No current evidence supporting risk of using Ibuprofen in patients with COVID‐19

Dear Editor

Severe Acute Respiratory Syndrome (SARS‐CoV‐2) is a novel RNA virus that infects cells expressing the angiotensin‐converting enzyme (ACE2) receptor and is associated with an acute respiratory disease named COVID‐19. It has been hypothesized that ACE2 expression can be increased by Ibuprofen leading to a higher risk for severe COVID‐19. ¹ Despite the reasonable mechanistic background and results from studies suggesting that Ibuprofen may be associated with complications of community‐acquired pneumonia in children, ² , ³ there is no current evidence that this NSAID aggravates a SARS‐CoV‐2 infection in any age group.

It is possible that potential negative outcomes related to patients using Ibuprofen to relieve respiratory symptoms are more likely to be observed due to a more severe infection rather than the drug, which is known as reverse causality bias. ⁴ In fact, the use of Ibuprofen and its effects on ACE2 expression in patients with SARS‐CoV‐2 infection remains an important and controversial issue. Despite animal models have found that Ibuprofen can enhance the ACE2 expression ⁵ and theoretically facilitate binding, internalization and viral infection, a recent paper ⁶ suggested that the mechanism of lung injury during the SARS‐CoV‐2 infection may be through inappropriate effects of excess free angiotensin‐II protein as a consequence of ACE2 downregulation leading to overstimulation of AT1 receptor (AT1R), pulmonary vasoconstriction in response to hypoxia, increased vascular tone and subsequent hydrostatic oedema formation. Angiotensin‐II is recognised to act as a powerful pro‐inflammatory mediator through stimulation of AT1R ⁷ , ⁸ and has been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS), ⁹ a condition commonly found in patients with critical COVID‐19. Although it seems counter‐intuitive, it has been suggested that a higher ACE2 expression followed by the use of AT1R antagonists may result to production of the vasodilator angiotensin 1‐7 and protect against acute injury. ⁶ Therefore, in this hypothetical scenario, it is paradoxically reasonable to assume that Ibuprofen can have positive effects against SARS‐CoV‐2 if used in conjunction with AT1R antagonists. To date, there is more speculation than robust scientific evidence that points to the true effect of NSAIDs, especially Ibuprofen, on COVID‐19. Therefore, further studies are urgently needed to verify if strategies to enhance ACE2 expression on cell membrane and the use AT1R antagonists can lead to a decrease in lung injury.

To date, there is no evidence supporting the association between Ibuprofen and increased risk of severity of COVID‐19. We strongly recommend observational studies reporting data on cases of SARS‐CoV‐2 treated with Ibuprofen and its consequences. This will allow the adoption of an evidence‐based practice.

DISCLOSURE

None.