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.
2021-01-31: Please see an important update regarding mutations in the SARS-CoV-2 viruses which cause COVID-19.
The British variant is more transmissible. The separately evolved, but
otherwise identical, South African and Brazilian strain are more
transmissible still. There's no reason to believe they are less
harmful, and some reasons to believe they are at least as harmful or
more.
Researchers in Israel and France ran experiments with yeast (not
viruses) to evolve, in an accelerated manner, the likely mutations
which would give rise to more transmissible variants of SARS-CoV-2, due
to the variations in the spike protein's Receptor Binding Domain having
a greater affinity for the ACE-2 receptor. Their experiments evolved
mutations including the same three which cause the South African /
Brazilian strain to be much more transmissible. Their experiments
also discovered other mutations which would make still more
transmissible variants of SARS-CoV-2, but which have not yet evolved in
the virus. The British strain has 3.5 times the RBD affinity for ACE-2 of the strains common in mid-2020. The South African / Brazilian strain has 12.7
times this affinity. Their experiments found multiple combinations of
mutations, including one which conferred an approximately 640 times the affinity of mid-2020 strains.
It is reasonable to expect that the viruses, in the wild, in the months
and years to come, will evolve to embody at least some, and perhaps
all, of the mutations this team discovered - and there may be other
mutations as well which increase transmissibility.
Therefore, we cannot assume that the strains which affected most
countries in the middle of 2020 will be the ones we have to contend
with now, in early 2021, much less later in the year and in the future.
These mutations tend to make immunity from prior infections or vaccines
against older strains less effective, so reinfection with new strains
seems possible and likely.
Perhaps future strains with very high RBD affinity for ACE-2 will
render any vaccine-induced immunity, and perhaps infection induced
immunity, much less able to prevent infection, or to reduce the extent
of an infection once it starts. If so, then vaccines, social
distancing, masks, lockdowns etc. will be even less effective than they
are today.
Since population-wide, year-in year-out, antiviral drugs are
impractical and undesirable, then the only option would be to do what I
and others have been suggesting since March 2020: population-wide
substantial supplementation with vitamin D3 and ideally other nutrients
to boost strong initial immune responses to the infection and, most
importantly, to reduce, as much as possible, the common tendency for
the dysregulated, hyper-inflammatory, self-destructive immune responses
which cause some people to have severe COVID-19 symptoms.
I worked unsustainably on these websites from March to December 2020.
I will try to update them with the very most significant research, such
as just mentioned - but in general I need to get back to my work with
electronic musical instruments.
|
|
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:
Temperatures over 40C are dangerous.
(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:
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:
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.
- There are arguments against adults deciding, without medical advice, to take ibuprofen, aspirin,
paracetamol/acetaminophen etc. to lower fever, unless it reaches some
temperature, such as 40C = 104F. (Two articles on fever in children are PMC4145646 and sci-hub-Hiller-2019 .)
- There are well researched arguments for not using
aspirin at all - since aspirin contributed significantly to the death
toll of the Spanish Flu, especially among young adults: academic.oup.com/cid/article/49/9/1405/301441
. "early deaths exhibited extremely 'wet', sometimes hemorrhagic
lungs". Now read a despairing report of COVID-19 patients from an
New Orleans ICU doctor www.propublica.org/article/a-medical-worker-describes--terrifying-lung-failure-from-covid19-even-in-his-young-patients
where the same red frothy symptoms appear, including in people in their
30s and 40s.
- France banned the use of ibuprofen, apparently due to a
report of four young people with severe symptoms which seem to have
resulted from their early use of and NSAID - and ibuprofen and aspirin
are the most commonly used NSAIDs. (Paracetamol/acetaminophen is not
usually considered and NSAID).
- #aspibupar
2020-03-23 update: see www.bmj.com/content/368/bmj.m1168
which cites advice in recent days from authorities, including:
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.”
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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:
in which:
- For 44 patients the aggressive approach to temperature control was used: > 38.5C: 650mg paracetamol/acetaminophen
every 6 hours and > 39.5C: cooling blankets.(101.3F and 103.1.)
- For 38 patients the permissive approach was used - > 40.0C: both these measures. (104F.)
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.
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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
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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
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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.
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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:
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.
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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.
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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.
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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.
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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.
../ to the main COVID-19 page of this site.
To the index page of this site: ../../
Contact details and copyright information: ../../contact/
© 2020 Robin Whittle Daylesford, Victoria, Australia