NSAIDs in the context of COVID-19

The Swiss Society of Clinical Pharmacology and Toxicology advise on the use of Nonsteroidal anti-inflammatory drugs (NSAIDS) in the context of COVID-19

Non-steroidal anti-inflammatory drugs (NSAIDs) may be associated with worsening of complications in case of viral or bacterial infection. An association between the use of some NSAIDs and worsening of some bacterial infections has been endorsed in May 2019 by the French National Agency for Medicines and Health Products Safety (ANSM) (1). To date, there is no scientific evidence specifically linking NSAIDs use with worsening of SARS-CoV2 (COVID-19) infection, and potential concerns are based mostly on anecdotal reports of young patients developing severe symptoms after use of NSAIDs in the early stage of the disease and not on clinical or population-based data. Even though a causal link is not currently established, the principle of precaution commands against indiscriminate use of NSAIDs to control COVID-19 symptoms. SSCPT is monitoring the situation closely and actively reviewing the available evidence.

Recommendations :

o In the presence of fever and influenza-like illness, self-medication with NSAIDs* is not recommended. Paracetamol should be preferred in the first instance if necessary (fever that is poorly tolerated).

o The maximal recommended dose of paracetamol is 4 grams/day, and in the presence of risk factors (malnutrition, prolonged fasting, acute and chronic alcoholism, intake of cytochrome P450 inducers, acute or chronic liver diseases), the maximal dose should not exceed 2 grams/day in order to reduce the risk of hepatotoxicity. Particular attention should be paid to combination treatments with paracetamol*.

o Long-term NSAID* therapy prescribed for chronic disease should not be systematically discontinued; questionable situations should be evaluated case by case.

o Low-dose aspirin (100mg) has no anti-inflammatory action and should not be discontinued

* Nonsteroidal anti-inflammatory drugs (NSAIDs) are drugs that reduce fever (antipyretic) and painkillers.

DCI

Tradenames
acetylsalicylic acid and derivativesAspégic®, Aspirine®

celecoxib

Celebrex®, Celecoxib®

diclofenacDiclac®, Diclo-Acino®, Diclofenac®, Dicloren®, Ecofénac®, Inflamac®, Olfen®, Vifenac®, Voltarène®
etodolacLodine®
flurbiprofen

Angisil-X Dolo mint, FlurbiAngin®, Neo-angin®, Strepsils®

ibuprofenAlges-X forte, Algifor®, Aspégic® Ibu, Brufen®, Contre-Douleurs®, Dismenol®, Dolo-Spedifen, Dolocyl®, Grefen®, Ibu Sandoz®, Ibufelan, Ibufen-L®, Ibuprofen®, Irfen®, Nurofen®, Optifen®, Saridon®, Sonotryl®, Spedifen, Treupel®
indometacin

Elmetacin®, Indocid®

ketoprofenFastum®
naproxene

Aleve®, Apranax®, Naproxen®, Proxen®, Vimovo®

piroxicam

Felden®, Piroxicam®

metamizoleMetamizol®, Minalgine®, Novalgin®, Novaminsulfon

**Many preparations containing paracetamol are available on the market (e.g. Acetalgine, Amavita Paracetamol, Becetamol, Ben-u-ron, Pain Relief P, Coop Vitality Paracetamol, Dafalgan Odis, Dafalgan, Doloran, Kafa, Mepha-Grippal C, Osa, Panadol, Paracetafelan, Paracetamol, Paraconica, Perfalgan, SUN STORE Paracetamol, Tylenol, Zolben).

In depth information

Translated and modified from Geneva University Hospitals NSAIDs and COVID-19 guidelines https://www.hug-ge.ch/sites/interhug/files/structures/coronavirus/documents/ains_et_covid-19.pdf

Use of NSAIDs for viral and bacterial infections

In recent years, NSAIDs have been the subject of several reports to the national pharmacovigilance authorities in France in the context of worsening of symptoms in cases of viral infections, according to a press release from the French National Agency for the Safety of Medicines and Health Products (ANSM, 18.04.2019). Indeed, out of all cases reported since 2000, 337 cases of infectious complications with ibuprofen and 49 cases with ketoprofen were retained after taking into account only the most serious cases in children or adults (often young) without risk factors or co-morbidity. These infection complications were observed after 2 to 3 days of treatment and manifested mainly as streptococcal or pneumococcal infections (1).

According to an expert report published as part of this report (2), in vitro data suggest that NSAIDs may increase the severity of infections by three main mechanisms:

1. An inhibitory effect on phagocyte function;

2. An increase in the production of inflammatory cytokines such as TNF-α, IL-1, IL-6 ;

3. Inhibition of serine hydrolase (FAAH), which is responsible for the degradation of anandamide, one of the main mediators of the endocannabinoid system, since endocannabinoids are involved in the aggravation of bacterial infection - especially sepsis.

