Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists
BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m1086 (Published 17 March 2020) Cite this as: BMJ 2020;368:m1086Read an update to this news story
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Dear Editor
I have read this article with great interest but would like to bring some issues into notice as many patients come with this query about the use of ibuprofen rather than paracetamol in COVID-19.
The author mentions that taking anti-inflammatory drugs (ibuprofen, cortisone) could be an aggravating factor for the infection. However, according to the University of Minnesota where a cohort study was conducted, patients showed no difference in use of NSAIDs and use of non-NSAIDs among COVID -19 patients (1). Furthermore, a Plos one study revealed that NSAIDs may not boost levels of ACE2 in humans which is a receptor allowing coronavirus to enter target human cells, ACE2 may not increase the risk of severe COVID-19, and that reported deleterious effects of NSAIDs in patients with pneumonia may have been specific to only bacterial (not viral) infections.(1)(2)
Secondly, use of steroids like corticosteroids is well known since it helps in decreasing inflammatory markers like interleukin-1, interleukin -6 and other cytokines; it has shown promising results among critical COVID-19 pneumonia patients.(3)
Thirdly, the author's explanation for the use of tocilizumab has been widely established but at the same time I would like to add for readers that the drug anakinra is also beneficial for critical Covid-19 Pneumonia, reducing both the need for invasive mechanical ventilation in the ICU and mortality among patients with severe forms of COVID-19, without serious side-effects. (4)
References:
1. NSAIDs like ibuprofen not tied to severe COVID-19, death Filed Under: COVID-19
Mary Van Beusekom | News Writer | CIDRAP News | Sep 09, 2020,https://www.cidrap.umn.edu/news-perspective/2020/09/nsaids-ibuprofen-not...
2. National Institute of Allergy & Infectious Diseases. Considerations for Certain Concomitant Medications in Patients with COVID-19. Available from: https://www.covid19treatmentguidelines.nih.gov/concomitant-medications/. Accessed June 15, 2020.
3. Corticosteroid use in COVID-19 patients: a systematic review and meta-analysis on clinical outcomes
Judith van Paassen, Jeroen S. Vos, Eva M. Hoekstra, Katinka M. I. Neumann, Pauline C. Boot & Sesmu M. Arbous
Critical Care volume 24, Article number: 696 (2020),https://ccforum.biomedcentral.com/articles/10.1186/s13054-020-03400-9
4. Anakinra for severe forms of COVID-19: a cohort study
Thomas Huet 1, Hélène Beaussier 2, Olivier Voisin 3, Stéphane Jouveshomme 4, Gaëlle Dauriat 5, Isabelle Lazareth 6, Emmanuelle Sacco 2, Jean-Marc Naccache 4, Yvonnick Bézie 7, Sophie Laplanche 8, Alice Le Berre 9, Jérôme Le Pavec 5, Sergio Salmeron 4, Joseph Emmerich 6 10, Jean-Jacques Mourad 3, Gilles Chatellier 11, Gilles Hayem 1
PMID: 32835245 PMCID: PMC7259909 DOI: 10.1016/S2665-9913(20)30164-8,
https://pubmed.ncbi.nlm.nih.gov/32835245/
Competing interests: No competing interests
Dear Editor
The effects of ibuprofen on the epithelial sodium channel ENaC may explain its deleterious effects on COVID-19 patients. Ibuprofen inhibits sodium reabsorption in epithelial cells because it inhibits the enzyme COX2 and thus reduces prostaglandin E2 (PGE2 ) synthesis (Pavlov et al, 2011, Am J Physiol Renal Physiol, 301:F672-F681). Reducing PGE2 inhibits epithelial ENaC activity and thus sodium entry into lung epithelial cells. This reduction, in turn, promotes lung edema (fluid accumulation in the lung) by reducing the flow of water and salt across lung epithelia. Acetaminophen does not inhibit COX2 and this fact may explain why it does not adversely affect COVID-19 patients. Interestingly, the SARS cov 2 E and S proteins also inhibit ENaC activity in epithelial cells. The effect of these two viral proteins on ENaC expression could also contribute to lung edema (Ji et al, 2009, Am J Physiol Lung Cell Mol Physiol, 296:L372-L383) by reducing sodium reabsorption. Treating patients with Ibuprofen may worsen the edema already caused by the S and E viral proteins. Viral inhibition of ACE2 could further worsen lung edema also by inhibiting ENaC activity and/or expression.
