Welcome to another MedCram COVID-19
update we've got a lot of news to cover
today there's been a lot of things that
have come back from a medical standpoint
or over 200,000 total confirmed cases
worldwide total deaths almost nine
thousand total recovered eighty four
thousand if we look country by country
on the world ometer site we can see here
only 34 new cases total in China at this
point most of the cases are outside of
China in facts more cases in Italy in
terms of active cases then there is
anywhere else in the world at this point
the United States cases have jumped to
almost 10,000 that's probably because of
increased testing that is now coming
online in the United States despite that
we only have about 64 serious or
critical cases in the United States out
of a total of 92 hundred we also have
news here from the CDC in their
morbidity and mortality weekly report
that was released yesterday on March 18
it says that the first preliminary
description of the outcomes among
patients with kovin 19 in from the
United States indicates that the
fatality was highest in persons greater
than 85 years of age ranging from ten to
twenty seven percent followed by three
to 11 percent mortality among persons
aged 65 to 80 for one to three percent
mortality among persons 55 to 64 and
less than one percent among persons
twenty to fifty four years of age and no
fatalities among persons in less than 19
years of age here we see the number of
new Kovan 19 cases reported daily here
in the United States from February 12 to
march 16 and you can see that that has
gone up steadily and here you can see it
by age group how many hospitalizations
in the lights lavender and ICU
admissions in the darker blue and then
deaths in the darkest blue and you can
see that there is a stepwise
increase here in the different ages for
the greater than 85 years of age there
were more deaths than there were in the
intensive care that may be because
palliative care or hospice where you
have patients that are hospitalized but
never go into the intensive care unit
before they pass and here is the
breakdown for age groups here in terms
of hospitalization percentage ICU
admission percentage and case fatality
percentage this is the big news that was
published today in the New England
Journal of Medicine it was the trial of
lope in aver and Ratana ver which are
HIV medications in hospitalized adult
patients with severe covin 19:00 this
was a trial that was done in China so
this was a trial that was a randomized
controlled but open label trial because
they couldn't have time to prepare the
placebo pills and they gave it to
randomized patients of course to see how
they would improve with kovat 19:00 and
the end point here was either discharge
from the hospital or an improvement on a
seven-point scale which we'll talk about
the primary endpoint was the time to
clinical improvement defined as the time
from randomization to an improvement of
two points on a seven category ordinal
scale or live discharged from the
hospital whichever came first
this has been used before the
seven-point scale in other influenza
studies and this is the scale one if
you're not hospitalized with resumption
of normal activities - if not
hospitalized but unable to resume normal
activities three hospitalized not
requiring supplemental oxygen for
hospitalized requiring supplemental
oxygen five hospitalized requiring nasal
high flow oxygen therapy non-invasive
mechanical ventilation or both six
hospitalized requiring ECMO invasive
mechanical ventilation or both and seven
death so if there was a movement down of
two points or a discharge from the
hospital that would indicate improvement
so you had 357 participants that were
assessed for eligibility there were some
that dropped out leaving a hundred and
ninety nine which underwent
randomization and you had 99 that were
assigned to the intervention group which
was lepen aver ritonavir and a hundred
that were assigned to the standard care
group and like any good study should do
they show you what the two groups were
and what their characteristics were and
if you look up and down the lepen aver
ritonavir
category and the standard care there
really wasn't much difference between
them at all statistically which means
that the randomization was pretty good
and if you look at these you can kind of
get a sense about who these patients
were the median age in both of these was
58 there was a majority of males here
which we've seen before body temperature
interestingly was not febrile so in
terms of the median 36.5 is not a fever
in terms of those that had a fever
we had 89% and 93% we had a number of
people that had respirations above 24
those who had a systolic blood pressure
of less than 90 notice were very very
small percentage of people so most of
these people's blood pressures are
actually elevated the other thing that