In animal models, a meta-analysis of 8 randomized controlled trials involving the use of antipyretics (acetylsalicylic acid, diclofenac or paracetamol) in the treatment of Influenza virus found an increased risk of mortality for the animal groups treated with anti-inflammatory drugs, with a combined fixed effects pooled odds ratio of 1.34 (95% CI [1.04-1.73]) for the groups treated with antipyretics (3). In terms of pathophysiological mechanisms, several studies in mice have shown that mortality in COX-1 deficient mice was significantly higher than in the COX-2 deficient group, in the context of influenza infections (4). A second study showed that administration of COX-1 inhibitors (SC-560) two weeks prior to influenza A infection had a significantly greater impact on mortality, body temperature and weight in mice compared to groups treated with a COX-2 inhibitor (celecoxib) or no treatment. In the same study, the number of inflammatory cells in the bronchoalveolar fluid of mice treated with celecoxib was significantly higher (5).

In humans, the manufacturer of ibuprofen has reported urinary (9% incidence) and respiratory (19% incidence) infectious adverse events. According to the product monograph, patients receiving ibuprofen at a dose of 400 mg (n1 = 31), 200 mg (n2 = 30) and 100 mg (n3 = 30) every 4 hours for 24 hours experienced bacterial pneumonia with an incidence of 7%, 3% and 10%, respectively, compared with a placebo group (n = 28) (6). The manufacturer also reports an incidence of up to 13% of bacteremia following intravenous injections of ibuprofen: indeed, three groups of patients treated with 400 mg (n1 = 31), 200 mg (n2 = 30), 100 mg (n3 = 30) had an incidence of 0%, 0% and 13% of bacteremia following intravenous ibuprofen injection, respectively (6).

In the literature, the following studies have been conducted with NSAID therapy for various viral conditions:

- Respiratory tract infections: a multicentre case-control study that matched children aged 3 months to 15 years with acute viral infections of various types - grouped into 3 categories: upper respiratory tract infection (URTI), lower respiratory tract infection (LRTI) and others. This study showed that the use of NSAIDs had an adjusted odds ratio of 2.79 (95% CI [1.40-5.58]) for an increased risk of empyema (7).

-Skin and soft tissue infections: A case-control study of two population cohorts followed between 1994 and 2005 - one with primary varicella infection (n = 140,111, mean age 10.7 years) and the other with shingles (n = 108,257, mean age 60.9 years) - examined the rate of skin and soft tissue complications in association with NSAID use, occurring in 386 and 681 cases at 2 months, respectively. The rate ratio of such complications in association with NSAID exposure was 1.6 (95% CI [1.1-2.4]); the risk of complication was not significantly increased with paracetamol therapy (8).

The use of NSAIDs has also been studied in a variety of bacterial infections:

- Lower respiratory tract infections: in adults, a recent cohort study in 221 patients treated with NSAIDs for community-acquired pneumonia showed a significant association between NSAIDs and the occurrence of pleuro-parenchymal complications - defined according to criteria validated by the British Thoracic Society - with an OR = 2. 57 (95% CI [1.27-5.69], p = 0.049); 24 patients with such complications were significantly younger, had fewer co-morbidities and a longer duration of illness (9). Another prospective study of a group of 90 patients with community-acquired pneumonia treated with antipyretics and short-term analgesics showed that 32 of the patients who received NSAIDs prior to hospital admission had a significantly increased frequency of pleuropulmonary complications and bacteremia (25% versus 5%, p = 0.014). This was particularly the case in patients who did not receive antibiotics concomitantly with NSAIDs (69% versus 27%, p = 0.009). The suggested mechanism is a delay in systemic immune response (10). In 57 patients hospitalized for pleural effusion pneumonia with or without NSAID therapy prior to admission, NSAID use was an independent risk factor for prolonged hospitalization longer than 10 days (β = 5,025, 95% CI [1,433-8,618], p = 0.007) (11). A retrospective study identified 20 patients receiving NSAIDs prior to admission among 106 patients admitted to intensive care for community-acquired pneumonia who had a significantly increased incidence of pleural effusion (20% versus 2.3%, p = 0.010), and more frequently required non-invasive ventilation (25% versus 4.6%, p = 0.003) (12).

- Skin and soft tissue infections: Another study conducted on the basis of French national pharmacovigilance data between 2000 and 2004 found soft tissue infections in 38 pediatric patients (including 10 considered "adults" from the age of 15 years), 25 patients treated with ibuprofen, including 24 infected with chickenpox, out of a total of 1951 reported skin adverse events. Exposure to ibuprofen had an adjusted odds ratio of 31.38 (95% CI [6.40; 153.84]) of causing a necrotizing soft tissue infection caused by group A hemolytic streptococci β (13).