Competing interests: No competing interests
Dear Editor
In these times of uncertainty about this unprecedented new coronavirus pandemic it is critical to remember that science can only advance on the basis of sound ground evidence.
It is also more than ever worth remembering the sacred principle "first do not harm" that must prevail over any other consideration.
That is why I consider it is very relevant to pay attention to this rapid response that was posted on bmj.com in 2003: https://www.bmj.com/rapid-response/2011/10/29/coronavirus-may-be-killed-...
In this publication, a physician from Hong Kong who treated SARS patients during the 2002-2003 outbreak shares his clinical experience.
Given the apparent similarities between both coronavirus it is worth taking his observations into account.
Maybe it is not ibuprofen that is the problem but the subsequent reduction in body temperature.
According to the "do not harm" principle, we should consider seriously the option of not "treating" fever in COVID-19 patients.
Attentively
Beatriz Bandrés
Competing interests: No competing interests
Dear Editor,
Given the consistent nature of the feedback received to this article and the continued position taken by many recognised bodies (including but not limited to the FDA, EMA, WHO) I would respectfully request that the BMJ consider changing the misleading title of this article to something more balanced as soon as possible.
As many have commented the evidence to avoid ibuprofen would appear to be unsubstantiated. We know there is an emerging shortage of paracetamol and are all too aware of its narrow therapeutic index and the potential for stacking. (1)
Patients and healthcare professionals should not be receiving such definitive messages as portrayed by your headline when unsupported by proven science.
(1) Paediatr Child Health. 2011 Nov; 16(9): 544–547.
doi: 10.1093/pch/16.9.544
Competing interests: I am employed by RB, the makers of Nurofen amongst other healthcare products.
Dear Editor,
We read this article with interest and hoped to supplement these observations with some pharmacological underwriting.
In the context of COVID-19, NSAIDs may worsen symptoms through their effects on the renin-angiotensin system. SARS-CoV-2 binds to target cells through angiotensin-converting enzyme 2 (ACE2), which counters the vasoconstrictive actions of ACE by converting angiotensin to the vasodilator heptapeptide angiotensin 1-71. Binding of the virus spike to ACE2 leads to ACE2 downregulation, which leads to excessive production of angiotensin by ACE and in turn contributes to lung injury; angiotensin-receptor (AT1R) enhances pulmonary vascular permeability, inducing pulmonary oedema [1]. While seemingly counterintuitive, ACE2 upregulation is thus pneumoprotective.
Most NSAIDs, such as Ibuprofen, act as nonselective inhibitors of cyclooxygenase (COX) enzymes, including COX-1 and COX-2, to diminish the formation of prostaglandins and thromboxanes from arachidonic acid. Prostaglandins have vasodilatory effects to increase renal and pulmonary perfusion. Inhibition of synthesis leads to increased sodium and water retention, which may lead to pulmonary oedema and thus lung injury [2]. In COVID-19, this pulmonary oedema is aggravated by blunted ACE2 levels and thus decreased angiotensin 1-7 mediated vasodilation.
The protective effect of ACE-inhibitors in COVID-19 may involve two complementary mechanisms: blocking the excessive angiotensin‐mediated vasoconstriction caused by viral-spike binding, as well as upregulating ACE2 and increasing vasodilation. NSAIDs are known to oppose the therapeutic actions of ACE-inhibitors, with adverse cardiovascular and renal implications such as increased risk of acute kidney injury [3].
We note the seminal work of Bao et al [4], who used human ACE2 transgenic mice that were then infected with SARS-CoV-2. In these transgenic mice, weight loss and viral replication (via qRT-PCR) were observed every day up to 7 days post infection. The typical histopathology has been reported as interstitial pneumonia with infiltration of significant lymphocytes and monocytes and accumulation of macrophages in alveolar cavities. This was not seen in wild-type mice. This offers conformational evidence to previous in vitro and observational data to show that SARS-CoV-2 has a similar infective mechanism to its predecessor.
Furthermore, Lei and colleagues [5] generated a novel recombinant protein by connecting the extracellular human domain of ACE2 to the Fc region of the human IgG1. This fusion protein neutralised both SARS-CoV and SARS-CoV-2 in vitro. At a glance, this finding presents a promising avenue for therapeutic development.
