Research indicates that fever from COVID-19 or most other infections should not be lowered with ibuprofen, aspirin or paracetamol / acetaminophen etc. - and some research which may indicate to the contrary

With some exceptions for neurological injury and heart disease, research shows that except to limit temperature to 40C (104F) or so, drugs such as these should not be used to reduce fever in adults - because it is an important part of the body's defense against viral and bacterial infections.

I believe that health authorities should issue clear, consistent advice such as this to reduce the chances of millions of people suffering from COVID-19 at home lowering their fever and so suffering worse symptoms, including lasting disability and death.

This page is written primarily for doctors, nurses, researchers and public health leaders - so they can read the research for themselves.

I am not a doctor
so my views on the matter should not affect anyone's decisions.  What counts here is the research articles I link to.

The focus of this page is the use of drugs to lower fever, but in principle most or all of the evidence against this practice would also apply to other techniques, such cooling the body mechanically.

The updates/ page lists all the significant updates to these cv19 pages.

Robin Whittle rw@firstpr.com.au .   2020-03-21  Last update 2020-06-21 01:10 UTC

../ to the main COVID-19 page of this site.


Lay people please read the disclaimer (../#disclaimer) on the main COVID-19 page http://aminotheory.com/cv19/ which is also written primarily for doctors, nurses and researchers.  There I present research which supports my argument that a number of readily available micronutrients should be taken by all adults now, together with reducing excessive salt intake, in order to reduce their over-inflammatory response to COVID-19. 

The other page, again primarily for doctors and nurses, is http://aminotheory.com/cv19/kna/ concerning the use of mild-tasting potassium gluconate solution to achieve substantial potassium supplementation, which - combined with avoiding the saltiest foods -  would ensure that many or most people's blood pressure remained healthy without the need for drugs.   This would also reduce the risk of stroke and other diseases.

I am an electronic technician and computer programmer. I created this website http://aminotheory.com in 2011 primarily for my new observations and etiological theory of Restless Legs Syndrome: http://aminotheory.com/rlsd/briefsumm/ .  This is not a commercial site.  It generates no revenue and puts no cookies in your browser.  I am not selling anything.  (I never got around to getting the certificates etc. for encrypted https.)

If you quote selected passages in your social media feeds, discussion forums etc. - always with a link to this page's URL: http://aminotheory.com/cv19/fever/

Please do not copy the entire page, or substantial parts of it, to other sites, since I update the text and don't want out-of-date versions floating around the Web.





UK official guidance on NSAIDs and some other updates

Please see this UK government guidance on the use of NSAIDs with COVID-19.  As far as I know they assume that it is acceptable or desirable to reduce fever.  They are primarily concerned with which of several drugs to use.

https://www.nice.org.uk/covid-19 This has the latest guidance documents for COVID-19 in general, one of which is Acute use of non-steroidal anti-inflammatory drugs (NSAIDs) for people with or at risk of COVID-19 - ES23.

I have not had time to fully read these items cited by Shin Jie Yong's Medium articles https://medium.com/@shinjieyong/fever-can-hurt-or-help-depending-on-what-started-it-40ac0876105a and https://medium.com/@shinjieyong/dont-fret-about-ibuprofen-worsening-covid-19-studies-find-b8ac4e1a5565 .  Here are a few quick notes:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944485/

Temperatures over 40C are dangerous.

https://sci-hub.tw/10.1016/j.bbi.2015.07.012

(1) the association between fever early in the course of critical illness and mortality is different between infectious and non-infectious diseases; (2) reducing temperature in the “infection group” may be harmful, as fever in this group was associated with a decreased risk of death. Vice versa one could also interpret these studies to suggest that antipyretic therapy provides some advantage for patients with high fever of non-infectious origin.

Please see his second article for links which to research which apparently indicates that ibuprofen may be helpful in COVID-19.  However, I think there's a difference between taking it in the early stages, typically at home (where I am concerned that lower fever will increase infection) and taking it later when excessive inflammation is a problem.
#key

Key points for lay people

Paracetamol (Panadol) is the same as acetaminophen (Tylenol etc.)  It reduces fever and is generally not regarded as an NSAID [en.wikipedia.org/wiki/Nonsteroidal_anti-inflammatory_drug] - a class of drugs which includes aspirin and ibuprofen (Advil).  All these drugs are anti-pyretics - they lower the body's temperature during fever.

