invasive mechanical ventilation or death.
Methods
Study design and population
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It contains detailed inpatient and outpatient records, as well as drug exposure information, for a racially, ethnically, and geographically diverse group of individuals. Data are reviewed for completeness and accuracy by a data quality team, and the data are harmonised using the Observational Medical Outcomes Partnership Common Data Model.
As of June 17, 2021, the N3C had records for more than 2 130 000 COVID-19-positive individuals, the majority of which were from outpatient encounters. We used individual patient data to conduct our analyses. The N3C data transfer to the National Center for Advancing Translational Sciences (NCATS) is performed under a Johns Hopkins University Reliance Protocol (#IRB00249128) or individual site agreements with the NIH.
We defined a COVID-19-related hospitalisation as the first inpatient visit up to 21 days after the date of confirmed or suspected SARS-CoV-2 infection. To account for delays in test reporting while minimising the possibility of nosocomial infections,
we also included hospitalised individuals designated as COVID-19-positive up to 5 days after admission. We limited our analyses to individuals with complete hospitalisation episodes, documented by either discharge or death.
Exposure
We defined two mutually exclusive exposure groups: immunosuppressed individuals and non-immunosuppressed individuals up to and including at the time of admission. Individuals were considered immunosuppressed if…
Long-term use of immunosuppressive medicines and in-hospital COVID-19 outcomes: a