Covid-19: NICE advises against using NSAIDs for fever in patients with suspected cases
BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1409 (Published 06 April 2020) Cite this as: BMJ 2020;369:m1409Update available
The guidance this News story refers to has been updated
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Dear Editor,
Further to my response yesterday I would like to update your readers that the guidance has now been updated and the CHM has issued a statement.
https://www.gov.uk/government/news/commission-on-human-medicines-advice-...
It seems that evidence based medicine has prevailed and it reassuring to see the conclusions of the CHM. I note a CAS alert has also been issued.
https://www.cas.mhra.gov.uk/ViewandAcknowledgment/ViewAlert.aspx?AlertID...
Perhaps the BMJ can now run a news article with an appropriate headline to help dispel any remaining myths around NSAID use in COVID-19?
We will continue to monitor the situation and are committed to understanding any link between ibuprofen and COVID-19.
Competing interests: I am employed by RB, the makers of Nurofen.
Dear Editor,
Firstly for the benefit of all readers I would like to raise an objection to your use of a title which is not really reflective of the content. This article is not as the title would suggest focussed on the use of NSAIDs in COVID-19. The title of this article pulls out only one small element of the broader matters being discussed. A better title may have been 'NICE issues guidance on COVID-19 management' or similar.
Secondly, I would like to express my confusion as regards the UK advice being offered, and ask your learned readers to consider whether the guidance is in keeping with evidence based medicine (EBM). EBM is the conscientious, explicit, judicious and reasonable use of modern, best evidence in making decisions about the care of individual patients. To date, as acknowledged by the EMA, FDA, TGA and other reputable healthcare agencies, and as is supported by our own pharmacovigilance efforts, there is no conclusive evidence linking NSAID usage with COVID-19 outcomes, adverse or otherwise, and neither is there any evidence to inform relative safety conclusions about paracetamol in COVID-19.
There is neither a proven mechanistic basis for NSAIDs having a deleterious effect in COVID-19 nor any conclusive association between NSAID usage and symptom worsening. In fact there is probably as much (i.e. very little) emerging evidence to suggest NSAIDs may have a beneficial effect in COVID-19, at least mechanistically. There is also at present an absence of safety data for many other drugs, including paracetamol, which I am sure has been taken by many patients with both poor and positive outcomes. A temporal association with an outcome is in no way a marker of causality and we would be foolish to jump to inaccurate conclusions, especially about medicines with proven utility in managing the symptoms of infection.
How is it then that in the absence of any compelling evidence on either molecule the advice is - 'Advise patients to take paracetamol if they have fever and other symptoms that antipyretics would help treat. Tell them to continue only while the symptoms of fever and the other symptoms are present. Until there is more evidence, paracetamol is preferred to non-steroidal anti-inflammatory drugs (NSAIDs) for patients with COVID‑19.' A preference would surely need to be evidence based?
If we are to take this approach to clinical practice I believe we are ignoring the very principles of EBM, taking the approach of guilty until proven innocent. I very much welcome all research into the subject and into all the medicines being used to manage this pandemic, but I think we should always be cautious about rushing to unsupported conclusions and ignoring the very basis of sound decision making; that being EBM. Doing so may inadvertently lead to other issues such as medication overuse, loss of confidence in molecules with a good safety profile and confusion amongst both healthcare professionals and patients in a time of self-care need.
Competing interests: I am employed by RB, makers of Nurofen
Dear Editor
NSAIDS and COVID-19: urgent critical analysis of all anti-inflammatory drugs, especially those for cardiovascular diseases and type 2 diabetes, is required
This is the 3rd BMJ article recommending avoiding non-steroidal anti-inflammatory drugs. (1-3) I would like to widen the discussion to all drugs based on 5 features of COVID-19 infection that, potentially, provide important information understanding the clinical course and outcome and need explaining:
1 the extreme variation in the spectrum of disease at any age, with most people virtually unaffected and others in jeopardy
2 unusually large differences in the severity and outcome of disease by age group,
3 the much higher mortality in men compared with women in most countries,
4 the high mortality in people with cardiovascular diseases, especially hypertension, and type 2 diabetes, and,
5 the delay in the occurrence of extremely severe disease until the 3rd week after symptoms.