Some technical terms are followed by a [W] link to the relevant Wikipedia page.

You may also be interested in this 2020-04-08 article by Markham Heid:

The Argument for Letting a Fever Run Its Course
It may lead to better outcomes, some experts say
elemental.medium.com/...letting-a-fever-run-its-course

This cites a number of other research reports which come to the same conclusions as the ones I found.

Also, from the US Center for Disease Control, regarding COVID-19:

What to Do If You Are Sick

The following points are stripped of arguments and references, and are a guide to the message below #msg for clinicians, which would ideally be a much longer exposition.  Please read the message, with the research it cites AND read the disclaimer that you shouldn't act on suggestions regarding health from an electronic technician unless you have researched the arguments to your satisfaction, read and ideally consulted very widely and take full responsibility for your decisions.

Paul Little, professor of primary care research at the University of Southampton, . . . said  “reasonable evidence of a link between NSAIDs and both respiratory and cardiovascular adverse effects,” and therefore caution was the best policy.

“Pending further research, a pragmatic and cautionary approach would be for the public to avoid these plausible harms. Regular NSAID use should probably not be recommended as the first line option for managing the symptoms of covid-19,” he said. But he added that patients on low dose aspirin for secondary prevention of cardiovascular disease should be advised to continue, noting that aspirin has anti-inflammatory effects only at much higher doses.

Researchers at the Centre for Evidence-Based Medicine in Oxford have opened up another avenue for debate, however, by questioning the traditional advice of using over-the-counter pills to lower a fever in those with acute respiratory illness in an analysis published on 19 March. They said that the benefits of fever should not be overlooked. “Fever is common and is a good prognostic sign in acutely unwell patients with infection, associated with higher rates of survival.”

They concluded: “The current evidence does not support routine antipyretic [temperature lowering] administration to treat fever in acute respiratory infections and covid-19,” adding that the rapid and widespread purchase of antipyretic medication over-the-counter has led to temporary shortages.”


YouTube videos: US pulmonologist Dr Roger Seheult (pr. Swelt) has an excellent series of COVID-19 video updates: www.youtube.com/user/MEDCRAMvideos/videos .  He discusses fever in his 44th update www.youtube.com/watch?v=A4eu-h_owaI&t=378s) and advises (as best I understand what he said, and doctors "caution against" things rather than say you shouldn't do it) against lowering fever with drugs.  He didn't mention any upper temperature limit.

UK nurse and nurse trainer (Dr) John Campbell PhD explains the role of fever in supporting multiple aspects of the immune system's response to viral and bacterial infections.   www.youtube.com/watch?v=gJqSdmNNwW4 and www.youtube.com/watch?v=rDijpnCOoFc .




#msg

For clinicians and researchers

This is an updated version of part of an email message I sent to COVID-19 clinicians and researchers, starting on 2020-03-21.  Now, when I write to them, link to this and the two other pages mentioned above.

I believe that doctors, nurses and health authorities should issue guidance to the public along these lines.  Without clear, consistent, advise such as this, many people will lower their COVID-19 induced fever and so suffer more serious symptoms - including lasting disability and death.

Fever is an important part of the body's defense against viral and bacterial infections.  Except when fever becomes dangerous (you need to specify temperature and other conditions - I guess 40C or lethargy) it is best to allow the fever to continue, by rugging up and avoiding the use of aspirin, ibuprofen, paracetamol or other such drugs.  I have heard that hot drinks are preferred to cold.  Sleep helps the immune system so staying as warm as possible in bed seems like a good idea.

Aspirin contributed enormously to the Spanish Flu death toll, especially among young adults:  academic.oup.com/cid/article/49/9/1405/301441 . Reye syndrome may have played a part in this. Even though these deaths resulted from larger doses than might, ideally, be used today, most people will be tempted to self-medicate their COVID-19 fever and breathing difficulties at home - and many or most people think that fever is bad and must be suppressed.  