A large number of COVID-19 patients presenting to hospitals have comorbidities that are treated with ACE-inhibitors, such as diabetes and hypertension. We therefore caution the use of NSAIDs in these patients as they may worsen infection and counter the potentially protective effects of the ACE-inhibitors [6,7]. Moreover, we suggest assessing the therapeutic role of ACE-inhibitors in COVID-19, through an observational study comparing the outcomes of COVID-19 patients on ACE-inhibitors or AT1R-inhibitors to that of the general population.
BIBLIOGRAPHY
1. de Wit E, van Doremalen N, Falzarano D, et al. SARS and MERS: recent insights into emerging coronaviruses. Nature Reviews Microbiology 2016;14:523–34. doi:10.1038/nrmicro.2016.81
2. Li XC, Zhang J, Zhuo JL. The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacological Research2017;125:21–38. doi:10.1016/j.phrs.2017.06.005
3. Voiriot G, Philippot Q, Elabbadi A, et al. Risks Related to the Use of Non-Steroidal Anti-Inflammatory Drugs in Community-Acquired Pneumonia in Adult and Pediatric Patients. Journal of Clinical Medicine 2019;8. doi:10.3390/jcm8060786
4. Bao L, Deng W, Huang B, et al.The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice. bioRxiv Published Online First: November 2020. doi:10.1101/2020.02.07.939389
5. Lei C, Fu W, Qian K, et al.Potent neutralization of 2019 novel coronavirus by recombinant ACE2-Ig. bioRxiv Published Online First: February 2020. doi:10.1101/2020.02.01.929976
6. Ohkubo T, Chapman N, Neal B, et al. Effects of an Angiotensin-converting Enzyme Inhibitor–based Regimen on Pneumonia Risk. American Journal of Respiratory and Critical Care Medicine 2004;169:1041–5. doi:10.1164/rccm.200309-1219oc
7. Dreischulte T, Morales DR, Bell S, et al. Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin–angiotensin system inhibitors in the community increases the risk of acute kidney injury. Kidney International 2015;88:396–403. doi:10.1038/ki.2015.101
Competing interests: No competing interests
Dear Editor
Is it safe to use antihistamines in early Covid - 19 infections?
Antihistamine may interfere with the first line defence mechanism against respiratory tract infections like corona virus.
Like other respiratory tract viruses Covid-19 enter the upper respiratory tract invading nasal and pharyngeal mucosa. Then it gradually spreads to the lower respiratory tract invading the alveolar epithelial cells (1).
The first line defence mechanism the body takes against viral infections is nasal secretions containing non-specific anti bodies which will neutralise the invading viruses and induce sneezing, taking the viruses out of the respiratory tract with the nasal secretions (2).
When a patient takes antihistamines due to early symptoms of rhinorrhoea, the nasal secretions and the sneezing will be reduced. This will increase the viral population in the upper respiratory tract and also prevent the natural mechanism by which the body prevents viruses reaching the lower respiratory tract.
This may enhance the spread of the virus to the lower respiratory tract epithelium covering the bronchial and invading the type two pneumocytes , resulting in decreased production of surfactants and stimulating macrophage production of inflammatory mediators (1).
Inflammatory mediators will increase capillary permeability, increasing interstitial fluid causing alveolar collapse, resulting in the reduction of gas exchange (1).
Therefore, it's important to review the early use of antihistamine in viral respiratory tract infections that have a potential ability to invade alveoli.
1) Weiss S., Navas-Martin S., 2005. Coronavirus Pathogenesis and the Emerging Pathogen Severe Acute Respiratory Syndrome Coronavirus., Microbiology and Molecular Biology Reviews, [online] 69(4), pp.635-664. Available at:
2) Klimpel G.R., Immune Defenses., 1996. Chapter 50., In: Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX).,[ebook] Available at:
Competing interests: No competing interests
No clinical data to support the notion NSAIDs and ibuprofen should be avoided in COVID-19 infections
I disagree with the interpretation of the available evidence and argument supporting the notion of avoiding NSAIDs and specifically ibuprofen in patients with COVID-19 infection and the recommendations of the article by Mr Day in BMJ 2020;368:m1086. The recommendation of avoiding ibuprofen in patients infected with COVID-19 was initiated by the French Health Minister Dr. Olivier Veran and his tweet on March 14 2020.
