Non-steroidal anti-inflammatory drugs and covid-19
BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m1185 (Published 27 March 2020) Cite this as: BMJ 2020;368:m1185Read our latest coverage of the coronavirus outbreak
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Dear Editor,
We read with interest Professor Little’s editorial (BMJ 2020;368:m1185) and the rapid responses that followed.
Professor Little noted that “….it seems likely that that intermittent or occasional use could help patients with COVID-19—for example, to relieve nighttime symptoms and aid sleep if paracetamol is inadequate…”. Dr. Ioannou suggested that indomethacin might have a role in the treatment of COVID-19.
As primary care physicians based in the Brooklyn and Queens boroughs of New York City, we have treated a great many COVID-19 patients. Our experience with indomethacin has been positive and beneficial to patients. To date we have prescribed indomethacin for more than 60 patients with COVID-19 and suspected COVID-19. Many patients with COVID-19 symptoms are not sufficiently sick to require hospitalization but experience extensive musculoskeletal pain, incessant (and exhausting) coughing, and chest pain associated with inspiratory effort. We have found that treatment with indomethacin relieves the pain, stops coughing, and leads to a feeling of general wellbeing. Patients report “not feeling sick anymore.” This may be because they are able to manage several hours of uninterrupted sleep for the first time in days.
We have not seen this beneficial effect with hydroxychloroquine treatment or with ibuprofen and we have formed the impression that it is specifically related to indomethacin.
The first patient that we treated was one of our own colleagues. We now routinely prescribe indomethacin 25-50mg, twice daily to patients who have passed the early stage of COVID-19 and who are experiencing intractable coughing.
We do not advance indomethacin as a cure for COVID-19 but as a symptomatic treatment that helps patients. In the light of our experience and the conclusion of the WHO Scientific Brief1, we feel that the use of indomethacin in COVID-19 patients is justified and that the drug should be made available to relieve suffering when required.
We hope to collate our results and write a formal report when the rate of infection in New York City subsides.
Robert Rothstein, MD
Jonathan Leibowitz, MD
Aline Benjamin, MD
Christine Clark BSc, MSc, Ph.D., FRPharmS
Competing interests: No competing interests
Dear Editor
I respond to Dr Soeiro and colleagues.
1. I agree that commonsense dictates, “No NSAIDs”
2. I beg to disagree that Paracetamol be used INSTEAD. Why? You ask.
Because: Paracetamol does lower the temperature. We do not want to lower the temperature, unless the patient is moving towards hyperpyrexia - which is unlikely. The virus does not love high temperatures.
Although the full range of Covid-19 pathogenicity does not include liver damage, we do know that terminally there is a degree of thrombotic phenomenon. (Hence Dr Friedrich Flachsbart has suggested in these columns, the use of Heparin.)
Competing interests: At risk .
Dear Editor,
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
Dear Editor,
I read carefully Professor Little’s article entitled “Non-steroidal anti-inflammatory drugs and covid-19.”, (1) as well as its rapid response by Dr D’Costa, which are both skeptical regarding the use of NSAIDs in patients with COVID-19. (2) Indeed, there could be several arguments against the use of NSAIDs in patients with COVID-19, with some of them having an immunological basis, since NSAIDs could affect T-cell proliferation and delay the resolution of inflammation, (3) and other arguments focusing on the effect that other NSAID-associated coinciding events, such as cardiovascular complications or kidney injury could have on patients with COVID-19. (1)
However, current scientific evidence does not indicate that patients with mildly symptomatic COVID-19 could be harmed by using NSAIDs. From a pharmacologic perspective, NSAIDs could have a non-predictable effect on inflammation, since prostaglandins like PGE2, PGD2 and prostacyclin (PGI2), that are inhibited by NSAIDs, can both promote and reduce inflammation. On the other hand, it is notable that SARS-CoV can bind directly to the COX-2 promoter and increase its expression, while PGE2 can inhibit replication of SARS-CoV, which is closely related to SARS-CoV-2. (4,5,6) In a very recent study, Gordon et al aimed to study the intracellular protein-protein interactions between SARS-CoV-2 and the human cells in order to identify the human proteins that are occupied by SARS-CoV-2 and to allow for identification of molecules that could be used against those human proteins. (7) Interestingly, Nsp7, a non-structural protein of SARS-CoV-2, was found to interact with PTGES2, a known target of indomethacin, which is a well-known NSAID. This implies that indomethacin could be tested in COVID-19 patients, as it could indirectly affect the activity of Nsp7, and thus, affect the ability of SARS-CoV-2 to multiply intracellularly.