Beyond the concerns about reducing fever, this report is extremely concerning and I hope you will be able to find out more about it:  www.bmj.com/content/368/bmj.m1086   Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists  "(An infectious diseases doctor in south west France) is reported to have cited four cases of young patients with covid-19 and no underlying health problems who went on to develop serious symptoms after using non-steroidal anti-inflammatory drugs (NSAIDs) in the early stage of their symptoms.".    The English translation of a recent French directive: dgs-urgent.sante.gouv.fr/dgsurgent/inter/detailsMessageBuilder.do?id=30500&cmd=visualiserMessage in  includes: "paracetamol, without exceeding the dose of 60 mg / kg / day and 3 g / day. NSAIDs should be banned.".

I am concerned about millions of people taking paracetamol at home while their symptoms increase, with impaired liver function from IL-6-driven [W] sepsis [W] leading to high levels of NAPQI and so potentially deadly liver and/or kidney damage. [en.wikipedia.org/wiki/Paracetamol_poisoning]  If paracetamol is recommended, I suggest you specify a maximum dose and the temperature for which it should be used - I guess 40C = 104F.. 

See also Basille et al 2017: pubmed/28005149  "Our findings suggest that NSAIDs, often taken by young and healthy patients, may worsen the course of CAP [community acquired pneumonia] with delayed therapy and a higher rate of pleuropulmonary complications."  Alcohol abuse also drives symptoms. Cited by 11.  SciHub: sci-hub.tw/10.1007/s00408-016-9973-1 .

Olga Khazan wrote a good article on this messy antipyretic debate: www.theatlantic.com/health/archive/2020/03/coronavirus-fever-ibuprofen/608233/ .
She cites a 2002 to 2003 trial in Florida, written up in 2005:

Schuman et al. 2005 16433601   The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study.   sci-hub.tw/10.1089/sur.2005.6.369

in which:
There were 131 infections in the aggressive group and 85 in the permissive group (n = 38) - p = 0.26.  The trial was stopped after 7 deaths in the aggressive group and 1 in the permissive group - p = 0.06.

The 196 Google list of articles citing this one look interesting.  I mention one of these below.  This is not the sort of experiment anyone wants to repeat.

See the responses to the first (2020-03-17) BMJ article on this topic www.bmj.com/content/368/bmj.m1086 and the 2020-03-23 update www.bmj.com/content/368/bmj.m1168 , highlights of which are above: #aspibupar .  My impression is that none of these drugs should be used by COVID-19 patients, except perhaps those on low-dose aspirin. 

The responses to the first article are interesting, including a citation of a 2003 hypothesis from Chan Kam Ping, MD in Hong Kong that high temperatures are effective against the SARS virus, that children do better than older people because children's basal metabolic rate is higher, and that air conditioning and cold air temperatures favour the virus.  www.bmj.com/rapid-response/2011/10/29/coronavirus-may-be-killed-higher-body-temperature

If the hypothesis is correct, then control is straight forward:

1. Put on more clothes to make body really warm,

2. maintain room temperature at least above 23C,

3. do exercise for 30 minutes daily, make sure you really sweat.


Here are some notes on and quotes from one of the articles citing Schuman et al. 2005

#evans

Fever and the thermal regulation of immunity: the immune system feels the heat (Evans et al. 2015)

PMC4786079
 
This detailed article deals with cancer, bacterial and viral infections.  I have attempted to highlight parts of it most relevant to viral infections and sepsis. Google lists 342 articles citing this one.  It is my impression that this is an authoritative article which has not been surpassed by later work.

Interleukin 6 (IL-6) - along with Tumor Necrosis Factor and some other pro-inflammatory cytokines - is well known to drive the potentially deadly inflammation of sepsis.  These are  pyrogenic cytokines - and we know that in general, increasing the temperature slows viral reproduction.

This article cites several others in the following statements, which I think concerns mid- and end-stage inflammation.  I consider refs 10 (Almeida et al. 2006) and 11 (Launey et al.) below.

However, fever is not universally beneficial, particularly in cases of extreme inflammation where lowering, rather than raising body temperature has evolved as a protective mechanism.7–10 Thus, uncontrolled fever is associated with worse outcomes in patients with sepsis or neurological injuries, whereas treatments that induce hypothermia [cooling] can have a clinical benefit.11,12


A statement on page 2 concerning poliovirus replication being highly temperature dependent probably cannot be generalised to all viruses, since this is not due to host defenses, but to to temperature dependent conformal changes at one end of the viral RNA where it first engages with the ribosome.

