NSAIDs in patients with COVID-19: what evidence is available?

Declared a pandemic by the World Health Organization in mid-March 2020, by 3 May 2020 SARS-CoV-2¹ had more than 3,356,000 confirmed cases and about 238,700 official deaths.² The priority of health authorities is to limit the spread of the virus by avoiding overcrowding of hospitals to provide the best possible care to patients. In this critical health scenario, the safety of the most commonly used drugs is of considerable importance.

Spotlight on NSAIDs

SARS-CoV-2, like other human pathogenic coronaviruses, binds to target cells through the angiotensin converting 2 enzyme (ACE2).³ In an article published in Lancet Respiratory Medicine, some authors argue that the expression of ACE2 may be increased by some drugs, including ibuprofen, and that this increase may facilitate infection with SARS-CoV-2 and promote the development of severe and fatal forms of COVID-19.⁴ However, there is little evidence to support such a mechanism for ibuprofen.
The safety of non-steroidal anti-inflammatory drugs in patients with COVID-19 has been officially challenged by a communication from the French Ministry of Health concerning serious adverse reactions to ibuprofen in four patients with COVID-19.⁵ Although the cases reported have not been confirmed or made available in the literature, the possible relationship between NSAIDs and COVID-19 has rapidly gained public attention due to wide and heterogeneous media coverage.^6-8

Available evidence

In response to the French Minister's communication, the major regulatory and health agencies promptly gave their views on the use of NSAIDs in the context of the current pandemic. The FDA and EMA have reported that there is no sound scientific evidence to prove a relationship between NSAIDs and the worsening of COVID-19.^9,10 At the same time, they urge patients on NSAIDs for chronic inflammatory diseases not to stop treatment. In addition, the EMA added that all NSAIDs and also paracetamol should be considered before starting anti-inflammatory or antipyretic therapy, specifying that most European guidelines for the treatment of fever and pain propose paracetamol as the first choice.¹⁰
In line with EMA and FDA recommendations, WHO has stated that there are no recent studies to evaluate the data, but recommends the use of paracetamol as an alternative to ibuprofen in case of SARS-CoV-2 infection.¹¹ In fact, agencies have stated that, as already reported in the data sheets of many NSAIDs, their anti-inflammatory effects can mask the symptoms of a worsening infection. In addition, the antipyretic activity exerted by some NSAIDs and paracetamol to control fever could counteract the effects of high body temperature, probably useful to reduce the replication capacity of pathogens.¹² WHO, FDA and EMA have all stated the need for further investigation through appropriate epidemiological studies.^9-11
The scientific community has also expressed concerns about the potential effects of ibuprofen or NSAIDs in patients with COVID-19, mainly pointing out the absence of scientific evidence.^13-16 However, some researchers have expressed concerns about the association between NSAIDs and increased risk of adverse effects if these drugs are taken by patients with acute viral respiratory infections, including COVID-19.^17,18
On 19 April 2020, the WHO published the results of a systematic review,¹⁹ which aimed to assess the effects of past and current use of NSAIDs on a range of outcomes (including mortality, acute respiratory distress syndrome, acute organ failure and opportunistic infections, acute health care use, quality of life and long-term survival) in patients with viral respiratory infections.
The review selected 73 studies focusing on acute viral respiratory infections, but none had been specifically conducted in patients with COVID-19, SARS or MERS. Evidence of increased mortality in adults and children is rather weak. The effects of NSAIDs on the risk of ischemic and haemorrhagic stroke or myocardial infarction in selected patients are unclear. Furthermore, there are no differences between ibuprofen and paracetamol related to hospitalization and mortality for all causes in children with fever. No particular adverse events have been detected either. Finally, the analysis showed that there is no evidence of effects of NSAID use on access to the emergency room, quality of life or long-term survival. The main limitation of this study is the absence of data directly related to COVID-19, SARS or MERS. In addition, the different types of NSAIDs were often not distinguished in the various studies, which were mostly controlled randomised trials.

In practice

There is currently no scientific evidence establishing a correlation between NSAIDs and a worsening of the course of the COVID-19 disease. There is an urgent need to improve pharmacological and pharmacoepidemiological knowledge in this regard through targeted studies.