To conclude, even though there are arguments against the use of NSAIDs in COVID-19 patients, one can find several arguments for their use. Thus, only clinical studies could give real-life evidence regarding their effect on COVID-19 patient outcomes.
References
1. Little P. Non-steroidal anti-inflammatory drugs and covid-19. BMJ. 2020 Mar 27;m1185.77
2. D'Costa JJ. Re: Non-steroidal anti-inflammatory drugs and covid-19; An Immune-Modulatory perspective. BMJ 2020;368:m1185
3. 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;8:E786.
4. Amici C, Di Caro A, Ciucci A, Chiappa L, Castilletti C, Martella V, Decaro N, Buonavoglia C, Capobianchi MR, Santoro MG. Indomethacin has a potent antiviral activity against SARS coronavirus. Antivir Ther. 2006;11(8):1021-30.
5. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270-273.
6. Yan X, Hao Q, Mu Y, Timani KA, Ye L, Zhu Y, Wu J. Nucleocapsid protein of SARS-CoV activates the expression of cyclooxygenase-2 by binding directly to regulatory elements for nuclear factor-kappa B and CCAAT/enhancer binding protein. Int J Biochem Cell Biol. 2006;38(8):1417-28.
7. Gordon DE, Jang GM, Bouhaddou M et al. biorxiv http://doi.org/10.1101/2020.03.22.002386
Competing interests: No competing interests
Dear Editor,
I am writing in reference to Professor Little’s article entitled “Evidence in the use of non-steroidal anti-inflammatory drugs in Covid-19.” (1) I reiterate the conclusion, and propose that there may be immune-modulatory justifications to avoid NSAIDs until there is further research into their use in COVID-19.
There is a growing body of evidence that suggests that there is a subset of patients who develop cytokine release syndrome as part of their response to COVID-19. (2).(3) Cytokine release syndrome (CRS) is a constellation of inflammatory symptoms that is usually seen in the context of Chimeric Antigen Receptor T Cell therapy (CAR-T therapy).(4) It consists of headaches, fevers, pulmonary oedema, disseminated intravascular coagulation, acute kidney injury and elevated liver enzymes. Cytokine Release syndrome is characterised by an increase in pro-inflammatory cytokines. (4) While the mechanism behind CRS is not fully understood, there appears to be a role for T cells given that CRS is most frequently seen in T cell engaging therapies. (4) Indeed unpublished data from our group hypothesise the role for T cells in the cytokine release syndrome in COVID-19.
NSAIDS are unselective inhibitors of the cyclooxygenase enzymes. (5) Blocking the cyclo-oxygenase enzymes prevents conversion of arachidonic acid into prostaglandins and shifts the conversion of arachidonic acid via the 5 lipoxygenase enzyme to produce LTA4, which is an unstable precursor of all bioactive leukotrienes. These subsequently undergo reactions to produce cystineyl leukotirenes. (6) Cysteinyl Leukotrienes are implicated in the pathogenesis of asthma via binding to CysLT1. Furthermore, activation of CysLT1 promotes a Th2 or T-helper immune response. (6)
Blocking of the cyclooxygenase pathways via the use of NSAIDs not only shifts more production of leukotrienes but also reduces the amount of PGE2 being produced. (7) Prostaglandin E2 is also derived from arachidonic metabolism via the perioxidase function of cyclo-oxygenase. PGE2 has been shown to inhibit pro-inflammatory cytokine production and inhibit T cell proliferation. (7)
If there is indeed a hyper-inflammatory phenotype or cytokine release syndrome mediating mortality in COVID-19 then there could be a link for anti-inflammatory drugs to cause a paradoxical hyper inflammatory phenotype via T cell activation. Young et al suggests that clinical deterioration of COVID-19 patients coincides with activation of the adaptive phase of immune response. (8) T cell function is essential to an effective adaptive immune response. One notes that there could be an increased proliferation of T cells in NSAIDS. Therefore, one could hypothesise that NSAIDs may in the context of COVID-19 mediate a cytokine release syndrome via dysregulation of a T cell response and through the release of pro-inflammatory cytokines.