Surprisingly, the case-fatality in people with CVD and type 2 diabetes is similar if not higher than in people with chronic obstructive pulmonary disease who would be expected to be at extremely high risk. Ethnic minority groups, including African Americans, and UK African Caribbeans and South Asians also have relatively high case mortality.
Is there a unifying hypothesis for these observations? Could it be an interaction between immune function and the time available for the virus to replicate? What factors might be important? Standard explanation such as the amount of exposure are likely to be important. What about other factors? The role of drugs that alter immune function has not, in my view, received sufficient attention.
Little recommends that on pragmatic grounds we should not use non-steroidal anti-inflammatory drugs (NSAIDS) until further research is done. (2) He cites research on community-acquired pneumonia by Voiriot et al suggesting that these drugs reduce polymorphonuclear recruitment and have other effects that delay the resolution of inflammation. This argument should extended to many medications. Alternatively, might some drugs delay the mobilisation of the immune system allowing the virus to replicate faster?
Many drugs, including those for cardiovascular diseases and type 2 diabetes, have complex effects on the immune system. Cardiovascular diseases and type 2 diabetes are very common in people over 40 years of age, and those even younger, especially in ethnic minority groups including those of South Asian origin and African-Americans. (4) (5-9)
As cardiovascular diseases are more common in men, they are more likely to receive such drugs than are women, and there is evidence that women are less likely to be given these drugs, independent of need, than are men. Some drugs may delay the mobilisation of the immune system, or affect it in other ways, impairing the response to infection.
A major review has been published and, understandably, focused on ACE (angiotensin converting enzyme) inhibitors, given the virus enters cells via the ACE-2 receptor. (10) This receptor is also found in the lung, heart (including the vascular endothelium), intestine and kidneys and is activated in hypertension, heart failure and atherosclerosis. (10)
Drugs such as aspirin, metformin and statins and many other cardiovascular/diabetes drugs have complex effects on the immune system and are usually seen as beneficial in countering the pro-inflammatory effects of cardiovascular diseases and type 2 diabetes. (5) As one of many millions of people on a statin for the primary prevention of cardiovascular disease I examined the evidence in relation to this class of drug, but the principles apply to many drugs.
The benefits of statins are thought to be partly from their anti-inflammatory effects. Statins affect macrophage function and other functions relating to the immune system, not just on cellular activity but also on pro-inflammatory pathways including on interleukins. (5)
Specialist societies, including the World Heart Federation (https://www.world-heart-federation.org/covid-19-and-cvd/), American Heart Association (https://www.heart.org/en/coronavirus/coronavirus-questions/if-youre-a-pa...) and the British Heart Foundation (https://www.bhf.org.uk/informationsupport/heart-matters-magazine/news/co...), have recommended that people should not alter their drugs regimens without consulting their physicians. (Websites accessed on 11 April 2020.)
The advice from specialist societies is sensible and should be followed as the effects of altering medications, even temporarily, could outweigh the potential benefits. Nonetheless, urgent, in-depth analysis is required for every drug that has important effects on the immune system. Some are likely to be beneficial in staving off severe infection but others, as is suspected for NSAIDS, could be potentially harmful. We need scholars and researchers to prioritise this issue.
References
1. Day M. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. 2020;368:m1086.
2. Little P. Non-steroidal anti-inflammatory drugs and covid-19. 2020;368:m1185.
3. Torjesen I. Covid-19: NICE advises against using NSAIDs for fever in patients with suspected cases. 2020;369:m1409.
4. Carnethon MR, Pu J, Howard G, Albert MA, Anderson CAM, Bertoni AG, et al. Cardiovascular Health in African Americans: A Scientific Statement From the American Heart Association. Circulation. 2017;136(21):e393-e423.
5. Blake GJ, Ridker PM. Are statins anti-inflammatory? Trials. 2000;1(3):161.
6. Chou R, Dana T, Blazina I, Daeges M, Jeanne TL. Statins for Prevention of Cardiovascular Disease in Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2016;316(19):2008-24.
