More people with fever and body aches are turning to nonsteroidal anti-inflammatory drugs (NSAIDs) to ease symptoms, but the drugs have come under new scrutiny as investigators work to determine whether they are a safe way to relieve the pain of COVID-19 vaccination or symptoms of the disease.
Early on in the pandemic, French health officials warned that NSAIDs, such as ibuprofen, could worsen coronavirus disease, and they recommended switching to acetaminophen instead.
The National Health Service in the United Kingdom followed with a similar recommendation for acetaminophen.
But the European Medicines Agency took a different approach, reporting "no scientific evidence" that NSAIDs could worsen COVID-19. The US Food and Drug Administration also opted not to take a stance.
The debate prompted discussion on social media, with various reactions from around the world. It also inspired Craig Wilen, MD, PhD, from Yale University School of Medicine in New Haven, Connecticut, and his team to examine the effect of NSAIDs on COVID-19 infection and immune response. Their findings were published online January 20 in the Journal of Virology.
"It really bothered me that nonevidence-based decisions were driving the conversation," Wilen said. "Millions of people are taking NSAIDs every day and clinical decisions about their care shouldn't be made on a hypothesis."
One theory is that NSAIDs alter susceptibility to infection by modifying angiotensin-converting enzyme 2 (ACE2). The drugs might also change the cell entry receptor for SARS-CoV-2, alter virus replication, or even modify the immune response.
British researchers, also questioning the safety of NSAIDs in patients with COVID-19, delved into National Health Service records to study two large groups of patients, some of whom were taking the pain relievers.
"We were watching the controversy and the lack of evidence and wanted to contribute," lead investigator Angel Wong, PhD, from the London School of Hygiene and Tropical Medicine, told Medscape Medical News.
And with nearly 11 million NSAID prescriptions dispensed in primary care in England alone in the past 12 months, the inconsistency was concerning.
The team compared COVID-19-related deaths in two groups: one group of more than 700,000 people taking NSAIDs, including patients with rheumatoid arthritis and osteoarthritis; and another of almost 3.5 million people not on the medication.
NSAIDs work by inhibiting cyclooxygenase (COX)-1 and COX-2 enzymes in the body, which are crucial for the generation of prostaglandins. These lipid molecules play a role in inflammation and are blocked by NSAIDs.
The investigators found no evidence of a harmful effect of NSAIDs on COVID-19-related deaths; their results were published online January 21 in the Annals of the Rheumatic Diseases.
The results, they point out, are in line with a Danish study that also showed no evidence of a higher risk for severe COVID-19 outcomes with NSAID use.
"It's reassuring," Wong said, "that patients can safely continue treatment."
More New Evidence
Wilen's team found that SARS-CoV-2 infection stimulated COX-2 expression in human and mice cells. 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 their mouse model of SARS-CoV-2 infection, the investigators saw that NSAIDs impaired the production of proinflammatory cytokines and neutralizing antibodies. The findings suggest that NSAIDs influence COVID-19 outcomes by dampening the inflammatory response and production of protective antibodies, rather than modifying susceptibility to infection or viral replication.
Understanding the effect of NSAIDs on cytokine production is critical, Wilen pointed out, because they might be protective early in COVID-19 but pathologic at later stages.
Timing is crucial in the case of other immunomodulatory drugs. For example, dexamethasone lowers mortality in COVID-19 patients on respiratory support but is potentially harmful for those with milder disease.
There is a lot to learn, still, Wilen acknowledged. "We may be seeing something similar going on with NSAIDs, where the timing of treatment is important."
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