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
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