This premise is thought to have first originated from a research letter published by Fang et al on March 11 2020 in Lancet Respir Med 2020. In their research letter, Fang et al reviewed 3 studies which were cohort studies of patients with confirmed COVID-19 infection. Reviewing the baseline characteristics of these described COVID-19 patients, he noted that commonly reported comorbidities in these studies were hypertension and diabetes. He also observed that these patients were often treated with angiotension converting enzyme inhibitors (ACEI).
As it is postulated that COVID-19 virus enters the host cell through the ACE2 pathway and in animal studies, use of ACEI would upregulate and increase the density of ACE2 receptors. Based on this premise, it is theorized that use of ACEI may facilitate COVID-19 viral entry into host cells and thus, may aggravate COVID-19 infection. Fang et al also made the comment that "ACE2 can also be increased by thiazolidinediones and ibuprofen".
This research letter, which is the basis of all the controversy regarding ibuprofen use and COVID-19 infection, deserves scrutiny. First, Fang et al reported on the comorbidities in the patients diagnosed with COVID-19, yet there is no comparison to the comorbidities of patients who were diagnosed as COVID-19 negative or survivors of COVID-19 infection. Thus, it is still yet unclear if these comorbidities differ from non-COVID-19 infected patients and its relation to outcomes of COVID-19 infection. Secondly, the authors comment on the use of ACEI in COVID-19 patients and that ACEI may be contributing to poor outcomes. However, the use of ACEI is likely only a marker for underlying comordibities, rather than the drug having a direct influence on patients' clinical course. Finally, the authors make a speculative comment that "ACEI2 can also be increased by thiazolidinediones and ibuprofen". This is based purely on animal studies and their research letter present no data to implicate ibuprofen as having influence on COVID-19 infection. Thus this research letter can only conclude that diabetes and hypertension were common comorbidities in COVID-19 infected patients. The influence of ACEI use and especially ibuprofen is very speculative based on the available data.
From this published research letter, Dr. Olivier Veran tweet a recommendation that "taking anti-inflammatory drugs (ibuprofen) could be a factor in worsening the infection" on March 14 2020. This tweet led to rampant speculation and dissemination on social media to avoid ibuprofen in COVID-19 infection. The WHO published a statement on March 18 stating that "it does not recommend against the use of ibuprofen". The European Medicines Agency also published a statement March 18 that " there is currently no scientific evidence establishing a link between ibuprofen use and COVID-19 infection. Similarly, the US FDA published a statement on March 19 that 'at this time, FDA is not aware of scientific evidence connecting the use of NSAIDs, like ibuprofen, with worsening COVID-19 symptoms". Canada also published a statement on March 20 stating " There is no scientific evidence that establishes a link between ibuprofen and the worsening of COVID-19 symptoms". Therefore, all international professional and regulatory bodies consistently state that there is no clinical data or evidence to suggest that ibuprofen or NSAIDs would worsen COVID-19 infection.
All the controversy regarding ibuprofen use was originally based on extremely preliminary data on comorbidities and possible ACEI use in COVID-19 patients, applied to ibuprofen based on speculative extrapolation of theoretical observations and fueled by social media. This has caused concern for patients and confusion for clinicians. In the time of a pandemic and era of social media which is not subject to peer review or professional interpretation of data, it is even more imperative to scrutinize preliminary data to ensure it does not cause more harm than good for patients and prescribers.
References
1. Day M. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. BMJ 2020;368:m1086 doi: 10.1136/bmj.m1086
2. [Accessed March 20 2020] https://twitter.com/olivierveran?lang=en
3. [Accessed March 20 2020] https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30116-8/fulltext
4. [ Accessed March 20 2020] https://twitter.com/WHO/status/1240409217997189128
5. [Accessed March 20 2020] https://www.ema.europa.eu/en/news/ema-gives-advice-use-non-steroidal-ant...
6. [Accessed March 20 2020] https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-patie...
7. [Accessed March 20 2020] https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2020/72633...
Competing interests: No competing interests
Dear Editor
This is great and timely advice that could save countless lives. But in light of the fact that Ibuprofen is contraindicated for use in this current pandemic, how harmful a role do you think the use of aspirin played in the Pandemic of 1918? Some reports cite that patients were given the equivalent of 3 aspirin/hour. Do you think the use of such high levels of this anti-inflammatory could have contributed to the deaths of some of the victims in 1918?
