Pharmacotherapy and pulmonary fibrosis risk after SARS-CoV-2 infection: a prospective nationwide cohort study in the United States
Ayodeji Adegunsoye, Rachel Baccile, Thomas J. Best, Victoria Zaksas, Zhang Hui, Rasika Karnik, Bhakti K. Patel, Anthony Solomonides, William F. Parker, Julian Solway
Abstract
Background: Pulmonary fibrosis is characterized by lung parenchymal destruction and can increase morbidity and mortality. Pulmonary fibrosis commonly occurs following hospitalization for SARS-CoV-2 infection. As there are medications that modify pulmonary fibrosis risk, we investigated whether distinct pharmacotherapies (amiodarone, cancer chemotherapy, corticosteroids, and rituximab) are associated with differences in post-COVID-19 pulmonary fibrosis incidence. Methods: We used the National COVID-19 Cohort Collaboration (N3C) Data Enclave, which aggregates and harmonizes COVID-19 data across the United States, to assess pulmonary fibrosis incidence documented at least 60 days after COVID-19 diagnosis among adults hospitalized between January 1st, 2020 and July 6th, 2022 without pre-existing pulmonary fibrosis. We used propensity scores to match pre-COVID-19 drug-exposed and unexposed cohorts (1:1) based on covariates with known influence on pulmonary fibrosis incidence, and estimated the association of drug exposure with risk for post-COVID-19 pulmonary fibrosis. Sensitivity analyses considered pulmonary fibrosis incidence documented at least 30- or 90-days post-hospitalization and pulmonary fibrosis incidence in the COVID-19-negative N3C population. Findings: Among 5,923,394 patients with COVID-19, we analyzed 452,951 hospitalized adults, among whom pulmonary fibrosis incidence was 1.1 per 100-person-years. 277,984 hospitalized adults with COVID-19 were included in our primary analysis, among whom all drug exposed cohorts were well-matched to unexposed cohorts (standardized mean differences <0.1). The post-COVID-19 pulmonary fibrosis incidence rate ratio (IRR) was 2.5 (95% CI 1.2-5.1, P = 0.01) for rituximab, 1.6 (95% CI 1.3-2.0, P < 0.0001) for chemotherapy, and 1.2 (95% CI 1.0-1.3, P = 0.02) for corticosteroids. Amiodarone exposure had no significant association with post-COVID-19 pulmonary fibrosis (IRR = 0.8, 95% CI 0.6-1.1, P = 0.24). In sensitivity analyses, pre-COVID-19 corticosteroid use was not consistently associated with post-COVID-19 pulmonary fibrosis. In the COVID-19 negative hospitalized population (n = 1,240,461), pulmonary fibrosis incidence was lower overall (0.6 per 100-person-years) and for patients exposed to all four drugs. Interpretation: Recent rituximab or cancer chemotherapy before COVID-19 infection in hospitalized patients is associated with increased risk for post-COVID-19 pulmonary fibrosis. Funding: The analyses described in this publication were conducted with data or tools accessed through the NCATS N3C Data Enclave https://covid.cd2h.org and N3C Attribution & Publication Policy v1.2-2020-08-25b supported by NIHK23HL146942, NIHK08HL150291, NIHK23HL148387, NIHUL1TR002389, NCATSU24 TR002306, and a SECURED grant from the Walder Foundation/Center for Healthcare Delivery Science and Innovation, University of Chicago. WFP received a grant from the Greenwall Foundation. This research was possible because of the patients whose information is included within the data and the organizations (https://ncats.nih.gov/n3c/resources/data-contribution/data-transfer-agreement-signatories) and scientists who have contributed to the on-going development of this community resource (https://doi.org/10.1093/jamia/ocaa196).