welcome to another MedCram COVID-19 update one of the things that a
lot of people are thinking about lately is getting
back to school and of course this is a big
topic about whether or not it's safe to go back to school
we're not going to weigh in on that today but what we are going to weigh
in on today is a new idea that might make going back to school more of a
reality and that has to do with testing and i want to thank the folks
over at this week in virology which put together
a great podcast that they do every week and
we'll put a link in the description below
to their podcast and this last week they had someone on
from harvard to discuss a new idea that i think may actually be a step in
the right direction and the question really boils down to
testing do we need better tests or do we need more
of tests that maybe aren't so good but just more of them
and that's really where the question boils down to and it's a really
important question especially now that we've essentially
inundated our current testing capabilities
and we'll get more to that but before we do we've got to sort of review a little
bit about how the virus behaves and some of the
numbers that we use to track it so let's talk about that first so there
was this paper that was published in the new england journal of medicine that
looked at sars covi viral loads and upper respiratory specimens
of infected patients and i want you to notice something here
these are all different patients and they're looking at for instance nasal
swabs throat swabs and then they looked at
something called the aggregated ct value so this is something that's really
important that i want you to understand here are the days since onset of
symptoms on the x-axis starting off at zero and then they have
something called the ct value so the ct value is a way of measuring
the viral load and for every three if you went from 40 down to
37 that's a movement of three points on the ct value
and you're actually going down in value from 40 to 37
but that movement of 3 actually translates
into a 10-fold increase that's right increase in the viral load and so in
fact ct values are inversely proportional to
viral loads as you go down in ct value you go up in viral load
and so if you were to move about nine to ten points that would be
three times three and so that would be not ten not a hundred but a thousand
times larger so you can see going from a viral
load that's very very low here at forty going to a viral load perhaps in the
billions or even trillions as you get up to fifteen ten or 5.
so that's something to keep in mind that ct values that are low
mean that there's a lot of virus particles
and ct values that are down here in the 40 range are almost undetectable
i bring that up so you can understand because the rest of the discussion is
going to be around these ct values so let's take a look at the natural
history of a virus specifically coronavirus in this case
what typically happens is the virus starts infecting and there is
exponential growth and then as it tapers off
the viral particles can actually last for some period of time
before they taper off to zero and again those ct values this would be
around 40. we can go all the way up to five up here
i think the key number that we're going to need to look at here is around 35
and of course that can go up and these are approximate values
what we have right now is we have something called
reverse transcriptase pcr RT-PCR and we're going to put that in green now
real time pcr or reverse transcriptase pcr is
pretty expensive the gold standard stuff it's about a hundred dollars a test
right now we're experiencing pretty long turnaround times anywhere
from three to four days all the way up to i've seen it as high
as nine days to get that test back and there's not
that many of them but it's very sensitive
let's say just for argument's sake it's around
35 ct values so that means it can detect all the way down to 35 or even as low as
40. that means that we're able to detect
using reverse transcriptase pcr all the way
out to here and so all of these patients
if they were to test would test positive on this test now apparently
there are some tests that are known as paper tests
and apparently all you need to do with these paper tests
because they're paper coated with monoclonal antibodies that can detect
antigens they're not detecting actual rna but
antigens these are more along the lines of one to
two dollars each but they're not as sensitive some
would say that they're maybe even 50 percent sensitive now
it's not a random 50 percent sensitive no it's maybe somewhere in this range
so that this is the range of people that we're talking about
so in other words here to here and the ct level that we're talking about is
in the low 30s and these numbers may be a little bit
different but you're getting the idea of what i'm talking about
one of the things that has been made clear to me is that
the threshold of transmissibility is actually more narrow than we thought
it was well this is exactly what dr mina from
the t.h chan school of public health at
harvard university was making a point of on this week in
virology so people who are transmitting probably um have ct values that are
below 30 and the vast majority probably have
them below 25 or so how do we know that do we have evidence
that people are still positive but they're not transmitting the virus
and the answer to that is yes if you look back at one of our
updates we highlighted a south korean study
where these people that kept on testing positive were checked
and they looked at household members and they were found
not to be infective in fact they did background
checks and these patients and found that not a single case of transmissibility
occurred in these patients that were persistently positive and the
reason is because the nature of this test
RT-PCR is you're looking for fragments of rna and fragments of rna
while they will turn the test positive fragments of rna are not enough to
actually cause transmissibility a lot of people are
saying well we need the really sensitive tests to to be able to detect people
early on in their infection but almost all of the time that people
spend with this virus near the limit of
detection of pcr is on the tail end of their infection
this is a virus that once it hits pcr positivity
levels it's growing well in its exponential phase and it's probably a
matter of hours not days before it passes the threshold
to be detected on some of these slightly lower sensitivity assays
and then it will sort of persist for weeks potentially or months even in some
people at very low rna levels so it's it's it's after people are well
beyond their transmissible period that we're actually seeing the loss and
sensitivity of these assays it's very rare that you
that you actually detect somebody with a ct value of 39
in that window on their way up because they're only sitting there for a few
hours before they get down to a 33. so if you're missing ct values of 39
in my perspective who cares it's really not that important and so the point here
is that yes these tests here may actually be
maybe 50 percent sensitive but in comparison to what it's
in comparison to a test that may be overly sensitive
and so in fact the question is is if your threshold of transmissibility
is closer to this threshold of actually being positive
on these much cheaper tests these are tests that can be repeated
on a daily basis and so these tests may actually be more beneficial
in terms of controlling an outbreak of the virus because you're able to do it
more quickly and by the way there's one thing i