Competing interests: No competing interests
Dear Editor
The BMJ article by Michael Day refers to 'remarks attributed to an infectious diseases doctor in south west France' citing 'four cases of of young patients with covid-19' with serious symptoms after using NSAIDs in the early stage of symptoms.
In a 17/3/2020 article, the BBC refers to presumably the same incident involving four young Toulouse patients, citing this incident as '"fake news", and also referring to similar "fake news" incidents in Cork and Vienna.
Which of these reports is correct?
References:
Day, M. " Avoid ibuprofen in covid-19 care." BMJ 2020;369:m1086.
Rachel Schraer, Jack Goodman and Alistair Coleman. Coronavirus and ibuprofen: Separating fact from fiction. BBC online: Reality check. 17 March 2020. Accessed online on 20/3/2020 at https://www.bbc.co.uk/news/51929628.
Competing interests: No competing interests
Re: Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists
Dear Editor,
Having erroneously neglected ibuprofen, further drugs were considered. The Italian Ministry of Health was fully persuaded by the Government Scientific Committee that the only therapeutic drug correctly suitable for addressing the early symptoms of COVID-19 was acetaminophen, i.e. paracetamol. In an official document dated Nov 30th 2020, the Italian Government recommended only paracetamol and watchful waiting, to address fever and pain during the early onset of COVID-19 or in mild COVID-19 (1).
In a recent paper of mine, held with coauthors and experts in the field (2), we highlighted why acetaminophen worsens the development of COVID-19, so leading patients to a compulsory hospitalization and possibly death. Having recommended only paracetamol and not NSAIDs led to the catastrophic effect observed in 2020, at least until April 26 2021, when the Italian Government added NSAIDs in the official protocol.
The recent evidence that COVID-19 is an endothelial dysfunction due to inflammation, which assessed the autoptic data, which leads to immuno-thrombosis in the micro-circulation (3), should suggest that paracetamol worsens an immuno-thrombotic event, by reducing glutathione, exacerbating pro-oxidative mechanisms, reducing endothelia prostacyclin production and lately promoting the formation of active platelet microparticles (PMPs), which induce thrombosis.
So far, only a civil outcry held by a social organization of physicians, psychologists, caregivers, lawyers and practitioners is raising, on the basis of their experience on patients healed with EBM and their full professional practice, this evidence to the attention of politics and the mainstream, so to thoroughly revise home therapy against COVID-19. The Association, funded by Erich Grimaldi, claims the crucial and urgent warning that paracetamol is dangerous during the early symptoms of COVID-19 including fever and must be reduced or removed from early home therapy. Their civil effort may have rescued many individuals from undergoing hospitalization and ultimately even death.
Yes, someone rejected ibuprofen and selected paracetamol, which was highly used during the March 2020 tragic increase in mortality in Italy. The recent Remuzzi's paper clearly shows that patients using paracetamol instead of COX-2 inhibiting NSAIDs exhibited a higher risk of hospitalization (4).
References
1. https://www.trovanorme.salute.gov.it/norme/renderNormsanPdf?anno=2020&co...
2. Pandolfi S, Simonetti V, Ricevuti G, Chirumbolo S. Paracetamol in the home treatment of early COVID-19 symptoms: a possible foe rather than a friend for elderly patients? J Med Virol. 2021 Jun 25. doi: 10.1002/jmv.27158
3. Bonaventura A, Vecchié A, Dagna L, Martinod K, Dixon DL, Van Tassell BW, Dentali F, Montecucco F, Massberg S, Levi M, Abbate A. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nat Rev Immunol. 2021 May;21(5):319-329.
4 Suter F, Consolaro E, Pedroni S, Moroni C, Pastò E, Paganini MV, Pravettoni G, Cantarelli U, Rubis N, Perico N, Perna A, Peracchi T, Ruggenenti P, Remuzzi G. A simple, home-therapy algorithm to prevent hospitalisation for COVID-19 patients: A retrospective observational matched-cohort study. EClinicalMedicine. 2021 Jun 9:100941. doi: 10.1016/j.eclinm.2021.100941
Competing interests: No competing interests