Is the risk of ibuprofen or other non‐steroidal anti‐inflammatory drugs increased in <scp>COVID</scp>‐19?

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) include medications such as ibuprofen (often referred to by one brand name, Nurofen) commonly used to treat pain, inflammation and reduce fever. Recently, concerns have been circulating in both the media and medical literature regarding the use of NSAIDs in patients with COVID-19. Concern was initially sparked following the publication of a letter published in The Lancet on 11 March 2020.1 This letter discussed three studies, which found a significant proportion of patients with COVID-19, particularly those with severe disease, had diabetes mellitus and/or hypertension. The letter then goes on to speculate that, given angiotensin-converting enzyme 2 (ACE-2) has been implicated in viral entry into cells of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),2 patients taking ACE inhibitors or angiotensin II receptor blockers theoretically may be more vulnerable to COVID-19 infection due to up-regulation of ACE-2. The letter further hypothesises that thiazolidinediones and ibuprofen may affect disease outcomes by indirectly raising ACE-2, although this has not been clinically observed. Of note, during the 2003 SARS-CoV outbreak, reduced ACE-2 levels, rather than increased, were associated with severe disease and acute lung injury3 countering this theory. Taking anti-inflammatory drugs (ibuprofen, cortisone…) could be an aggravating factor of the infection. If you have a fever, take paracetamol. If you are already on anti-inflammatory drugs or in doubt, ask your doctor for advice.4 Later the same day, the French Ministry of Health released an official statement re-affirming Minister Veran's tweet, advising to avoid NSAID use in possible or confirmed cases of COVID-19. The statement, however, did not provide any details regarding adverse event reports, nor reference any studies as evidence for their decision. This tweet was widely circulated on social media causing lots of concern and confusion amongst health-care professionals and the public alike. Based on currently available information, WHO does not recommend against the use of ibuprofen.6 Subsequently, numerous other global authorities have released statements agreeing there is no indication that people with confirmed or suspected COVID-19 have worse outcomes with the use of ibuprofen (or other NSAIDs) based on current best evidence. These include Australia's Therapeutic Goods Administration7 the U.S. Food and Drug Administration,8 the European Medicines Agency,9 the UK's National Institute for Healthcare and Excellence,10, 11 National Health Service12 and the U.S. National Institute of Health.13 In the absence of new evidence, these statements support the continued use of NSAIDs within usual analgesia and antipyretic guidance for those with COVID-19. Additionally, the recommendation for people already taking regular NSAIDs for other indications, is to continue them (unless there is an alternative indication to cease). It is also recommended that the use of NSAIDs in each individual be reviewed with their doctor as an opportunity to stop any unnecessary use. Unfortunately, despite the lack of evidence of harm and clear consensus for continued use, there has been ongoing circulation of misleading and even fictitious information,14 particularly through social media, leading to ongoing community concern. While there is no clear evidence that ibuprofen use is harmful in suspected or confirmed COVID-19, it is important to consider, as with any medication, the risks and adverse reactions associated with its use. NSAID use has been associated with complications such as: kidney injury, gastrointestinal complications and bleeding risk. These need to be weighed up against the benefits on an individual basis, taking into consideration a patient's pre-existing risk factors and conditions. Prescribing NSAIDs in a considered approach to manage pain and discomfort, rather than isolated fever in an otherwise comfortable child, is important to avoid unnecessary use. In conclusion, despite initial concerns from theoretical postulations and unsubstantiated reports on social media, there is no evidence that NSAID use increases the risk of disease in those with COVID-19, a position which has been supported by numerous national and international authorities. A child with confirmed or suspected COVID-19 should be managed as per normal guidelines, which can include the use of NSAIDs where clinically indicated. Those already on regular NSAIDs should not discontinue them over concern of COVID-19. As with any medication, the benefits and risks of known adverse outcomes need to be weighed up on an individual basis and be prescribed accordingly, with consideration of the indication for use.