コロナウイルスパンデミックアップデート46温冷療法は免疫力を高めることができるか？ヒドロキシクロロキンの詳細 (Coronavirus Pandemic Update 46: Can Hot/Cold Therapy Boost Immunity? More on Hydroxychloroquine)

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welcome to another COVID-19 update us continues to top the charts in
terms of infections if you go to world ometer and sort by deaths per 1 million
population you can still see that the highest concentration of deaths are
occurring in italy at this point in terms of new cases USA is still leading
in the united states new york and new jersey lead and california is a distant
third and of course in new york and now in california we're starting to have
issues regarding saturation of health care delivery systems okay let's discuss
exactly what's going on right now with COVID-19 what we have here are
three different populations we have the entire population as a whole and we have
those that are going to be infected and we have those that are going to need
hospitalization and you may have noticed that the situation that we're having
right now in new york especially also in other parts of the country is that this
population of people who need hospitalization is not able to get into
our tunnel here which is in fact the hospital and because of that we're
having issues with shortages of ventilators of ICU beds etc and so right
now all of the work is going into trying to increase the capacity of the hospital
system to allow this type of bolus of patients if you will to get through and
to be treated effectively now of course these graphs are not drawn to scale
remember that there's only a certain amount of the population that will
become infected and the way to reduce that even more is with isolation but
there's a certain percentage of those people that become infected that will
need to go to the hospital and as it stands according to the data that we
have right now that's about twenty percent which means that eighty percent
of the people that get the infection won't need to go to the hospital and
that is almost totally related to that patient's immune system so the immune
system is rather complicated and that's why i want to talk
about a little bit imagine your immune system is like this country's armed
forces you have the army the Navy the Marines the Air Force they all have
specific functions but they all work together to protect the organism to
protect the country let's face it there are a lot of threats that can happen to
a human being but in this case the SARS cub to virus affects the human body in a
very specific way and so if we can learn what part of the immune system is being
diminished then we can learn potentially how to fight this virus effectively and
reduce the number of people that might need to have hospitalizations so enter
this article where they actually look at the immune responses to not only this
corona virus but the SARS coven and the MERS coronavirus that was there
previously so this article was published in the Asian Pacific Journal of allergy
and immunology immune responses in kovat 19 and potential vaccines lessons
learned from SARS and MERS so let's take a look and see what they found they do a
comparison in the number of cases between those three viral infections
they also break down the demographics and they show the issues here with the
SARS cuff to the current viral infection in terms of the immune players that we
were just talking about and the thing that they bring up in this article which
is very interesting is this first point here which is delayed or suppressed type
1 interferon response during the initial infection in fact in the article they
say here to mount an antiviral response innate immune cells need to recognize
the invasion of the virus often by pathogen associated molecular patterns
so remember what the innate immune response is it is those cells that do
not require a little piece of the virus to be presented to them and so these are
not T cells and B cells that are making antibodies but rather innate cells so
these would be like macrophages monocytes natural killer cells this
would be like the airforce of the Armed Services and the things
that activate them in this case are these PA MPs or these molecular patterns
that are associated with path in this case for the coronavirus it
would be viral genomic RNA they go on to say here that for SARS coven MERS Cove
the response to viral infection by type 1 interferon is suppressed both corona
viruses employ multiple strategies to interfere with the signaling leading to
a type 1 interferon production watch what else they say here with similar
changes in total neutrophils and lymphocytes during kovat 19 SARS cub 2
probably induces a delayed type 1 interferon and loss of viral control in
an early phase of the infection what they're saying here is that the virus is
able to down regulate your immune system in the early phase of the infection and
this may be the reason why most people with this infection are initially
asymptomatic until the very end when there's a storm of cytokines in addition
no severe cases were reported in young children when innate immune response is
highly effective this may explain why young children aren't getting the
disease as severely these facts strongly indicate that innate immune response is
a critical factor for disease outcome analysis of two MERS Cub infected
individuals with different severity found that the type 1 interferon
response in the poor outcome patient which died was remarkably lower than the
recovered patients so if we go back to our picture again we see here that those
patients that are ending up in the hospital are about 20% of those that