7. Volgman AS, Palaniappan LS, Aggarwal NT, Gupta M, Khandelwal A, Krishnan AV, et al. Atherosclerotic Cardiovascular Disease in South Asians in the United States: Epidemiology, Risk Factors, and Treatments: A Scientific Statement From the American Heart Association. Circulation. 2018:CIR.0000000000000580.
8. Misra A, Bhardwaj S. Management of the Metabolic Syndrome and the Obese Patient with Metabolic Disturbances: South Asian Perspective. Nestle Nutr Inst Workshop Ser. 2015;82:61-73.
9. Bhopal RS. Epidemic of Cardiovascular Disease and Diabete: explaining the phenomenon in South Asians worldwide. Oxford: Oxford University Press; 2019, 384 p.
10. Clerkin KJ, Fried JA, Raikhelkar J, Sayer G, Griffin JM, Masoumi A, et al. Coronavirus Disease 2019 (COVID-19) and Cardiovascular Disease.0(0).
(Acknowledgement: Professor Laurence Gruer give helpful advice to orientate my thinking at an early stage but is not responsible for any of the views expressed here.)
Competing interests: No competing interests
Re: Covid-19: NICE advises against using NSAIDs for fever in patients with suspected cases
Dear Editor,
This summary of advice on NSAIDs is accurate, but promulgates a common misconception, that also appears in some of the published guidelines. There is no indication to ‘manage a fever’. Working as a GP answering many calls to 111, it is clear that the majority of people remain under the misapprehension that they need to ’treat’ or ‘control’ a fever as though it were a bad thing that might in itself cause damage. In fact, the opposite is true. It may be appropriate to use paracetamol or an NSAID to help relieve symptoms, and one could ask if there is any harm in that. For self-limiting infections, probably not, but for untreatable infections posing a significant risk, the potential for harm becomes an important factor. So what do we know?
Antipyretic drugs increase mortality from influenza in animal studies: pooled odds ratio 1.34 (1.04 - 1.73). It has also been demonstrated that treatment with antipyretics may increase the risk of mortality in experimental Streptococcus pneumoniae in animals. In mice, treatment with aspirin prior to or immediately after Streptococcus pneumoniae inoculation increased mortality rates two to three-fold. Eyers 2010, doi: 10.1258/jrsm.2010.090441 See also reference 48 therein.
Antipyretic drugs inhibit antibody production in humans. Plus all the evidence regarding a reduced response to immunisation if paracetamol is given routinely. Bancos 2009, doi: 10.1016/j.cellimm.2009.03.007
Reducing fever may increase transmission of infections. Population-level effects of suppressing fever. Earn 2014, doi: 10.1098/rspb.2013.2570
In serious infection, fever is beneficial. Body Temperature at the Emergency Department as a Predictor of Mortality in Patients With Bacterial Infection: <36, 36 to 36.9, 37 to 37.9, 38 to 38.9, 39 to 39.9, and ≥40 °C, with respective mortalities of 32.5%, 14.1%, 8.7%, 8.2%, 5.7%, and 5.3%. Yamamoto 2016, doi: 10.1097/MD.0000000000003628
Bacterial and viral replication can be suppressed by fever. Dixon 2010, doi: 10.1136/bmj.c450 and Eyers as above cited references 34-37.
Fever has been used to treat ‘untreatable’ infections in the past. Julius Wagner-Jauregg won the Nobel prize in 1927 for treating neurosyphilis, at the time a fatal incurable illness, by infecting his patients with malaria to induce a high fever and then curing the malaria with quinine. With the advent of effective antibiotics, his legacy has been largely forgotten.
For children the primary goal of treating the febrile child is to improve the child's comfort rather than the normalization of body temperature. Antipyretic use does not prevent febrile seizures. Sullivan 2011, doi: 10.1542/peds.2010-3852 Rosenbloom 2013, doi: 10.1016/j.ejpn.2013.04.008
It would be a great social injustice if people were not informed that taking antipyretic medications for the wrong reason offers no benefit in the face of potential harm to their recovery.
Competing interests: No competing interests