Dr Michael Mina MD, PhD is interviewed about Rapid Testing. We discuss the difference between PCR and rapid antigen testing with regards to detection of SARS-CoV-2; the sensitivity of rapid antigen tests and their ability to detect contagious people early and the use of CT values. We also explore how the Omicron variant affects our immune system, the incubation period of this variant and how the rapid antigen tests work in this scenario.

Watch the full interview here: https://youtu.be/qg941B4snZU

Learn more at: https://kojalamedical.com/covid19theanswers/

“TWiV 640: Test often, fast turnaround, with Michael Mina” - https://www.microbe.tv/twiv/twiv-640/

“Test sensitivity is secondary to frequency and turnaround time for COVID-19 screening” - https://www.science.org/doi/full/10.1126/sciadv.abd5393

“COVID-19 testing: One size does not fit all” - https://www.science.org/doi/full/10.1126/science.abe9187

“Active epidemiological investigation on SARS-CoV-2 infection caused by Omicron variant (Pango lineage B.1.1.529) in Japan: preliminary report on infectious period” - https://www.niid.go.jp/niid/en/2019-ncov-e/10884-covid19-66-en.html

“To Interpret the SARS-CoV-2 Test, Consider the Cycle Threshold Value” - https://europepmc.org/article/pmc/pmc7314112

Twitter Feed for Dr Michael Mina - @michaelmina_lab

"COVID-19 Incidence and Death Rates Among Unvaccinated and Fully Vaccinated Adults with and Without Booster Doses During Periods of Delta and Omicron Variant Emergence — 25 U.S. Jurisdictions, April 4–December 25, 2021" -

https://www.cdc.go/mmwr/volumes/71/wr/mm7104e2.htm

#covid19theanswers #Kojalamedical #DrFunmiOkunola #DrMichaelMina #rapidtest #covidtesting #covidtests #covidtestathome #covidvaccine #covid #omicron #booster #unvaccinated #science #rapidtest #pcr #antigentest #contagious #rapidtesting #rapidtestkit #rapidpcr #infectious

Kojala Medical presents Covid-19 The Answers.  The show that delivers the scientific

evidence-based knowledge that can safely  return us all to our pre-Covid lives.

My name is Dr. Funmi Okunola  and I'll be hosting the show.

Every week you can listen to me  interview a highly respected professional

about the science that can reduce your risk  of becoming infected with this coronavirus.

Welcome to COVID-19 the Answers Episode 8  Part 1 – Rapid Testing. Today I’d like to

introduce you all to Dr Michael Mina  MD, PhD, Chief Science Officer of

eMED a biotechnology software company providing  virtual authentications of at-home tests.

Dr Mina joined eMed in 2022 from Harvard  T.H. Chan School of Public Health in the USA

where he was Associate Professor of Epidemiology,

Immunology and Infectious diseases, as well  as a core faculty member of the Center for

Communicable Disease Dynamics (CDCC). Dr. Mina  earned his Ph.D. and M.D. from Emory University

and performed postdoctoral research at  Princeton University and Harvard Medical School.

Dr Mina’s research involved the development  of new technologies using mathematical and

epidemiological models to understand the  pathogenesis of vaccine preventable diseases,

with a specific focus on  measles infections and vaccines.

His research also explored more  fundamental questions of immunity.

During the COVID-19 pandemic, Dr Mina has been  a leading voice and proponent of rapid testing

as a major public health screening tool for  detecting contagious people early and quickly.

Welcome! Well thank you so much! Really happy to  be here Michael how did you get into rapid testing

Well it's a great question so I'm I am an  epidemiologist and an immunologist first and

foremost I'm also a physician where I, where  prior to the pandemic and during the pandemic

I was the associate Medical Director  of Molecular Virology Diagnostics at

one of Harvard's main teaching hospitals  called Brigham and Women's Hospital and at the

beginning when Covid-19 started to circulate and  SARS-CoV-2 virus started to circulate in China.

