Covid-19: European drugs agency to review safety of ibuprofen
BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m1168 (Published 23 March 2020) Cite this as: BMJ 2020;368:m1168Read our latest coverage of the coronavirus outbreak
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
Letter to the Editor,
Day pointedly details the concerns that have been raised with the use of anti-inflammatory medication in the context of COVID-19 infection.(1,2) A search for corroborative or contrary data for any association of such medication with lesser clinical outcome draws only a few citations; none of these are inclusive of proposed implications for non-steroidal anti-inflammatory medication (including ibuprofen) whether in case reports or small patient series.
What is quite likely, however, is considerable confusion with the etymology of ‘anti-inflammatory’ treatment. To the lay consumer, the term commonly would refer to medications that are available over-the-counter and include examples such as paracetamol/acetaminophen, acetyl salicylic acid, and various non-steroidal anti-inflammatory (NSAIDS) medications. In the strictly medical domain, there are a considerable number of medications (too numerous to mention) that could conceivably provide an anti-inflammatory effect, but even in this context, both generalists and specialists yet often confuse overlapping pharmacological functions. Some may even mistakenly exclude paracetamol/acetaminophen in the context of ‘anti-inflammatory’ treatments.
It is likely, more than not, that confusion in these regards is related to the discrepancy in applying the term ‘anti-inflammatory’ to corticosteroids, NSAIDS, or both. In particular, the used of corticosteroids in coronavirus treatment as an ‘anti-inflammatory’ has drawn published concerns.(3,4,5) Lee et al. found an association with greater viral load after early corticosteroid treatment for SARS-CoV.(3) Arabi and colleagues found that corticosteroids did not improve mortality from MERS infection and delayed viral genome clearance.(4) More recent evidence now with COVID-19 raises skepticism in regard to corticosteroid impact for lung injury.(5) Therefore, that one raises concern with using ‘anti-inflammatory’ medication in the context of COVID-19 is at this time solely concerned with corticosteroids, not paracetamol/acetaminophen, acetyl salicylic acid, or NSAIDS (including ibuprofen). Even the above findings would benefit from the accrual of further science.
The use of steroids in presumed sepsis or focused infections is not without history or promise. In the author’s experience, corticosteroids were being using in an open label fashion as far back as the late 1970s for acute respiratory distress syndrome (ARDS). For similar purposes, such study continues to recent times.(6,7) Potential benefits for complications of various specific infections have been published on many occasions.(8) All of the latter have had at times supportive or contrary outcomes and/or critiques.
It is easy to see how the confusion of ‘anti-inflammatory’ medication in the context of COVID-19 has occurred in both lay and medical circles. The overall societal and medical anxiety over an emerging pandemic is justified but nevertheless has the potential to lead some to quick comments let alone conclusions. That is not to say, however, that further science may show some such associations with treatment and worse outcome for any particular pharmacological agent. We maintain an open mind, but at least can be reasonably reassuring that some claims of adverse association at this time are scientifically limited.
References
1. Day M. Covid-19: European drugs agency to review safety of ibuprofen. BMJ 2020 Mar 23;368:m1168.
2. Day M. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. BMJ 2020 Mar 17;368:m1086.
3. Lee N, Allen Chan KC, Hui KS, et al. Effects of early corticosteroid treatment on plasma SARS-associated coronavirus RNA concentrations in adult patients. J Clin Virol 2004;31(4):304-9.
4. Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for critically ill patients with Middle East Respiratory symptoms. Am J Respir Crit Care Med 2018;197(6):757-67.
5. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-mCoV lung injury. Lancet 2020;395(10223):473-5.
6. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med 2018 ;378(9) :797-808.
7. Venkatesh B, Finfer S, Cohen J, et al. Hydrocortisone compared with placebo in patients with septic shock satisfying the Sepsis-3 diagnostic criteria and APROCCHSS Study inclusion criteria: a post-hoc analysis of the ADRENAL Trial. Anesthesiology 2019;131(6):1292-1300.
8. Cimolai N. Corticosteroids and complicated Mycoplasma pneumoniae infection. Pediatr Pulmonol 2006;41(10):1008-9.
Competing interests: No competing interests
Dear Editor,
Currently there are some concerns about the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin at conventional doses in the management of COVID-19 (coronavirus disease-19) in adult infected patients (1). We wish to briefly discuss the potential role of high doses of aspirin as a host direct strategy.
The main predictors of critical outcome in COVID-19 infections encompass age, the presence of underlying diseases, the presence of secondary infection and elevated inflammatory indicators in the blood (2). In fact, following COVID-19 infection a highly acute respiratory syndrome may be observed with release of pro-inflammatory cytokines, including interleukin (IL)-1b and IL-6, and a strategy based on their signaling is currently under evaluation (3). In parallel, the recent awareness that COVID 2019 uses ACE2 (receptor Angiotensin converting enzyme 2) as its receptor (4) has led to a focus of attention in the use of angiotensin converting enzyme (ACE) inhibitors (ACEi) and angiotensin receptor blockers (ARBs) as a strategy to counteract COVID infection. Considering the crosstalk between ACE2 signaling and inflammation, Kickbusch and Leung G hypothesized that ACE2 dysregulation of the renin angiotensin system (RAS) may have a central role in the pathophysiology of COVID-19 associated acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). They additionally speculated that the virus binding to ACE2 may attenuate residual ACE2 activity, further skewing the ACE/ACE2 balance to a state of predominant ACE/AngII/AT1 axis signaling (5).
On the other hand, several seminal studies have previously investigated in renal and cardiovascular apparatus the link between Ang II and nuclear factor κB (NF-κB) (6-7) showing that Angiotensin II activates NF-kB through AT1 and AT2 receptors (8). NF-kB is a ubiquitous master regulator of immunology/inflammatory response (9-10). Consequently, the inhibition of its activity could be a successfully strategy in controlling also AT2 signaling.