was interesting to note here is that the
amount of people with relatively low
white blood cells is pretty
extensive so typically this is what
you're going to see and you can look at
the other characteristics when you look
at the types of interventions that were
done you can see again pretty much
similar going up and down the categories
let's take a look at the results so
again here we've got days on the x-axis
and we have the cumulative improvement
rate that we see in greater than two
points and so if this is working well we
should see that these things go up
rather quickly and in fact what we see
here is that while there is some space
between the lepen aver and the Ratana
vert it is not statistically significant
and so it turns out that this is a
negative study it did not show a
difference between lepen aver and
ritonavir and the control group at least
in these pretty severe hospitalized
patients you can see here in terms of
the viral load which should be coming
down very nicely over time again no real
difference between the intervention
lepen aver ritonavir group and the
control group and so the authors drew
this conclusion in hospitalized adult
patients with severe Kove at 19 no
benefit was observed with lepen aver
ritonavir treatment beyond standard care
there's been a number of questions about
NSAIDs and a recent issue in terms of
the French minister saying that we
should not use NSAIDs in kovat 19 and
there's been a number of media posts
about that
this one particularly the World Health
Organization Beck's call to avoid
ibuprofen for coronavirus the
announcement supported a recent
statement by the French Health Minister
that ibuprofen may worsen the effects of
Kovan 19 and should be avoided there's
also this really good summary of the key
points that's put out by a pharmacists
organization in Canada which we'll put a
link to in the description below that
also goes through the salient points
about the possible risks and benefits of
NSAIDs in kovat 19 but let's talk a
little bit about what our NSAIDs and
what does it have to do with viruses so
NSAIDs stand for non-steroidal
anti-inflammatory drugs
and the reason why is because for a long
time the thing that reduced inflammation
were steroids so these were a new
category of medications that were not
steroids but could reduce inflammation
probably the earliest one that was
invented was aspirin back in 1899 more
on that one later very importantly we'll
talk though about ibuprofen ibuprofen is
probably one of the most widely used and
said in the world and it's used to
reduce inflammation reduce fever it's
used for osteoarthritis a number of
indications for NSAIDs well NSAIDs among
other things have a special impact on an
enzyme that we're going to talk about
which is cox-2 cox-2 stands for
cyclooxygenase 2 as opposed to
cyclooxygenase 1 which it also can
inhibit but that's not really germane to
our discussion what does Cox to do it
takes a substance called arachidonic
acid which will abbreviate AAA and it
converts it into prostaglandins
specifically pge2 now coxswain also
makes thromboxane and that is used in
platelets but that's not really germane
to what we're talking about what we want
to look at here is the cox-2 enzyme
which converts arachidonic acid into
prostaglandin e2 now why is that
important because prostaglandin e2 is
involved with pain which is why we would
give it it's also involved with fever
which you would see in a viral infection
but it's also involved in antibody
production or more specifically cox-2 is
involved in antibody production and what
NSAIDs do to that is they halt it they
prevent it now antibodies are important
antibodies are made by B cells and B
cells make these antibodies to go out
into the serum and attack things that
should not be there things like viruses
so you could see why NSAIDs may cause a
problem yes while they get rid of pain
and fever they can also hit your
antibody production but NSAIDs
specifically ibuprofen
and to a lesser extent other and SEDs as
well they also have another function
because they also inhibit some other
things they apparently can inhibit viral
replication and it's been shown to hit
the Czar's Cove v-not too but the
original the one that was from 2002 it's
also been shown to attack the canine
version of corona virus and it's also
been shown to be toxic and inhibitory to
both influenza A and B so the question
is is which one is it doing more and you
can see why there might be benefits on
either side and risks on either side
what do we do
so this pharmaceutical organization that
put out this statement from Canada that
was prepared a couple of days ago they
say here further research including
randomized control trials is required to
determine the impact of NSAIDs on
coronavirus infection and subsequent
disease they go on to talk about
confounding variables the NSAIDs could
be treating comorbid conditions which