My team at the Harvard School of Public Health,  a group of Epidemiologists, we were working

on monitoring and really trying to evaluate was  this virus going to become a pandemic was how

quickly was it spreading, where was it going and  so we started researching the virus very early in

January of 2020 and wearing that epidemiology hat.  I realized very early on that we were going to

I mean it was very essentially incontrovertible  that we were going to have a pandemic and

the virus is going to spread in the united  states so then I went back to the hospital

where I had my secondary appointment at Harvard  and said and pleaded really with the hospital

administration to give me the resources to build  COVID PCR testing capacity for our patients I had

a lot of resistance early on a lot of comments  like oh why would we need a Covid test? This is

a virus that's in China and you know it's not in  the United States. What are you talking about?

And ultimately I succeeded in securing resources,  but it took about a month of really arguing with

the hospital administration and through that  experience I realized pretty quickly that we were

not going to have enough capacity for what we  really needed, so I went to the broad institute

which is a major biotech engineering institute,  that is a combination between Harvard and MIT

and they've run a lot of the big sequencing  programs since the early 2000s for

for sequencing the human genome and  they have a massively sort of efficient

biological core for sequencing so I approached  them and I'm also an adjunct faculty at The Broad.

So I said 'hey, we're going to need more COVID  testing can we use your sequencing facility

to start doing PCR testing?' And myself and  another physician tried to set that up early

and actually that was very successful, but even  that and we've run you know on any given day the

broad now runs 150,000 or 200,000 PCR tests a  day at their lab. So it's massively efficient,

but even working with one of the most efficient  laboratory engineering groups in the world

it became very apparent, very quickly to me that  even that wasn't going to be enough testing. That

the demand was going to so overwhelm the supply.  That the speed required for testing for the

purposes of identifying people quickly enough,  so they don't go and spread was going to demand

a very fast test, so I started looking at rapid  tests and different antigen lateral flow antigen

test companies that were that were developing  these tests and all of them came back and said

'you know, this is great idea but we're not  going to get the sensitivity we need to match

molecular testing' so how so you know  this just isn't going to really work out

and that really set me off on this path of  exploring the question do we really need the type

of high, high sensitivity testing that molecular  diagnostics PCR provides. If we could have very

fast and massively accessible tests that maybe  lack a little bit of sensitivity but are much

quicker turnaround times and that set off this  whole cascade of research in my laboratory with a

number of my PhD students and postdocs ultimately  to develop some of the core theory underlying why

a rapid antigen test is actually not just  sufficient, but a better test for pandemic

response than laboratory-based PCR diagnostics so  that's kind of the sequence of how I got into this

territory. Thank god we've got wonderful minds  like you on the planet! Is all I can say. So, I first came

to hear about managing the COVID pandemic with  rapid testing through an interview that Dr Michael

Mina did for this week in virology or TWiV back in  July 2020. Michael brought a completely different

perspective to pandemic management through  testing that made so much sense to me and others.

For the first time there appeared to be a  breakthrough path forward to pandemic management

with the implementation of low-cost rapid antigen  testing as a screening tool even before the onset

of vaccines and on a personal note, I would say  your interview was one of the most influential

presentations of my medical career. This led on to  me influencing as many people as I could about the

benefits of rapid testing and joining a widespread  campaign to get rapid testing authorized in Canada.

So let's get started on the questions. Broadly speaking there are

two types of Covid tests those that measure a new  or acute infection such as the laboratory PCR or

rapid antigen tests and those that measure  a previous infection likely some time ago

by looking at your antibodies or T cells some you  get a fairly immediate result with others it takes

hours or in some cases days in this interview  we are going to focus on rapid testing of a new

or acute SARS-CoV-2 infection so present there are  two types of tests available that detect a new or

acute SARS-CoV-2 infection a molecular test or an  antigen test. Michael, can you please explain the

difference between the two and why the distinction  is important? Absolutely, so a rapid antigen test

and a PCR test are both looking for the  virus, but do so in different ways a PCR test

is using a technology that looks for the genetic  code of the virus the RNA that makes the blueprint