Infection debris triggers TLR4 (toll like receptors) which lead to the synthesis of pyrogenic cytokines IL-1, TNF and IL-6.  IL-6 seems to play a more crucial role in creating fever than the other two.  A positive feedback loop has been identified in which raised body temperature (including when raised externally in experiments) increases the rate at which TLR4 activation drives the synthesis of these three cytokines.  IL-6, COX2 and PGE, in this order, are all essential in the induction of fever.

Dendritic cells isolated from heated mice exhibit a superior ability to activate T cells.

Innate immune cells are the ‘first responders’, arriving within hours to directly destroy pathogens via phagocytic or cytotoxic activities. These activities limit infection until a peak adaptive immune response is generated, normally around one week later.


I guess that a week after initial infection, if this antibody response has not eliminated SARS-CoV-2 from the body, it will infect the lungs and other organs, beginning mid-stage
where the person at home has their final chance for survival by stopping it there.

Given the complexity of these immune mechanisms, it is remarkable that fever-range temperatures stimulate almost every step involved in this process, promoting both innate and adaptive immunity. The potential impact of the thermal element of fever has primarily been explored using hyperthermic temperatures within the febrile range for mammals (that is, ranging from 38 to 41°C; ΔT~1–4°C above baseline) in the various in vitro and in vivo studies  described below



Hasday and colleagues found that fever, or exposure to fever-range hyperthermia [induced mechanically, not created by the body itself], in an LPS [bacterial endotoxin induced] model increases neutrophil localization to the lung, which can have negative consequences due to inflammation-induced local tissue damage.


A note on excessive IL-6 regarding sepsis vs. IL-6 being essential for the febrile response which is known to reduce viral infection, at least in the early stage:

In the main COVID-19 page ../ , concerning nutritional methods of improving immune response regulation, I am primarily concerned with the ability of adequate vitamin D, boron, omega 3 PUFAs etc. to reduce levels of IL-6 in the mid-stage and late stage, to the extent that such levels are in excess of whatever is beneficial when fighting the virus, as can be seen from the divergent IL-6 levels in the graph C from Zhou et al. on that page, reproduced here:

Excessive Interleukin-6 drives deadly sepsis in COVID-19

This is all late-stage - people who got to ICU.  Those with ever-rising IL-6 levels do not survive.  This is presumably because those excessive levels of IL-6 drive the excessively inflammatory response which contributes to (as we know from May 2020, but not when I first wrote this in March 2020) the lung endothelial damage and the hypercoagulative state which results from this.  The ca. 6 pg/mL levels are presumably healthy in these circumstances.


My guess is that fever to 40C with accompanying IL-6 mediated actions are vital in the early and perhaps mid-stages of the infection, and that the sepsis excesses of inflammation and I guess temperature, also mediated by excessive levels of IL-6, are only a problem in the mid-stage and end-stage of the body's fight against the virus.

I think we want a strong IL-6 response in the early stage, but not an excessive response in mid-stage or end-stages.

[Externally applied] whole-body heating (to ~39.5°C) improves bacterial clearance and also increases serum concentrations of TNF, IL-1, and IL-6 in mice challenged with LPS.  The source of these cytokines was found to be the macrophages of the liver (that is, Kupffer cells) as well as macrophages in other organs.



Some investigators have paradoxically observed an anti-inflammatory role for Heat Shock Proteins. .

Taken together, the data regarding innate immune cells, body temperature and HSPs reveal fascinating, yet still poorly understood, layers of interdependency between the febrile response and the more ancient HSP response.


The article contains far more on IL-6 than is mentioned above.  The section Return to homeostasis contains material on febrile temperatures reducing the synthesis of pro-inflammatory cytokines.  This would be in late-stage and probably relates to the healthy immune regulation which is disrupted in severe COVID-19 - a state which I think is occurring due to lack of helminths (../#helminthsgone) and by inadequate and easily corrected nutritional deficiencies, especially inadequate vitamin D. 

My gut feeling is that we shouldn't be messing with any of these mechanisms with NSAIDs and the like.  We barely understand how they work under ideal conditions.  The disregulation which leads to life-threatening sepsis is something we must solve - by proper nutrition, not by inserting more disturbing drugs into the system.