put them at increased risk of more
severe kovat 19 disease and so the
bottom line is you need a randomized
controlled trial so I think the answer
at this point is we don't know based on
this data so then I did something really
weird I went back in time to an epidemic
of a viral illness that was a pandemic
and at the time they actually had an end
set and it was given quite liberally and
so the question is what happened at that
time and what were the observations and
it actually was really quite interesting
and here's a paper that was published in
2009 salicylates and pandemic influenza
mortality 1918 to 1919 pharmacology
pathology and historic evidence and
we'll put a link to this as well in the
description below and what it talks
about is that aspirin had just come out
in 1899 and it was a fresh drug to be
used at the time and it was a great way
to get rid of fever and some people
thought that if you could just treat the
symptoms of the flu the patient would
get better and one of the big symptoms
of the flu of course was the fever
the paper goes into discussing what the
toxic dosages are today based on what we
know at the time people would be given
large doses of aspirin until they saw
toxicity then they would sort of pull
back they talk about four lines of
evidence support the role of salicylate
intoxication in 1918 influenza mortality
the pharmacokinetics the mechanism of
action pathology and official
recommendations for toxic regimens of
aspirin immediately before the October
1918 death spike and for those who don't
know one grain equals 65 milligrams so
when we talk about grains you'll see the
aspirin regimens recommended in 1918 are
now known to regularly produce
toxicities and you can read about that
here we do know that salicylates cause
immediate lung toxicity and may
predispose to bacterial infection by
increasing lung fluid and protein levels
and impairing mucociliary clearance and
at the pathology of early deaths that we
saw back in 1918 was consistent with
aspirin toxicity and a virus induced
pathology and remember aspirin which is
a salicylate is also an NSAID so this
kind of makes an interesting twist on
the discussion about whether we should
be using NSAIDs in kovat 19 and then
interestingly it's talks about the
aspirin advertisements in August of 1918
and a series of official recommendations
for aspirin in September early October
preceded the desk by of October 1918 and
it's interesting that the young adults
coming back from World War one were more
likely they felt to take aspirin whereas
the lower mortality in younger children
may have been the result of less aspirin
use and interestingly the major
pediatric text of the time in 1918 and
remember they have no antibiotics they
have no antivirals they have no
ventilators essentially what would
happen in a major surge recommended not
aspirin not salicylate but actually
recommended hydrotherapy for fever these
were the great thinkers working with
what they had at that time and we can
see at the time that there was a
dichotomy that was set up in the
treatment of the Spanish flu back in the
1918 1919 those that really believed
in the pharmacodynamics and
pharmacokinetics of aspirin and those
that would treat with hydrotherapy this
is dr. William a Pearson in 1999 quote
none are so blind as those who cannot
see that the average mortality of
influenza patients treated by
homeopathic physicians was actually only
about one thirtieth and that's a thirty
not thirteenth but one thirtieth of the
average mortality reported by all
physicians and then dr. C J Louise L
from Des Moines in 1919 and as the
German aspirin has killed more people
than the German bullets have so the
question boils down to what are we
getting in terms of risk benefits of
these NSAIDs and ibuprofen or even
aspirin are we confounding the mortality
of 1918 with the dose of aspirin some
would say yes is this just a larger
magnitude of the effect that we might be
seeing with NSAIDs with kovat 19 I think
it bears testing I think at this point
we don't have enough answers for that I
would say though that in my research of
the 1918 Spanish flu epidemic and
pandemic I think there are some
parallels that we might be able to learn
from because if in fact we do have a
surge in this country like what we are
having in Italy the question is going to
be what was it that worked back in 1918
and can we learn anything from there
because we may very well be in a similar
situation if we don't have ventilators
as they didn't have if we don't have
pharmacological interventions as they
didn't have back then we don't have
antivirals as they didn't have back then
and don't have antibiotics in other
words is there some lesson that we can
learn from them that we could apply in
our own homes for instance to improve
survival I think that bears thought and
deserves research thanks for joining us
you
