NSAIDs may exacerbate COVID-19, study suggests

Non-steroidal anti-inflammatory drugs (NSAIDs) reduced both antibody and inflammatory responses to SARS-CoV-2, the virus  that causes the novel coronavirus (COVID-19), in mice, according to a new study published in the Journal of Virology.

NSAIDs inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which mediate the production of prostaglandins (PGs). As PGs play diverse biological roles in homeostasis and inflammatory responses, inhibiting PG production with NSAIDs could affect COVID-19 pathogenesis in multiple ways, including altering susceptibility to infection by modifying expression of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for SARS-CoV-2; regulating replication of SARS-CoV-2 in host cells; and modulating the immune response to SARS-CoV-2.

For the study, researchers investigated these potential roles. The demonstrated that SARS-CoV-2 infection upregulates COX-2 in diverse human cell culture and mouse systems. However, suppression of COX-2 by two commonly used NSAIDs, ibuprofen and meloxicam, had no effect on ACE2 expression, viral entry, or viral replication.

In contrast, in a mouse model of SARS-CoV-2 infection, NSAID treatment reduced production of pro-inflammatory cytokines and impaired the humoral immune response to SARS-CoV-2, as demonstrated by reduced neutralizing antibody titers, the researchers said.

NSAIDs are one of the most used anti-inflammatory medications. In addition to taking NSAIDs for chronic conditions such as arthritis, people may take them for shorter periods of time during infections, during acute inflammation as experienced with COVID-19, and for side effects from vaccination, such as soreness, fever, and malaise, the researchers said.

The researchers said they found that NSAID treatment may influence COVID-19 outcomes by dampening the inflammatory response and production of protective antibodies rather than modifying susceptibility to infection or viral replication.

The study also suggests that the consequences of NSAID use during natural infection and vaccination should be evaluated in humans. NSAIDs' anti-inflammatory activity might be detrimental early in SARS-CoV-2 infection, because at this stage, inflammation is usually helpful. That changes at later stages of COVID-19, particularly if the patient undergoes an intense inflammation known as a cytokine storm, the researchers said. A cytokine storm is an immune response of inflammatory compounds that often occurs in COVID-19 patients, and can lead to complications, need for intensive care, and death.

A reduction in neutralizing antibodies caused by NSAIDs might be benign, or it might blunt the immune system's ability to fight the disease during the early stages of infection, the researchers said. Additionally, they said it could also reduce the magnitude or length of protection from either natural infection or vaccination.  

Craig Wilen, MD, PhD, principal investigator and assistant professor of laboratory medicine and immunology at the Yale University School of Medicine, said he and his team expected that there would be little to no effect of NSAIDs on viral infection. They also thought that NSAIDs would not significantly affect the antibody response to natural infection.

"We initially didn't even carefully look at the antibody response, because we didn't expect it to be altered by NSAIDs,” Wilen said in a statement. “This turned out to be wrong.”

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