actually get the infection and the reason why we may want to say is that
there is a decrease in the innate immunity that is the specific problem
with this virus and this seems to bear out in a recent publication in nature
medicine where they looked at immune responses and cells in a patient that
had non severe kovat 19 in fact this patient never needed to go to the
hospital and he recovered quite well of course we'll link to this and the
previous article in the description below but what they did look at here was
the amount of virus the symptoms the chest x-ray and then even more
importantly for our evaluation these monocytes and natural
killer cells so here we have monocytes and natural killer cells and if you look
at this triangle here you can see where the patient's monocytes were in relation
to where they should be in a normal healthy patient the monocytes which are
part of the innate immune system were much lower than they should have been
even though this patient only had mild disease reaffirming that it's the innate
immune response that seems to be suppressed in these kovat 19 patients
and even more so it seems monocytes and natural killer cells seem to be the
target so the question is is what is it that we can do to increase the number of
monocytes and perhaps gamma-interferon to elevate that early in the course of
this disease and we've talked before about not treating a viral fever because
we know that viral fevers are involved with the immune response as well but
I've gotten some interesting comments wondering if a patient with corona virus
doesn't have a fever what inducing a fever improve the
outcome and the immune response so knowing what we know already about
what's going on in covent 19 in terms of depressed monocytes made this German
publication back in 2002 even more interesting and here are the authors
zelner at all says that thermal effect of fever has been associated with better
survival and a shorter duration of disease in cases of infection and what
they wanted to do was to understand better what happened if they subjected
12 healthy volunteers in a 39 point five degrees centigrade hot water bath to
increase their body temperature and see what would happen to the expression of
monocytes and tumor necrosis factor alpha which is a cytokine that it
releases and they looked at this both in vitro and in vivo in humans that were
actually put into a hot water bath and what he found was that the in vitro data
showed that definitely there was an increase in the Amano sites they say
here that the expression of the endotoxin receptor cd14 and the
complement receptor CD 11 be increased after hot-water bath furthermore when
they looked at the healthy subjects after they were put into the hot water
bath they said here after three hours the response of monocytes to endotoxin
was enhanced in an ex-vivo lipopolysaccharide stimulation assay
which is basically a stimulant from a bacteria that might have infected a
human body when they stimulated the immune system they noticed that there
was greater TNF alpha release which was statistically significant so they
conclude that the thermal effect of fever directly activated monocytes the
very cells interestingly that are deficient in kovat 19 and that increased
their ability to respond to in this case a bacterial challenge but I'm sure they
would be equally as responsive to a viral challenge as well but this isn't
the only study that shows this there was a interesting article that was published
around 2000 titled immune changes in humans during cold exposure effects of
prior heating and exercise they took subjects and they had them sit
in a warm bath among other things and then they exposed them to cold to see
whether or not that would also improve immunity and you can see here for the
seven subjects in the white boxes sitting in a 38 degree centigrade water
bath increased their core body rectal temperature and then after they were
exposed to cold there was a drop in the core body temperature and here when we
see the data in this second set of bar graphs which are the ones where they sat
in 38 degrees centigrade water you can see here for leukocytes which are all of
the white blood cells that there was a significant increase in the number of
white blood cells here also for the granulocytes increases well for the
lymphocytes there was an increase and also for the monocytes there was an
increase remember the monocytes is the part of the innate immune system that's
deficient we're finding out in kovat 19 what they concluded in this report
despite popular beliefs that cold exposure can precipitate a viral
infection the innate component of the immune system is not adversely affected
by a brief period of cold exposure this is exactly the part of the immune system
that were talk about with kovat 19 they say indeed the
opposite seems to be the case the fall in core body temperature resulting from
cold exposure led to a consistent and statistically significant mobilization
of circulating cells an increase in NK cell activity natural killer and
elevations in circulating il-6 concentrations moreover in agreement
with one of our hypotheses prior exercise with a thermal clamp
significantly augmented the leucocyte granula site and monocyte response to
cold exposure prior passive heating and exercise without a thermal clamp also
tended to augment the effect of cold exposure alone but because of the small
sample size and inner subject variability these changes were not
statistically significant so interestingly what they're finding here
is that yes heat can improve the immune system like we've seen before but then
subjecting them to cold which goes against popular belief can actually