for the virus and every virus has RNA inside of  it so it makes sense to use that as something we

go and look for and the nice thing about that is  when you're looking for the genetic code the RNA

or in humans it would be the DNA usually we can  use PCR and the reason PCR is so critical and

so useful is that even if you only have a single  molecule. PCR has a what we call an amplification

step and it literally like zooms in or amplifies  the signal so if there's just one molecule

the machine can't see one molecule right off the  bat but it goes through what we call cycles of

replication or amplification so it takes that one  molecule and if it finds it it has a little probe

that goes and seeks out the exact part of the RNA  that it that we kind of program it to seek out

and that would be a part of the of the viruses  RNA that's very specific to that virus so you

get very few false positives and if there's even  just a single molecule it will amplify that one

into two molecules and then four molecules and  then eight molecules in each cycle it doubles

and what that does is eventually you'll have  enough molecules through that doubling process

that the machine can actually say aha there is a  signal here yes there was some starting material

from the Covid RNA SARS-CoV-2 RNA so that's  a really powerful tool when you're asking the

Is my patient infected with this virus,  or have they had an infection in the recent weeks

because the RNA lasts so even the smallest amount  that's of remnant RNA will still be there, which

could help a physician discern was my patient's  symptoms last week were those due to Covid. Now

On the other hand, we have antigen tests, or rapid  antigen tests and these very

powerful tools because of the speed. Now where  they differ is, there's no amplification step.

You don't find a protein and  multiply it into two and four. It's what you see,

will only be enough, there will only be enough  that the virus will only turn that test positive.

If there's enough virus there to actually, for the  person to see with the with sort of the reagents

that are on that test and why that's important  is that these tests are looking for the actual

protein of the virus not the genetic code so if  the protein is there and it's in its configured

states that the test can actually detect it  it means that you have live replicating virus

you're currently infectious you're you have actual  replicating virus that could potentially infect

somebody else so it's an active infection that  it's generally finding whereas PCR you don't know

if it's necessarily active or if it's two weeks  old eventually your body clears all of that RNA

but not immediately and so these rapid antigen  tests they're fast which makes them exceedingly

important and useful for pandemic response they're  accessible you can have them in your cupboard at

your home and they are specific to the question  most of us want to ask which is am I infectious

now do I need to isolate? Am I a risk to other  people around me and that's why most of us test

and that's really what these rapid antigen tests are looking for. Excellent answer, thank you.

Rapid tests can be molecular or antigen tests.

The molecular tests tend to be an expensive  lab in a box type test with cartridges

the rapid antigen test can be the lab in  the box handheld devices or paper-based tests

in this interview we're going to focus in on the  use of rapid antigen tests to detect Covid-19.

Laboratory-based PCR tests are often called the  gold standard tests rapid antigen tests often

get a bad press and are labeled less accurate  it appears to me that different types of tests

play different roles at potentially different  times in the virus cycle michael can you please

explain the roles that PCR and antigen  test play in the detection of SARS-CoV-2?

Absolutely, well that might help if I pull up my screen here.

All right. Brilliant. So you can see this? Yes. Okay, so PCR and antigen tests can find

the virus at different amounts of virus and for  different durations of time a PCR test so for when

whenever anyone gets exposed to the virus no test  will be positive right away and this is a period

of time that we call the incubation period when  the virus is literally incubating inside of people

it's just kind of situating itself in the cells  and it's figuring out is this going to be a host

that kind of kills me off before I even have a  chance to grow or is this going to be a host that

I can actually grow in and start replicating and  if it starts replicating and it really takes off

eventually it will pass what we call the threshold  of detection or the lower limit of detection for