It should be known there is no freely available retrospective cohort studies to suggest that NSAIDS convey a poor prognosis in COVID-19. However, if anecdotal evidence from French sources is correct in that anti-inflammatory drugs may lead to respiratory complications, I would propose that NSAIDs cause a T-cell dysregulation that mediates lung injury as part of the known cytokine release syndrome phenotype. However, with the current lack of robust evidence, I would reiterate the conclusion via Professor Little that until further research into NSAIDS in COVID-19, a cautionary approach must be followed with NSAID prescription.
1. Little P. Non-steroidal anti-inflammatory drugs and covid-19. BMJ. 2020 Mar 27;m1185.
2. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet [Internet]. 2020 Mar 16 [cited 2020 Mar 19];0(0). Available from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30628-0/abstract
3. Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ [Internet]. 2020 Mar 26 [cited 2020 Mar 31];368. Available from: https://www.bmj.com/content/368/bmj.m1091
4. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, et al. Cytokine release syndrome. J Immunother Cancer [Internet]. 2018 Jun 15 [cited 2020 Mar 31];6. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003181/
5. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med [Internet]. 2020 Mar 11 [cited 2020 Mar 19];0(0). Available from: https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30116-8/abstract
6. Okunishi K, Peters-Golden M. Leukotrienes and airway inflammation. Biochim Biophys Acta. 2011 Nov;1810(11):1096–102.
7. Wu D, Meydani SN. Age-associated changes in immune and inflammatory responses: impact of vitamin E intervention. J Leukoc Biol. 2008 Oct;84(4):900–14.
8. Young BE, Ong SWX, Kalimuddin S, Low JG, Tan SY, Loh J, et al. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore. JAMA [Internet]. 2020 Mar 3 [cited 2020 Mar 29]; Available from: https://jamanetwork.com/journals/jama/fullarticle/2762688
Competing interests: No competing interests
Re: Non-steroidal anti-inflammatory drugs and covid-19: Indomethacin or aspirin?
Long before the Covid19 pandemic, one of us had similar intense, protracted and violent coughing, but due to ramipril, an ACE Inhibitor (ACEI) which was inadvertently continued throughout this. One traumatic cough episode was followed by a thrombotic CVA, so anti-platelet therapy was started with aspirin at an intermediate 600mg daily dose. This abolished the cough for several weeks until aspirin was reduced to 75mg, when cough relapsed. The patient researched this at (1) and re-started aspirin at 600mg daily which abolished it; then after ramipril was at last stopped, reverted safely to 75mg.
This effect of aspirin at 600mg dose was established in 2000 by Tenenbaum et al. to be kinin-mediated (1,2). Further, aspirin in anti-platelet doses of 150mg or less was shown to be ineffective at reversing cough (3). This may be not well known because normally in clinical practice, a side-effect is treated by stopping the causal drug, not by prescribing a further drug.
Aspirin is a potent non-selective NSAID, and one other shown effective for ACEI-cough is indomethacin (4).
ACEI adverse reactions and Covid19 have many similarities:
● Cough is dry, hacking, exhausting and unresponsive to standard antitussives.
