Re: Non-steroidal anti-inflammatory drugs and covid-19
As the COVID-19 pandemic is spreading, safety of non-steroidal anti-inflammatory drugs (NSAIDs) in infections has been a topic of significant international media coverage. In his editorial, Little advocates for the pragmatic and cautionary approach of avoiding NSAIDs as the first line treatment for managing the symptoms of COVID-19.(1) Similarly, the French Minister of Health stated that people should use paracetamol for managing symptoms of COVID-19, because anti-inflammatory drugs may worsen the infection.(2) For the sake of completeness, we wish to underline the scientific rationale and the biological mechanisms backing these recommendations.
In 2019, prompted by noteworthy clinical observations of severe bacterial superinfections in patients who used NSAIDs for fever or non-rheumatologic pain, the French Medicines Agency requested a new assessment of this risk to the French Pharmacovigilance Centers, following the previous assessments in 2002 and 2016. On the basis of a multidisciplinary analysis of complementary sources of data (i.e. clinical narratives of the French pharmacovigilance cases, detection of signal in the WHO pharmacovigilance database, systematic review of pharmacoepidemiological studies, and in vivo and in vitro studies), this third assessment provided converging results confirming and strengthening the signal that the use of NSAIDs for fever or non-rheumatologic pain during the early stages of infection increases the risk of severe bacterial superinfection.(3) The level of evidence led the French Medicines Agency to forward this signal to the European Medicines Agency, where it is being collectively discussed by the member states, which will eventually lead to risk mitigation measures at the European level.
In particular, the French Pharmacovigilance Centers underlined that the use of NSAIDs in acute respiratory viral infection (e.g. influenza, influenza-like illness) increases the risk of severe pulmonary bacterial superinfection. The clinical characteristics of the French pharmacovigilance cases are particularly illustrative of the severity of these superinfections, which occurred after a brief use of NSAIDs, and required hospital management or intensive care, with sometimes fatal outcomes, regardless of age, even in young healthy patients with no risk factors or comorbidities. In most of these cases, an antibiotic was associated, which is not in favor of a delayed care of the infection.
Pharmacoepidemiological studies, conducted in children and adults in France and other countries, confirm that the use of NSAIDs in acute respiratory infection increases the risk of severe pulmonary bacterial superinfection.(4) In particular, a multicenter matched case-control study found an increased risk of empyema as of the first day of ibuprofen exposure for acute respiratory viral infection in children (odds ratio: 2.79, 95% confidence interval: 1.40-5.58), but not with paracetamol, while minimizing protopathic bias and confounding.(5) Little previously underlined that this study provides a possible explanation for the unexpected results in the ibuprofen group of two of his randomized trials (i.e. more frequent reconsultations with progression of symptoms, more frequent complications, and poor control of severe symptoms), which supports a causal link between NSAIDs and superinfections.(6)
In vitro and in vivo studies suggest several biological mechanisms strengthening this causal link, beyond the well-known risk of delaying the care of the infection, because NSAIDs may mask the warning symptoms of inflammation. On the one hand, NSAIDs have immunomodulatory effects that may disrupt the recruitment and the intrinsic properties of neutrophils (e.g. adhesion, degranulation, oxidative stress, phagocytosis) by inhibiting the synthesis of eicosanoids (e.g. prostaglandin E2, prostacyclin, leukotriene B4) in the initial phase of inflammation, and then prevent the switch toward pro-resolving lipid mediators (e.g. lipoxins, resolvins, protectins) by inhibiting cyclooxygenase-2 in the late phase of inflammation.(4) On the other hand, NSAIDs may directly facilitate Streptococcus pyogenes adhesion and proliferation by upregulating vimentin, increase the risk of severe soft tissue infections, and decrease the efficacy of antibiotics,(7) which may extend to other infections.
Therefore, clinical and biological evidences converge and support a causal link between NSAIDs and severe pulmonary bacterial superinfections, even if an antibiotic is associated. Although not yet confirmed by ad-hoc clinical studies, this risk is nevertheless suspected to extend to COVID-19. Moreover, specific mechanisms may be involved in COVID-19, and add to the risk. In particular, ibuprofen increases the expression of angiotensin-converting enzyme-2,(8) which is the receptor for SARS-CoV-2 in humans,(9) and whose expression is correlated with the risk of coronavirus infection.(10) Although the exact implications of these observations remain to be clarified, they suggest a deleterious effect of NSAIDs during the initial phase of SARS-CoV-2 infection.
In conclusion, pending further research, we more than agree on the pragmatic and cautionary approach of avoiding NSAIDs as the first line treatment for managing the symptoms of COVID-19, as proposed by Little,(1) the NICE,(11) and the French Society of Pharmacology and Therapeutics.(12) The existence of a safer alternative (i.e. paracetamol at the recommended dose) makes this recommendation of common sense even more legitimate.
1. Little P. Non-steroidal anti-inflammatory drugs and covid-19. BMJ. 2020 Mar 27;m1185.
2. Day M. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. BMJ. 2020 Mar 17;m1086.
3. CRPV de Tours, CRPV de Marseille. Rapport d’expertise - Infections bactériennes graves (de la peau et des tissus mous, pleuro-pulmonaires, neurologiques et ORL) rapportées avec l’ibuprofène ou le kétoprofène dans le traitement symptomatique de la fièvre ou de douleur non rhumatologique [Internet]. 2019. Available from: https://www.ansm.sante.fr/content/download/159487/2090277/version/1/file...
4. Voiriot G, Philippot Q, Elabbadi A, Elbim C, Chalumeau M, Fartoukh M. Risks Related to the Use of Non-Steroidal Anti-Inflammatory Drugs in Community-Acquired Pneumonia in Adult and Pediatric Patients. J Clin Med. 2019 Jun 3;8(6):786.
5. Le Bourgeois M, Ferroni A, Leruez-Ville M, Varon E, Thumerelle C, Brémont F, et al. Nonsteroidal Anti-Inflammatory Drug without Antibiotics for Acute Viral Infection Increases the Empyema Risk in Children: A Matched Case-Control Study. J Pediatr. 2016 Aug;175:47-53.e3.
6. Little P. Ibuprofen use in viral infection is associated with subsequent empyema. J Pediatr. 2017 Jan;180:291–4.
7. Bryant AE, Bayer CR, Aldape MJ, Stevens DL. The roles of injury and nonsteroidal anti-inflammatory drugs in the development and outcomes of severe group A streptococcal soft tissue infections: Curr Opin Infect Dis. 2015 Jun;28(3):231–9.
8. Qiao W, Wang C, Chen B, Zhang F, Liu Y, Lu Q, et al. Ibuprofen Attenuates Cardiac Fibrosis in Streptozotocin-Induced Diabetic Rats. Cardiology. 2015 Apr 15;131(2):97–106.
9. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Mar;S0092867420302294.
10. Hofmann H, Geier M, Marzi A, Krumbiegel M, Peipp M, Fey GH, et al. Susceptibility to SARS coronavirus S protein-driven infection correlates with expression of angiotensin converting enzyme 2 and infection can be blocked by soluble receptor. Biochem Biophys Res Commun. 2004 Jul;319(4):1216–21.
11. NICE. COVID-19 rapid guideline: managing symptoms (including at the end of life) in the community [Internet]. 2020. Available from: https://www.nice.org.uk/guidance/NG163
12. SFPT. Anti-inflammatoires non-stéroïdiens et infection COVID-19 [Internet]. 2020. Available from: https://www.elsevier.com/fr-fr/connect/medecine/anti-inflammatoires-non-...
Competing interests: No competing interests