PCR and this in this particular graph that  I've this is kind of a depiction it's not

for every individual might be a little  bit different but the limit of detection

for PCR might be around a thousand viral  copies and that's what I'm really showing

right here at day zero that might be the  first day that somebody is detectable

by PCR and then the antigen test might not catch  somebody until the virus grows to a hundred

thousand copies or maybe even a million copies  so that sounds like a big difference a thousand

versus a million but what's really important  and what is often lost when we think about

limits of detection and sensitivity of a test  is what does it really mean not from a molecular

number but from a time perspective and this  is really important in pandemic responses

time and it's almost never considered when we  think about the metrics of the test and the reason

is if you look here at this graph people will  go from the limit of detection of a PCR test to

hitting the limit of detection of a rapid antigen  test that might be a hundred or a thousand times

require 100 or a thousand times more virus but  that they might pass that threshold within just

a day or hours from passing the limit of detection  of the PCR and that's because the virus at this

point is growing so fast it's exponentially  replicating it's doubling and so it doesn't

take long for it for with exponential replication  for something to go from a thousand to a hundred

thousand or a million so within a day or or so  you end up passing both thresholds so you you may

worry if you're using a rapid antigen test that  you're not getting high enough sensitivity but

the chances of even sticking the swab in your  nose in between those two limits of detection

is a very short window of time let's say 15 hours  or 24 hours and then you're up here and both tests

will be positive at that point both tests will  be positive and 99 of all the virus somebody has

in their whole infection is going to be is going  to exist in just a two to four day period of time

and that's when the virus is at its  peak that's when you're most infectious

an antigen test and a PCR test will both detect  you at that period of time a difference being a

PCR test if it has to go out to a lab you won't  get the result back for a day or two or five

depending on what lab you're using so if you're if  you have to wait three days to get the result back

then by the time you get the result you're already  past your peak infectivity and so an antigen

test it will turn positive during this period  time but give you a result back in 10 minutes

so it's extremely important that if you're  trying to find the most infectious people

and stop them from spreading that results are  given back quickly and both of them will do that

at that point once you hit peak infectivity or  peak viral load your body necessarily has to start

clearing the virus the human body can't sustain  a billion or a trillion viral particles per mil

for more than you know a single replication  cycle before your immune system has to really

start battling it back down  or you end up in the hospital

and so our immune systems generally battle it  back down and at that point once our immune system

falls it battles the virus back down enough we  go below the limit of detection again for the

rapid antigen test and at that point you're no  longer infectious your immune system has cleared

99.9 of all the virus that was in your body at  peak transmissibility but your PCR test is still

positive because even if you only have a thousand  or ten thousand viral particles your antigen test

might not be able to detect it but the PCR test  surely will and it takes a long time for the PCR

then to completely go negative because you just  had this massive battle take place in your in your

nose and in your throat where you had literally  trillions of viral particles get beat down by your

immune system and then you're using a technology  that can detect as little as one viral particle or

one piece of RNA so for to get your body to clear  from a trillion to zero takes a really long time

for some people it takes weeks or even months  so the PCR will stay positive from day 10 in

this picture all the way to day 25 or 35 and some  people even until day 80 the PCR will keep being

positive so it's a really good test if you're a  forensics detective or a physician who's trying

to go back in after the crime has been committed  to say what caused these symptoms what was the

crime that was committed here oh there was a COVID  infection doctors might want that to know what

caused my patients symptoms two weeks ago but if  you're actively trying to stop spread you really

want to focus in on the peak viral transmissible  time and PCR is just a little bit too sensitive

to really be specific for that question because  it stays positive for so long so each of these

tests have their merits but one of them is  better than the other for detecting currently

infectious people in a time frame that's actually  useful for stopping them from spreading to others

thank you yeah my record for hearing positive  PCR detection was an athlete who who tested

positive for six months it it absolutely happens  and it was one of I remember in february of

2020 maybe it was early March I was asked to be  the peer reviewer on a research paper from China

that was showing people staying positive on PCR  for 80 days and that's actually what led the cdc

originally to say look if you're positive on  a on with Covid don't use a PCR test again for

three months because you might keep being positive  from the same old infection even though you're no

longer infectious so there has for the entire  duration of this pandemic this has been known

it unfortunately we've had a miscommunication  between what we knew and the CDC was saying

don't use a PCR test they're not specific to the  infectious period but then unfortunately there was

a lot of misinformation and miscommunication  and misunderstanding about when we use a PCR

test as the gold standard for a test meant to  detect the transmissible window. A lot of people

say 'oh these tests for the transmissible window  are not sensitive enough,' but it's not that they

weren't sensitive enough to detect that, it was  that the PCR was not specific enough to only be

positive in that period of time we care about and  it has led to massive confusion on a global level

literally across the globe about, well. Are antigen  tests good enough for what we need them for? And I

would argue. Absolutely. They certainly are. Yeah, and we're going to explore that.

