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Pre-infection exposures to rituximab (Rituxan) or chemotherapy were associated with an increased incidence of pulmonary fibrosis in adults hospitalized for COVID-19, a nationwide cohort study suggested.

Incidence of a new pulmonary fibrosis diagnosis at 60 days was significantly higher in both rituximab-exposed patients (incidence rate ratio [IRR] 2.5, 95% CI 1.2-5.1) and chemotherapy-exposed patients (IRR 1.6, 95% CI 1.3-2.0) when compared with matched COVID-hospitalized controls who did not receive these drugs, reported Ayodeji Adegunsoye, MD, of the University of Chicago, and colleagues.

Pre-COVID exposure to corticosteroids also was linked with a small increase in pulmonary fibrosis incidence (IRR 1.2, 95% CI 1.0-1.3, P=0.02), but the association didn't hold up as well in sensitivity analyses, according to the findings in .

"With over 640 million people diagnosed with COVID-19, and worldwide mortality exceeding six million deaths, there is a pressing need to identify factors that may complicate the post-infection course and increase the risk of post-COVID-19 pulmonary fibrosis," wrote Adegunsoye and co-authors.

To that end, they specifically focused their analysis on four therapies known to modify risk for pulmonary fibrosis, initially hypothesizing that a lower risk would be detected with steroids and rituximab and a higher risk with chemotherapy and amiodarone, an antiarrhythmic. As it turned out, however, no higher incidence of pulmonary fibrosis was observed with amiodarone (IRR 0.8, 95% CI 0.6-1.1).

In the U.S., new cases of pulmonary fibrosis have been increasing in recent years and patients hospitalized for severe COVID-19 may be at particular risk, according to the researchers. One study showed that up to 11% of patients hospitalized for COVID in the months after being discharged.

Adegunsoye's group repeated their analysis in nearly 1 million COVID-negative hospitalized subjects. In this cohort, the overall rate of a new pulmonary fibrosis diagnosis at 60 days was about half that of the COVID-19 group (0.5 vs 1.1 per 100 person-years, respectively).

Here they found associations between all four drugs and incidence of a new diagnosis of pulmonary fibrosis at 60 days, though to a lower degree with rituximab (IRR 1.7, 95% CI 1.0-2.9), "suggesting a synergistic effect with SARS-CoV-2 infection on the fibrotic process," the researchers said.

This isn't the first time rituximab has been linked with poor outcomes in COVID-19. Prior studies during the pandemic have shown an increased risk for severe COVID-19 for patients taking the anti-CD20 antibody for cancer, rheumatoid arthritis, and multiple sclerosis.

Ultimately, the researchers cautioned that "COVID might not necessarily have been the pulmonary fibrosis-causing exposure," as study participants on these drugs may simply have been at higher risk.

For their study, Adegunsoye's group plumbed the National COVID-19 Cohort Collaboration (N3C) Data Enclave, which aggregates and harmonizes COVID-19 data across the U.S. They identified 277,984 patients hospitalized for COVID-19 with no existing diagnosis of pulmonary fibrosis and at least 60 days of follow-up. Overall incidence of a new pulmonary fibrosis at 60 days was 1.1 per 100 person-years.

After exclusions, the propensity-score matched group included 1,032 patients who had been exposed to rituximab, 9,011 to a chemotherapeutic agent, 43,862 to systemic corticosteroids, and 5,861 to amiodarone. Each of these patients was matched to another patient without exposure to the drug.

Incidence of a new pulmonary fibrosis diagnosis was quite different when comparing the drug-exposed patients to their matched controls, reaching 2.8 per 100 person-years for the rituximab group (vs 1.1 for their matched controls) and 2.2 per 100 person-years in the chemotherapy group (vs 1.3 for their controls).

An exposure was included if the drug's effects could reasonably have been anticipated to persist when the COVID-19 infection developed. The rituximab exposure window was 6 months prior to infection date; systemic corticosteroids, 2 weeks prior; chemotherapy, 2 years prior; and amiodarone, 4 months prior.

All of the matched cohorts were predominately white (61-69%) and non-Hispanic (80-86%), with variance depending on drug exposure category. Women made up a majority of most of the groups (53-58%), with the exception of the amiodarone cohort (37%). Mean age ranged from 57 to 67 years across cohorts, and mean follow-ups were between 325 and 419 days.

Sensitivity analyses that examined relationships within a 30-day and 90-day follow-up period found that the risk for a pulmonary fibrosis diagnosis in the rituximab- and chemotherapy-exposed COVID patients increased over time.

Researchers cited a range of limitations to their study, many related to coding or data gaps within the N3C database. They also noted that analyses were not able to be performed based on the dominant variant at a particular time.

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