Cold-seeking behavior as a thermoregulatory strategy in systemic inflammation (Almeida et al. 2006)

[PubMed: 16820025 sci-hub ]

Rats given a low endotoxin dose warm themselves and developed fever.  Rats given a much higher dose, as if to emulate the systemic inflammation which drives sepsis, tried to cool themselves.

My thoughts: Does the immune disregulation of sepsis somehow prevent the body from trying, or succeeding, in cooling itself?  The best approach is to try to fix the disregulation with missing nutrients.  Failing that, or in addition, should the body be cooled mechanically or with anti-pyretics?  The next article suggests generally not.

Clinical review: fever in septic ICU patients--friend or foe? (Launey et al. 2011)

[PubMed: 21672276]
 
The use of paracetamol and NSAIDs are discussed in some detail.

There are good reasons to limit or lower fever in cases of neurological injury, including ischemic stroke, and some heart conditions - due to fever's high oxygen demands.  In most other scenarios the research discussed in this article supports fever being left to do its work. 

The ultimate effect of fever is determined by the balance between accelerated pathogen clearance and collateral tissue injury.  At a high fever level (>40 to 41°C), however, the beneficial immunomodulatory effect could be outweighed by the deleterious metabolic/inflammatory effect of fever.


With the above qualifications:

The balance of benefit to harm of fever in septic ICU patients is complex.  This balance is likely to be dependent on the stage and severity of the infection, on the intensity of the immune response, on the extent of systemic inflammatory response-induced collateral tissue damage as well as on the underlying physiological reserve of the patient. 

On the other hand, the widespread use of antipyretic methods in ICU patients is not supported by clinical data and fever control may be harmful, particularly when an infectious disease is progressing.



Some other articles which look interesting but which I have only glanced at so far

These are all articles which cite Evans et al 2015 (#evans). 
Experimental studies indicate that fever and inflammation are beneficial to the host.
Randomized clinical studies equivocal on value of fever in critically ill patients.
Antipyretics may alter inflammatory processes and increase viral transmission rates.
Fever in pregnancy or infancy is benign, but may be detrimental in some cases.

An increase in the body temperature is known to have deleterious effects on patients with acute nervous system injury and in most cases is associated with an increase in mortality and morbidity of these patients.

Low levels of the antioxidant glutathione can inhibit fever.   According to this Wikipedia article vitamin C and other antioxidants work with glutathione and can reduce its depletion.  Calcitriol (which apparently takes 10 days to be produced from vitamin D3 cholecalciferol, increases glutathione levels.

An increase in the body temperature is known to have deleterious effects on patients with acute nervous system injury and in most cases is associated with an increase in mortality and morbidity of these patients.


Fever, viral replication and temperature dependence of protein synthesis

In the 1990s my friend Marcia Clemmit (website) and I independently developed a hypothesis that fever's effectiveness against viruses was in part due to a finely tuned temperature dependence of mammalian ribosomal activity.  The attraction if this hypothesis was that it would slow viral replication in a way the virus could not alter, since the temperature of the cell is not at all affected by viral activity.  We had no evidence for such a sharp decline in protein synthesis above 37C, or an explanation of why this would be acceptable during exercise-driven hyperthermia.

It turns out that there is not much direct reduction in mammalian protein synthesis at 40C.  A chart in Fuhr 1974 sci-hub.tw/10.1002/jcp.1040840305 shows only a 20% drop.  Charts in McCormick and Penman 1969: sci-hub.tw/10.1016/0022-2836(69)90320-9  show an approximately 50% drop at 42C.

In the 1950s, fever was slowly recognised as a defence against viral replication, as described by Andre Lwoff 1971 www.annualreviews.org/doi/pdf/10.1146/annurev.mi.25.100171.000245 page 17.  However, the temperature dependence of the different strains of poliovirus he and others were working with was due to the temperature dependent conformations of the end of the viral RNA which first engages with the ribosome. This is not part of the host's defense system. 

To whatever degree febrile temperature and related inflammation processes do slow all viral protein synthesis beyond the ~20% just quoted, I imagine the mechanisms involve pH changes or more complex molecular mechanisms which are more susceptible to being thwarted by the virus.





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