enhance the immune system especially the innate immune system which I find very
interesting because that's the portion that's affected in kovat 19 so all of
this talk about being hot and then cold reminded me of the Finnish saunas that
are so famous in that part of the world and actually in most of the Nordic
countries but not to the degree that we see in Finland so here's a study that
looked at a single Finnish sauna session on white blood cell profile and cortisol
levels in athletes and in non athletes and in this study they only looked at
nine people which is kind of a low number so we might not be able to see
statistical significance but let's see what they found
so for those of you who don't know what a Finnish sauna is it's quite extreme
the sauna can go upwards of two hundred degrees Fahrenheit which is very close
to the boiling point of water during the sauna session the human body is
alternatively exposed to hot and cold stimuli hot air in the sauna room
affects the skin and the respiratory system this leads to a rise in body core
temperature up to as high as thirty nine degrees centigrade while the skin
temperature might be as high as forty two degrees centigrade and then after
this is done there is a fast cool down and then they go back into the
sauna to heat up once again so what happened to the white blood cells in
this situation they found here that there was a statistical significant
increase in the number of white blood cells particularly more noticeable in
the athletes than in the non athletes some of these were statistically
significant and some of them were not possibly related to the low number of
subjects in this study they found here that a significant increase in monocyte
count was accompanied by a significant increase in the number of neutrophils
and eosinophils only in the athletes which could have
been caused by a reduced cortisol secretion compared to the untrained
subjects remember this is only after one session in the sauna so let's take some
stock about what's going on we've got the infection that occurs here at this
point in time and then we have at this point in time some of those about 20%
will end up in the hospital with pneumonia secondary to cytokine storm as
it's been often called why is it that people are asymptomatic early on and it
may be that the immune system is being suppressed well if we inflame the immune
system if we increase the immune system with thermal regulation and hyperthermia
is it possible that we could actually precipitate a storm situation and get
the patients in the hospital sooner without actually helping out the
patients well that's a good question and it's a possibility and that's why I
found this publication so interesting they talked about this interleukin il-6
which has been implicated in the cytokine storm that patients with
pneumonia gets when they had kovat 19:00 the paper is long but I found this
paragraph very enlightening although febrile temperatures initially
increase the production of pro-inflammatory cytokines by
macrophages at sites of inflammation there is also evidence that thermal
stress dampens cytokine synthesis once macrophages have become activated this
sequence of events is analogous to a natural fever which often occurs after
macrophages and other and nate's immune cells initially encounter
PMPs remember PA and peas from that first article that we looked at in this
regard human monocyte derived macrophages produce less TNF less il-6
and less il-1 beta when exposed to febrile temperatures then heat in
experienced cells heat reduces transcription of pro-inflammatory
cytokines and also lowers cytokine mRNA stability thermal treatment of LPS
activated macrophages also appears to dial down inflammation so what they're
showing here is that fever can actually reduce the cytokine storm and improve
the innate immune system now they actually have a model of this with mice
who have arthritis collagen induced arthritis when they exposed the mice to
fever range hyperthermia they had significantly less joint damage so they
say that collectively these findings suggest that strategic temperature
shifts contribute to a biochemical negative feedback loop that actually
protects the tissues against damage from excessive cytokine release following
infection interesting so in this period of time between when you have infection
documented and hospitalization if there were to be a higher temperature it could
improve the immune system which seems to be high I'm strung already and it would
reduce the cytokine storm potentially that's leading to pneumonia requiring
hospitalization okay so up to this point we've looked at real people we've looked
at cells though as surrogates for a good immune system against viruses let's
actually put it to the test and here we have a article asking that very question
does regular sana bathing reduce the incidence of common colds
they took 50 people that had never been in a sauna before this was an Austrian
study and 25 of them stayed out of the sauna and they were used as controls the
other 25 had sauna bathing to see if they could reduce the incidence of
common colds and what they found was this in the six months time that both
groups were recording how many common colds they got there was
significantly fewer episodes of common cold in the sauna group this was found
particularly during the last three months of the study period when the
incidence was roughly cut in half compared to controls and so they
concluded that regular sauna bathing probably reduces the incidence of common
colds but they felt that further studies were needed to prove this and you always