forgot to put down on here you get the results back in 10 minutes
you can have them at home you can test serially maybe once a day maybe twice a
week three times a week and if your child is positive
then you hold them back from going to school if they're negative they go to
school and you have real time application of
this what the cdc's most recent announcement
maybe is last week 9 out of 10 people go undiagnosed with
this virus today in the u.s i would say that of
those of those one out of 10 that do get
diagnosed almost all of them are getting uh diagnosed through surveillance after
they've been infectious because their ct values we've seen the
average ct value kind of creep up to 35 or so so that means they're almost
all at the tail end so what that tells me is if we take a
step back and we we look at this virus and our testing program in the states
we're using a very sensitive test but our sensitivity to detect infections
is probably below five percent you know across the us right now it's the cdc
says it's 10 and if we actually say detecting
transmissible infections we're woefully under you know
underutilizing testing so if we know that viral the virus
transmits once people are above say a hundred
thousand or a million copies per mil then maybe we only need
a really crappy test if we can use it if it's cheap enough to use it very
frequently then if then it doesn't detect less than
five percent of people when they're transmitting maybe it detects
85 percent of people when they're transmitting and that's a huge win over
what we have right now and if you want to read the pre-print of
dr mina's work we'll have a link to its pdf
in our description below i think he makes a good case for this
and i'd like you to read it for yourself to me
the the short way to say it is if the test isn't as good but we do it every
day and you get the results quicker
you're going to be way ahead in the long run i mean that's the other thing we
haven't really touched on is the the turnaround time but the sensitivity
okay maybe not perfect but test every day get the results quickly
and if you test wrong the day one on day two
you'll probably test positive you know that's a that's exactly right and on
aggregate you'll drive the r effective you know this virus way down
below one i mean i think if you were to take this
and give everyone in miami or austin or wherever they're burgeoning
outbreaks right now you know give everyone a test or give 50
of the people a test you'd probably drive our effective down
overnight you know if everyone tomorrow could wake up
test themselves you'd immediately filter out
tens of thousands of people potentially who are who have the virus in them that
day and the other the other consequences you
don't have to worry about contact tracing because everyone would be doing
their own test every day it just you know it can be
done and um and this this is with a pin prick
right for a little bit of blood no no this is with uh uh that's a
different thing which i could talk about as the serology bit but no this is
actually i'm just kind of spitting on a paper
strip or taking a q-tip and putting it into a little
plastic tube of saline and dropping a paper strip in there i'm thinking about
school kids you get up in the morning and take the test it tells you whether
or not to go to school that solves the whole problem yep and it
doesn't need to be perfect you know you have
okay so you have one kid who tests a negative
and you know they actually go to school well that kid you know otherwise that
kid's not going to get tested at all you know so they'll find
themselves positive the next day and they'll infect
overall fewer people and anyone that they infect
will on average find that they have been infected and they'll stay home
so it very quickly compounds into a massive reduction of a virus in the
population very quickly the fda and the cdc and the nih have to
change their messaging they have to say look there is
actually a technology that a test could exist right now
i have some sitting in my office next to me um they're paper strips
they're just little pieces of cardboard printed with monoclonal antibodies that
can pick up an antigen it's essentially a lateral flow
assay can be printed into millions and you may be thinking well why didn't
these tests come out earlier well in fact they did but they
were kind of beat up because of the low
sensitivity and this is the paper that did the beating
up this was at a new york university grossman school of medicine
and if you go to the end of this print you can see some of the things
that were highlighted in terms of which tests had negative
results when the rt pcr had positive results and
you can see here the sensitivity of this test called
the abbott id now which is one of these cheap tests that can get done pretty
quickly it had a sensitivity of only 51.6 percent
but again as we showed the 51 sensitivity
was not just a random 51 percent the tests that it missed were probably
those patients that were past their infectivity in terms
of ct values and more specifically what is it going to help somebody if it takes
eight or nine days to get back a very accurate test
but now they can't do anything about the results
here this is a very quick test you get it back in 10 minutes
and as you can see here the positive predictive value was 94.1 percent which
of course would change based on the prevalence
but if you look at some of these tests that were done you can see here
that we have the cepheid result which is the gold standard in this case and then
you have the abbott id now result which had the lower sensitivity if you
see here this was negative when this was positive what kind of a
test result is it being missed on it's looking at the nuclear capsid ct which
is around 43 that's an extremely low viral count
and probably not going to make a big difference in terms of whether that
patient's isolated or not here is another one at 40.7 again not a
big difference that's such a low viral load
here 44. here's another one 44.3 here's another one at 36.3 whereas you
can see the higher viral load counts based on the lower ct numbers 29.7
27.6 19.7 18.6 it's all picking these up and so what
you have here potentially is a test like this that's pretty cheap
that you could pick up you could test daily find out whether
you're infective and if you were you could stay home and prevent
infection to other people this may be a way potentially to get out
and get kids back to school which is obviously the ideal situation
one of the reasons that dr mina points out that the reason why we're not seeing
these as much is because these companies may be having a little bit of
difficulty in terms of thinking that they're going
to get this past fda approval because the fda really wants to have
some rigid standards in terms of how accurate the test is going to be
and if they're working on that it's going to raise the price of these
tests and they believe that if there is a viral particle in the patient the test
should turn positive when in fact the practical definition
of what we're really looking for here when we're trying to curb an
outbreak is who is infective and who is not infective and that may be
a completely different question than who has the viral particle and who
doesn't have the viral particle ideally what you want is a very cheap
test that everybody can self-administer that is widely available
that will tell you whether or not you're ineffective
thanks for joining us and don't forget to see all of our medcram videos at our
website medcram.com we'll see you next time