● Abnormalities of smell and taste are common to both
● ACEI-cough has 4x greater prevalence in black subjects (5) – similarly to Covid19
These should be unsurprising, as the principal target for cell entry by SARS-CoV-2 is now well-known to be the ACE2 receptor (6–8). SARS-CoV-2 infection consumes ACE2, which releases its control over kinin systems (6), detailed here as: “reduced ACE2 function in the lung … in turn activates B1 receptors with release of pro-inflammatory cytokines and intense lung inflammation and injury.” Covid19’s “dysregulation” of the Renin Angiotensin Aldosterone System is like an exploding dose of ACE Inhibitor, so could its symptoms also respond to these drugs?
The treatment of Covid19 cough is of high value even if only for symptoms, but it is also the herald symptom of massive painful inflammation with risk of lethal coagulopathy (6,7). Some researchers propose to suppress this by selective drugs such as icatibant to block the action of bradykinin (6,9) but do not appear to have considered aspirin or indomethacin. Similarly, this review of S Korean hospital cases (10) assesses 17 NSAIDs for harm in Covid19 – but neither aspirin nor indomethacin were included.
The role of NSAIDs in Covid19 is much debated (10–13), but we also note these Rapid Responses (14)
● by Rothstein, Liebowitz et al. describing over 60 cases, with substantial benefit of indomethacin to well-being and pain as well as to cough
● by Ioannou calling for more research, and citing some antiviral actions of indomethacin, first suggested in Amici’s 2006 work (16) on activity against SARS-CoV, which shares the ACE2 target.
We would add that indomethacin now seems to have in-vitro anti-SARS-CoV-2 activity, confirmed in-vivo on canine coronavirus, per pre-print (15). Indomethacin’s other anti-viral properties were detailed by Amici in 2015 (17), also reporting that this mechanism (to enhance PKR) does not apply to aspirin.
Since indomethacin is proven in ACEI-cough to work as does aspirin 600mg (4), the mechanism to suppress kinins is shared by both drugs, and so may be part of an action against SARS-CoV-2.
The role of steroids in Covid19 is clearer since the RECOVERY trial supported low-dose dexamethasone in more advanced disease - but found possible harm in earlier phases, per Fig 1b (18). This is discussed as due to high viral replication in earlier phases, which steroids may promote by suppressing innate immunity. For such a controlled suppression of inflammation, timing and duration are critical attributes, and may vary with phase of disease.
We agree that further research is urgently needed on indomethacin for its reported suppression of inflammation in Covid19. Its anti-coronaviral properties are less well-known, although it is long-established (so also cheap).
Current research on indomethacin is a small RCT in Iran https://en.irct.ir/trial/47520 , and on aspirin is only on anti-platelet doses. Naproxen (19) and lipid-ibuprofen (13) are under trial, but will not report till next summer. Meanwhile, it is hardly a re-purpose for GPs to prescribe for compassionate use, following the lead of Drs. Rothstein, Liebowitz et al. - and report.
Colin Brown FRCGP FFCI Glasgow General Practitioner retd. colin.brown99@nhs.net
Glen Griffiths MSc Sunningdale Software Engineer griftech@gmail.com
1. Tenenbaum A, Grossman E, Shemesh J, Fisman EZ, Nosrati I, Motro M. Intermediate but not low doses of aspirin can suppress angiotensin-converting enzyme inhibitor-induced cough. Am J Hypertens [Internet]. 2000 Jul 1;13(7):776–82.
2. Fisman EZ, Grossman E, Motro M, Tenenbaum A. Clinical evidence of dose-dependent interaction between aspirin and angiotensin-converting enzyme inhibitors. J Hum Hypertens. 2002;16(6):379–83.
