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Clinical Infection & Immunity

Editorial

Volume 6, Number 1, March 2021, pages 4-5

Ibuprofen and COVID-19

In March of 2020, the World Health Organization (WHO) and the Food and Drug Administration (FDA) recommended to avoid the use of ibuprofen in individuals with coronavirus disease 2019 (COVID-19) symptoms. This recommendation originated after French Health Minister Olivier Veran stated that ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDs) could aggravate the infection, and recommended instead to use paracetamol (acetaminophen). Since 2019, the National Agency for the Safety of Medicines and Health Products in France advised French health workers not to treat fever or infections with ibuprofen [1]. Experts in the UK backed this opinion, citing evidence that prolonged illness, as well as respiratory, septic and cardiovascular complications may be more common when NSAIDs are used [1]. They postulated that ibuprofen’s anti-inflammatory properties could dampen down the immune system, slowing the recovery process.

The concern centers in the dysregulation of the renin-angiotensin system by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [2, 3] that could be aggravated by ibuprofen [4]. Ibuprofen has shown to increase the angiotensin-converting enzyme 2 (ACE2) within the renin-angiotensin-aldosterone system [5]. ACE2 is also a co-receptor for the entry of SARS-CoV-2 into cells [6], so a potential increased risk of contracting the infection or worsening of COVID-19 manifestations due to ibuprofen use was feared [5], as ibuprofen might upregulate ACE2, thereby increasing the entrance of SARS-CoV-2 into the cells [7].

The European Medicines Agency reviewed the safety of ibuprofen in the treatment of COVID-19, and said that NSAIDs could be considered for treating the viral illness in some cases [8]. The FDA later changed its statement, declaring that it is not aware of scientific evidence connecting the use of NSAIDs, like ibuprofen, with worsening COVID-19 symptoms [9]. So did the WHO, who reversed its stance, stating that based on current information, they do not recommend against the use of ibuprofen [10]. They announced that moderate to high certainty evidence showed little or no difference between ibuprofen and acetaminophen (paracetamol) among children with fever, in mortality for all causes, hospitalization for any cause, acute renal failure and acute gastrointestinal bleeding. They also stated that most studies report that no severe adverse events occurred, and that only mild or moderate adverse events were observed.

Animal studies have shown that SARS-CoV-2 hijacks ACE2 to invade and damage cells, downregulating ACE2 and reducing its protective effects while exacerbating injury via angiotensin II [3]. Human retrospective observational studies, however, have not shown higher risk of infection with ACE inhibitors or angiotensin receptor blockers (ARBs) [3]. In fact, data from mice studies suggest a potential protective effect of ARBs against COVID-19 pneumonia [6].

The effects of ACE2 upregulation after infection are not yet clearly understood. If ACE2 upregulation may mitigate COVID-19 symptoms, then ibuprofen could be beneficial [7], as the drug increases ACE2 levels [5]. Furthermore, a recent publication has pointed out that besides its anti-inflammatory properties, ibuprofen has bactericidal and virucidal effects [11], and proposed the utilization of a hydrosoluble form of ibuprofen to reach a high concentration in the lungs by using it via nebulization.

Ibuprofen may exacerbate severe asthma in some individuals [12], especially children [13]. The current epidemiologic evidence on COVID-19, on the other hand, has been rather vindicative, demonstrating that there is no strong enough causal link of a harmful effect of ibuprofen in patients with COVID-19. A recent cohort study of 403 COVID-19 patients showed that ibuprofen use was not associated with worse clinical outcomes, compared with paracetamol or no antipyretic [14]. A nationwide study from Denmark on 9,236 SARS-CoV-2 positive individuals found that outcomes in terms of mortality, hospitalization, intensive care unit admission, mechanical ventilation, or renal replacement therapy were similar between users and non-users of ibuprofen and other NSAIDs [15].

Overall, the existing literature information on mechanistic studies should be used with caution when making strong statements on the use of ibuprofen [16]. As with any other medication, the risks and adverse reactions associated with its use need to be weighed up against the benefits on an individual basis, taking into consideration a patient’s pre-existing risk factors and conditions.

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Data Availability

The author declares that data supporting the findings of this study are available within the article.

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