SARS-CoV2 infection

To date, no scientific studies have evaluated the role of NSAIDs in aggravating SARS-CoV2 infection (COVID-19).

In May 2019, the Safety Committee (PRAC) of the European Medicines Agency (EMA) started the review of two NSAIDs (ibuprofen and ketoprofen) following the April 2019 NSAID report. The EMA stated on 18.03.2020 that: “the product information of many NSAIDs already contains warnings that their anti-inflammatory effects may mask the symptoms of a worsening infection. PRAC is currently reviewing all available data to see if further action is needed”. (14)

The EMA and the WHO currently do not recommend avoiding NSAIDs when clinically indicated (14, 15), Also according to the Swiss Federal Office of Public Health there is currently no scientific data indicating an influence of NSAIDs on the course of the disease (16).

(written by Prof. Caroline Samer, MD, SSCPT Secretary, on May 04, 2020)

References

1) Anti-inflammatoires non stéroïdiens (AINS) et complications infectieuses graves - Point d’Information - ANSM : Agence nationale de sécurité du médicament et des produits de santé [Internet]. [cité 16 mars 2020]. Disponible sur: https://www.ansm.sante.fr/S-informer/Points-d-information-Points-d-information/Anti-inflammatoires-non-steroidiens-AINS-et-complications-infectieuses-graves-Point-d-Information

2) CRPV Tours, CRPV Marseille. 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. Marseille; 2018 juin.

3) Eyers S, Weatherall M, Shirtcliffe P, Perrin K, Beasley R. The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analyis. J R Soc Med. 1 oct 2010;103(10):403‑11.

4) Carey MA, Bradbury JA, Seubert JM, Langenbach R, Zeldin DC, Germolec DR. Contrasting effects of cyclooxygenase-1 (COX-1) and COX-2 deficiency on the host response to influenza A viral infection. J Immunol. 15 nov 2005;175(10):6878‑84.

5) Carey MA, Bradbury JA, Rebolloso YD, Graves JP, Zeldin DC, Germolec DR. Pharmacologic inhibition of COX-1 and COX-2 in influenza A viral infection in mice. PLoS ONE. 15 juill 2010;5(7):e11610.

6) Home - MICROMEDEX [Internet]. https://www.micromedexsolutions.com/micromedex2/librarian/

7) 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. The Journal of Pediatrics. 1 août 2016;175:47‑53.e3.

8) Mikaeloff Y, Kezouh A, Suissa S. Nonsteroidal anti-inflammatory drug use and the risk of severe skin and soft tissue complications in patients with varicella or zoster disease. Br J Clin Pharmacol. févr 2008;65(2):203‑9.

9) Basille D, Plouvier N, Trouve C, Duhaut P, Andrejak C, Jounieaux V. Non-steroidal Anti-inflammatory Drugs may Worsen the Course of Community-Acquired Pneumonia: A Cohort Study. Lung. 2017;195(2):201‑8.

10) Voiriot G, Dury S, Parrot A, Mayaud C, Fartoukh M. Nonsteroidal antiinflammatory drugs may affect the presentation and course of community-acquired pneumonia. Chest. févr 2011;139(2):387‑94.

11) Kotsiou OS, Zarogiannis SG, Gourgoulianis KI. Prehospital NSAIDs use prolong hospitalization in patients with pleuro-pulmonary infection. Respir Med. 2017;123:28‑33.

12) Messika J, Sztrymf B, Bertrand F, Billard-Pomares T, Barnaud G, Branger C, et al. Risks of nonsteroidal antiinflammatory drugs in undiagnosed intensive care unit pneumococcal pneumonia: younger and more severely affected patients. J Crit Care. oct 2014;29(5):733‑8.

13) Souyri C, Olivier P, Grolleau S, Lapeyre-Mestre M, French Network of Pharmacovigilance Centres. Severe necrotizing soft-tissue infections and nonsteroidal anti-inflammatory drugs. Clin Exp Dermatol. mai 2008;33(3):249‑55.

14) https://www.ema.europa.eu/en/news/ema-gives-advice-use-non-steroidal-anti-inflammatories-covid-19

15) https://www.sciencealert.com/who-recommends-to-avoid-taking-ibuprofen-for-covid-19-symptoms

16) https://www.bag.admin.ch/bag/de/home/krankheiten/ausbrueche-epidemien-pandemien/aktuelle-ausbrueche-epidemien/novel-cov/information-fuer-die-aerzteschaft/faq-gesundheitsfachpersonen.html