3. Davie AP, McMurray JJV V. Effect of aspirin on vasodilation to bradykinin and substance P in patients with heart failure treated with ACE inhibitor. Br J Clin Pharmacol [Internet]. 2002 Jan 11 [cited 2020 Jun 15];53(1):37–42. Available from: www.ncbi.nlm.nih.gov/pmc/articles/PMC1874546/
4. Rudd P, Rudd P. Indomethacin and nifedipine reduced coughing induced by captopril therapy. ACP J Club [Internet]. 1992 Sep 1;117(2):42. Available from: www.acpjournals.org/doi/abs/10.7326/ACPJC-1992-117-2-042
5. Elliott WJ. Higher incidence of discontinuation of angiotensin converting enzyme inhibitors due to cough in black subjects. Clin Pharmacol Ther. 1996;60(5):582–8.
6. van de Veerdonk FL, Netea MG, van Deuren M, van der Meer JW, de Mast Q, Brüggemann RJ, et al. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. Elife [Internet]. 2020 [cited 2020 May 22];9. Available from: https://elifesciences.org/articles/57555
7. Verdecchia P, Cavallini C, Spanevello A, Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med. 2020;76:14.
8. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-angiotensin-aldosterone system inhibitors in patients with covid-19. N Engl J Med [Internet]. 2020 Apr 23 [cited 2020 Jun 5];382(17):1653–9. Available from: www.nejm.org/doi/10.1056/NEJMsr2005760
9. Icatibant [Internet]. [cited 2020 Jun 22]. Available from: www.ncbi.nlm.nih.gov/pmc/articles/PMC2856042/
10. Eol H, Mph J, Lee H, Shin HJ, Choe YJ, Filion KB, et al. Association between NSAIDs use and adverse clinical outcomes among adults hospitalised with COVID-19 in South Korea: A nationwide study. Available from: https://doi.org/10.1101/2020.06.01.20119768
11. Little P. Non-steroidal anti-inflammatory drugs and covid-19. 2020 Mar 27 [cited 2020 May 26];368. Available from: www.bmj.com/content/368/bmj.m1185
12. The use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with COVID-19 [Internet]. [cited 2020 Jun 21]. Available from: www.who.int/publications/i/item/the-use-of-non-steroidal-anti-inflammato...(nsaids)-in-patients-with-covid-19
13. LIBERATE Trial in COVID-19 - Full Text View - ClinicalTrials.gov [Internet]. [cited 2020 Jun 15]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT04334629
14. Rothstein R, Leibowitz J, Benjamin A, Clark C. Re: Non-steroidal anti-inflammatory drugs and covid-19 | The BMJ [Internet]. New York; 2020 [cited 2020 Jun 15]. Available from: www.bmj.com/content/368/bmj.m1185/rr-3 and Ioannou P: www.bmj.com/content/368/bmj.m1185/rr-0
15. Xu T, Gao X, Wu Z, Selinger DW, Zhou Z. Indomethacin has a potent antiviral activity against SARS CoV-2 in vitro and canine coronavirus in vivo. bioRxiv [Internet]. 2020 Apr 5 [cited 2020 Jun 15];(December 2019):2020.04.01.017624. Available from: www.biorxiv.org/content/10.1101/2020.04.01.017624v1
16. Amici C, Di Caro A, Ciucci A, Chiappa L, Castilletti C, Martella V, et al. Indomethacin has a potent antiviral activity against SARS coronavirus. Antivir Ther. 2006;11(8):1021–30.
17. Amici C, La Frazia S, Brunelli C, Balsamo M, Angelini M, Santoro MG. Inhibition of viral protein translation by indomethacin in vesicular stomatitis virus infection: Role of eIF2α kinase PKR. Cell Microbiol [Internet]. 2015 Sep 1;17(9):1391–404. Available from: www.ncbi.nlm.nih.gov/pmc/articles/PMC7162271/
18. Horbye P. Dexamethasone reduces death in hospitalised patients with severe respiratory complications of COVID-19 | University of Oxford [Internet]. [cited 2020 Jun 22]. Available from: www.ox.ac.uk/news/2020-06-16-dexamethasone-reduces-death-hospitalised-pa...
19. ENACOVID Trial Hopitaux de Paris Available from: https://clinicaltrials.gov/ct2/show/NCT04325633
Competing interests: No competing interests