So with regards to assessing the accuracy of any test in  this case a test for Covid the scientific terms

sensitivity and specificity are often quoted.  Could you please explain what these terms mean

for our non-scientific audience and why are  they relevant? Absolutely, so the specificity is

asking essentially how likely if I'm not infected  am I how how many times do I have to test myself

with the test before I get a false positive  so if you have a very specific test that means

you'll only be positive your test will only read  positive when you're actually positive if you

have a low specificity test then let's say you  have a test that's only 90 specific that would

be very poor that would mean that if you were to  test yourself 100 times and you're not infected

that 10 of those tests would actually falsely  turn positive so specificity is something very

important to keep very, very high like 99.5%,  99.9% specific you don't really want a test

that's going to be falsely positive more than say  one in a thousand or one in a few thousand tests

sensitivity is if I'm infected how likely is  it that this test will actually detect that I

am in fact infected and the question there is  we have to be asking well sensitivity for what

is it sensitivity for having any viral RNA in your  body or is it sensitivity for being infectious

these are different states so we always have to  define what is my test sensitive to detect is

it any RNA do I have any remnants at all or is it  sensitivity to detect an ongoing active infection

I like to think about sensitivity in this  regard when I put it in an analogy of

detectives and security  guards at the scene of a crime

a test that we need in a pandemic for example for  a sensitive test is one that you could liken it to

a security camera, or a security guard  and you ask the question if there's a crime

going on over here. How likely is it that my  security camera is going to you know turn

on bright red flashing lights and say crime,  crime, crime, you know and you want that to be

you want it to go on when the crime is actually  happening and you want it to go on as much as

possible when the crime's happening, so if you have  100 crimes you ideally want it to go on 100 times

that there's somebody breaks in. But what you don't  want is you don't want it to start flashing red

two weeks after that crime took place you know we  would think that that was a glitch in the system

and that's kind of like what PCR does. It stays  it keeps turning on so it's very very sensitive

to detect a crime whether it was happening now  or two weeks ago so that can be good for some

uses like a forensics detective going in and  having a very sensitive test to say to pick up

even just a hair from the crime scene and say  aha yes there was a crime that occurred here

and so sensitivity is how likely are you to detect  the thing that you're looking for what I think has

been totally lacking in this pandemic is a proper  definition from physicians and public health

officials and the FDA and others to describe what  it is that we are trying to be sensitive to detect

and it and there's not a one-size-fits-all issue  we actually published a paper in science saying

for Covid-19 testing. One size does not  fit all because what you're looking for,

what you want to be sensitive for changes  depending on what your goals of testing

actually are yeah, no I read that paper and  I'll share it in the case notes a link to it

so when reading studies that try to assess  the validity of rapid antigen tests there

seems to be a range of sensitivities quoted  in different studies often for the same tests

and different scenarios the antigen tests are  often compared to PCR tests and found to be not

as sensitive can you please explain why this is  happening absolutely so I will share another slide

so why does this happen if you have an antigen  test or PCR test an antigen test. I have on this

slide. I'm showing a picture of somebody going  through the whole course of infection from getting

exposed to the virus replicating to very high  numbers to the immune system causing that viral

application to diminish and then to essentially  being cleared, but somebody's saying PCR positive.