Aspirin and salicylates at higher doses with respect to those used to inhibit cycloxygenase (COX) activity have been shown to inhibit NF-kb activity also in lung cells (11-12). Interestingly, in a model of rats harboring human renin and angiotensinogen genes high doses of aspirin were able to inhibit NF-κB and to protect from angiotensin II induced renal and cardiovascular damage (13). It is worth noting that 5 to 8 g aspirin, in multiple daily doses of 1 g, were traditionally administered in the management of rheumatoid arthritis (14). That a substantial inhibition of NF-κB activity “in vivo” by high doses of aspirin and salicylate could be achievable in clinical practice has been previously recognized and discussed as a potential anticancer strategy (15).
In conclusion, in COVID-19 infection, targeting NF-kb with high doses of aspirin or salicylate could be part of a host directed therapeutic strategy to treat or prevent fatal “cytokine storms” in which the immune system is at the basis of organ failure.
1. Day M. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. BMJ. 2020 Mar 17;368:m1086. doi: 10.1136/bmj.m1086.
2. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 Mar 3. doi: 10.1007/s00134-020-05991-x. [Epub ahead of print]
3. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 16. pii: S0140-6736(20)30628-0.
4. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. Wan Y, Shang J, Graham R, Baric RS, Li F. J Virol. 2020 Mar 17;94(7).
5. Kickbusch I, Leung G. Response to the emerging novel coronavirus outbreak BMJ 2020; 368 MJ 2020;368:m406
6. Ruiz-Ortega, M., Lorenzo, O., Ruperez, M., Konig, S., Wittig, B., and Egido, J. Angiotensin II activates nuclear transcription factor kappaB through AT(1) and AT(2) in vascular smooth muscle cells: molecular mechanisms. Circ. Res. 2000; 86, 1266–1272
7. Klahr, S., and Morrissey, J. J. The role of vasoactive compounds, growth factors and cytokines in the progression of renal disease. Kidney Int. 2000; 57 Suppl 75, S7–14
8. Wolf G, Wenzel U, Burns KD, Harris RC, Stahl RA, Thaiss F. Angiotensin II activates nuclear transcription factor-kappaB through AT1 and AT2 receptors. Kidney Int. 2002 Jun;61(6):1986-95.
9. Barnes, P. J., and Karin, M. Nuclear factor-kappaB: a pivotal transcription factor in
chronic inflammatory diseases. N. Engl. J. Med. 1997; 336, 1066–1071
10. Karin, M., and Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu. Rev. Immunol. 2000;18, 621–663
11. Kopp, E., and Ghosh, S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 1994;265, 956–959
12. Yoo CG, Lee S, Lee CT, Kim YW, Han SK, Shim YS.Effect of acetylsalicylic acid on endogenous I kappa B kinase activity in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2001 Jan;280(1):L3-9.
13. Muller DN1, Heissmeyer V, Dechend R, Hampich F, Park JK, Fiebeler A, Shagdarsuren E, Theuer J, Elger M, Pilz B, Breu V, Schroer K, Ganten D, Dietz R, Haller H, Scheidereit C, Luft FC. Aspirin inhibits NF-kappaB and protects from angiotensin II-induced organ damage. FASEB J. 2001 Aug;15(10):1822-4.
14. Gilman AG, Rall TW, Nies AS, Taylor P. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 8th ed. New York, NY: McGraw-Hill; 1993.
15. McCarty MF1, Block KI. Preadministration of high-dose salicylates, suppressors of NF-kappaB activation, may increase the chemosensitivity of many cancers: an example of proapoptotic signal modulation therapy. Integr Cancer Ther. 2006 Sep;5(3):252-68.
Competing interests: No competing interests
Potential danger of reducing the fever in patients with COVID-19
Dear Editor
'Fever is nature's engine against infection' and reducing the temperature in patients with COVID-19 may be counterproductive. Patients with this infection have been told to take the over-the-counter antipyretic paracetamol for symptoms and amazingly paracetamol can also be found in some routinely used cough medicines. While preferable to ibuprofen, use of paracetamol and other antipyretics can remove a valuable antiviral effect at a time when every resource against this serious infection is essential. (1, 2)
Data suggest that use of antipyretics has been counterproductive for influenza (1, 3) Aspirin's antipyretic effect in the 1918 influenza pandemic may have enhanced the virulence of the virus (4). Animal models have shown that treatment with antipyretics for influenza increases the risk of mortality (5).
Researchers from the Centre for Evidence-Based Medicine in Oxford make a valuable point in questioning the traditional advice of using such over-the-counter drugs to lower the temperature. The same point was made many years ago by the clinician Thomas Sydenham, father of clinical medicine and epidemiology, who commented that the potential of fever in treatment of infection remains unrecognised by the public and the medical profession. Basic physiology should remind today's clinicians not to ignore this valuable resource.
1. Fowler AW. A/H1N1 Flu Pandemic. Fever as nature's engine. BMJ 2009; 339: b3874
2. Yi Ming, Zhang Haolin. Adaptive and protective values of symptoms. BMJ 2010; 340:c1339
3. Husseini RH, Sweet C, Collie MH, Smith H. Elevation of nasal virus levels by suppression of fever in ferrets infected with influenza viruses of differing virulence. J Infect Dis 1982; 145: 520-4
4. Shimazu Tsunetoshi. Aspirin in the 1918 pandemic. BMJ 2009; 338: b2398
5. 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-analysis. J R Soc Med 2010; 103:403-411
Competing interests: No competing interests