Is it safe to use NSAIDs in COVID-19 patients?

Existing evidence on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) during lower respiratory tract infections in adults with regard to mortality, pleuro-pulmonary complications, and rates of mechanical ventilation or organ failure is of extremely poor quality and very low certainty, according to the results of a systematic review.

“[T]hese results must be interpreted with extreme caution given the high risk of bias of the included studies, the very low quality of evidence, and the results' generalizability to COVID‐19 is unclear,” the researchers said. “Despite this, the summary represents the best available evidence for NSAID use in adult patients with acute lower respiratory tract infections.”

Randomized controlled trials (RCTs) and observational studies were eligible for this systematic review, as well as studies of adult patients with short-term NSAID use during acute lower respiratory tract infections, including bacterial and viral infections. All-cause mortality was the primary outcome, and secondary ones included cardiovascular, renal, and respiratory complications.

Only eight studies (two RCTs, three retrospective, and three prospective observational studies) involving a total of 44,140 patients met the eligibility criteria. Five studies examined patients with pneumonia, two were in patients with influenza, and one in a patient with acute bronchitis. Meta-analysis was not carried out due to significant heterogeneity. [Br J Clin Pharmacol 2021;87:776-784]

A trend towards a reduction in mortality and an increase in pleuro-pulmonary complications following short-term NSAID use was observed, but all studies showed high risks of bias due to lack of adjustment for confounding variables. In addition, none of the included studies reported cardiovascular outcomes.

This review focused on adults, but the findings have been seen in paediatric studies as well. [Acta Paediatrica 2010;99:861‐866; Clin Infect Dis 2002;34:434‐440; Pediatr Pulmonol 2015;50:721‐726; J Pediatr 2016;175;47.e3‐53; Clin Respir J 2018;12:253‐261; J Clin Med 2019;8:786]

Two hypotheses could explain these findings, and both warrant further investigation. First, NSAIDs mask major symptoms of inflammation leading to patients presenting with more advanced disease, and there was confounding by indication, since patients developing pleuro-pulmonary complications are more likely to take NSAIDs. Second, NSAIDs remove protective prostanoids, slowing immune responses, resolution, and intensifying organ dysfunction. [Mediators Inflamm 2015;2015:349176; Nat Rev Drug Discov 2016;15:551‐567]

Of note, the included studies in the current review only reported short-term mortality, with the longest reported follow-up of 90 days in one study. While a trend towards a reduction in mortality was observed, individual studies reported wide confidence intervals; significant uncertainty remains on the effects of NSAIDs on mortality in lower respiratory tract infections.

“While initial reports suggested that NSAIDs may worsen the course and outcomes of COVID‐19, the World Health Organization and Public Health England stated otherwise,” the researchers noted. [https://www.england.nhs.uk/coronavirus/wp-content/uploads/sites/52/2020/04/C0211-NSAIDs-RPS_14-April.pdf; https://www.ema.europa.eu/en/news/ema-gives-advice-use-non-steroidal-anti-inflammatories-covid-19; BMJ 2020; 368:m1086]

“Our results appear to support the latter as there is insufficient evidence to support an association of NSAID use and worsening of outcomes in acute lower respiratory tract infections,” they added.