need further studies to make sure that what you're looking at is real here in
an editorial dr. Ernst who was the one responsible for publishing the sauna
Austrian study says here nevertheless it seems unwise to advocate sauna
indiscriminately thus whenever in doubt a medical check-up is mandatory once
this is done sauna can be fun and relaxing so we take dr. Ernst statement
at its face value but the question is a deeper one does this heat and then cold
help prevent and treats coronavirus 19 of course the answer to that question is
we don't know at this point because there hasn't been a randomized
controlled trial looking at that specifically but then again there hasn't
been a randomized placebo-controlled trial in anything that we're using for
Cova 19 at this point I know this is a long video but I needed to get some more
in here because it's just so interesting so this was a paper that was published
back in 2016 by the Salk Institute and very interesting review of all of the
data that was pertinent to their study that looked at this idea of hyperthermia
and hypothermia this initial proposal made by Kluger in the 1970s only
considered the fever response beneficial for host defenses however we suggest
that both fever and hypothermic responses are strategies of the host to
optimize host defenses during infection indeed
there is evidence to suggest that both fever and hypothermic responses are
beneficial for the host in the context of an array of diseases so the more I
thought about this the more I started to think about the Finnish sauna here is a
population of people that use the sauna extensively so here you have the
scanning in countries of Denmark Norway and
Sweden Finland's technically not a Scandinavian
country but they're all considered Nordic countries and so they're all
about in the same place but while the Finns extensively use saunas on a
regular basis maybe even two to three times a week not so much so in Sweden
and Norway and Denmark although they are used to some extent there's about 5.5
million people in Finland and there's estimated to be about 2 million saunas
so I got this idea to look up some of these Nordic countries on wool domitor
realizing of course that even though they're very similar in nature there
could be some confounding variables that make them difference but if this kind of
hot and cold that is being experienced if this could help the innate immune
system and if in fact it's the innate immune system that is deficient in a
kovat 19 case then we would expect to see some sort of improvement if it was
worthwhile so let's look at some of the numbers and so again this type of a
study really doesn't prove anything it can be affected by when the virus
started in each of these respective countries and where they are along the
process but it's going to be interesting to see what happens so what I decided to
do was take the different countries so Denmark Norway Sweden and Finland and I
put here approximately the population of each of these countries so Denmark being
5.6 million and so you can pull these numbers right off of World ometer what
about total deaths so this is an interesting question because perhaps if
the immune system is amplified with the sauna and the cold bathing maybe it
wouldn't prevent you from getting the infection but it might prevent you from
going towards cytokine storm and getting a pneumonia so we might see a difference
in the total deaths let's take a look and in Finland 11 interesting what about
total deaths per million what about new deaths for today it's going to be
interesting to keep track of this data as things go on there is another culture
that also likes to have very hot baths and then cool down afterwards and that
is the Japanese and in looking at their numbers there
doing to Bali again could be confounders but we need to look at this from the
microscopic level and the macroscopic level as well
switching gears I wanted to also talk to you about a new publication that just
come online regarding hydroxychloroquine and this is by the same author that
published the study that showed that the combination of a zero myosin and
hydroxychloroquine was effective there was some criticism at the low number of
patients in that group well now he's updated his results with 80 patients and
basically the results are very similar in conclusion we confirm the efficacy of
hydroxychloroquine associated with azithromycin in the treatment of Cova
19:00 and its potential effectiveness in the early impairment of contagiousness
given the urgent therapeutic need to manage this disease with effective and
safe drugs and given the negligible cost of both hydroxychloroquine and as if
through myosin we believe that other teams should urgently evaluate this
therapeutic strategy both to avoid the spread of the disease and to treat
patients before the severe irreversible respiratory complications take hold you
can see here that black bar is the number of patients tested and the tan
bar here is the number of patients with a CT value of less than 34 it's the
number of cycles that you have to do with reverse transcriptase PCR to
actually get a signal so what you really want here is a high high number that
means that the RNA is undetectable and so when you have a less than 34 that's a
bad thing and you want the number of patients with that to go down and that's
exactly what you're seeing here is it's going down and in fact it reaches zero
around day 11 or so and then you can easily see that with this green bar
which is the percentage of patients with a CT value of less than 34 and you can
see that that's a good outcome there a lot of stuff today more to follow
tomorrow thanks for joining us