Now if you are comparing an antigen test to to PCR  and you don't know where the person is in their

course of infection then you're actually more  likely to be positive on PCR after you've been

infectious so you actually spend more time being  PCR positive when you're no longer infectious

and you spend a fraction of your time being PCR  positive actually spreading to other people now

an antigen test is very specific for the period  of time when you're spreading to other people

so I'm showing when people are positive down here  on antigen tests it's maybe for about five days

but when somebody's positive on PCR it's maybe for  about 20 days or more and so the problem is you're

you're only infectious for about five days and  during those five days you're actually antigen

test positive, but if you don't have symptoms  for example let's say you have no symptoms you

don't know where somebody is in this whole  timeline when you take that swab from them

so it's actually just very very likely that you're  going to collect a sample from somebody who's PCR

positive but not infectious and then if you go  and collect an antigen test from that same person

you're going to get a discordant result  it's going to say antigen test negative

PCR test positive and you're going and so the way  that researchers often look at this unfortunately

are physicians have been saying well that's that  means that the antigen test is failing because the

PCR is positive and the antigen test is negative  but this is a big problem with not defining what

it is is our target for detection because just  based on this graph alone I think you can see that

you actually don't want to have somebody start  isolating at day 16 into their infection just

because they're PCR-positive they have already  completely cleared their virus from their body

in terms of infectious levels of virus you don't  need to isolate anymore if you've just happened to

stick the swab in your nose at day 16 to me that  would actually be a failure of the testing program

if it told you you're positive and you  had to go and isolate because of that

and so the real issue with what we've seen in  so many scientific publications and the way that

regulatory agencies across the world value these  tests especially in america but also in canada and

many other countries is that they keep insisting  that an antigen test for one thing gets compared

to a PCR for another thing I liken it to the same  reason we don't ever compare an x-ray to an MRI. An

MRI is expensive it takes a lot of time to perform, you have to schedule it you're not generally going

to use it in the emergency room but it's going  to find even the smallest little stress fracture

but if you're looking for somebody who has a  completely broken femur you just need an x-ray,

you don't need the power of an MRI and so we  don't compare x-rays to MRIs and say that they

have to live up to the sensitivity of an MRI because we understand they have different uses

and unfortunately in this pandemic we have yet  to fully recognize that the two tests have very

different uses and very different qualities and we  should not be comparing an antigen test to a PCR

because they're literally looking for different  molecules that have very different half-lives

in the body an antigen test is looking for  molecules that disappear after five days

A PCR test is looking for molecules that disappear after 25 days. Very different uses

Thank you. So what are the most important characteristics required for a test,

in order to stop the spread of infection during a  pandemic i.e to manage transmission of infection?

Well that's a great question. So normally in  medicine, the characteristics of a test we usually

care about are sensitivity and specificity.  The characteristics that are generally

not even considered, especially at sort of a  medical regulatory evaluation are speed and access

and what we've shown is actually when your goal  is to limit spread access becomes absolutely

essential. In fact, speed and access to the  test are much, much more important than the

molecular sensitivity for all the reasons we just  discussed, where you don't need all of the amazing

sensitivity of PCR. You just need to test that  will detect a million viral particles, or more.

For detecting somebody's infectious, so  the issue is that if you had a very fast

very accessible PCR test, then great you know  use it if you want to use it you can be aware

of you know you'd have to be aware that  you might stay positive for a very long time

but the fact of the matter is that PCR is not  generally fast and not generally accessible.

We want a test that can live in people's homes. At  the moment you think maybe I was exposed, maybe I

have symptoms that might be COVID. You can pull  out the test without having a big barrier to

entry and you can get an immediate result and  immediacy is just so critical if your test takes

two days to return, then it's not going  to be good enough to stop spread and I  have a slide here that I'll show you.

So, I have a slide here that's  very relevant to this question.

If you are charged with limiting  spread in a business, you can choose a

test that's a hundred percent sensitive,  massively sensitive.It's going to catch every

single person that's ever been infected  but it takes two days to get a result

or you can choose an 80 sensitive rapid test which  would be a very poor performing rapid test but it

has a result in 15 minutes which test do you want  to use to help limit spread in your workplace and

the answer is actually very straightforward most  people without thinking about speed would say I

want the 100% sensitive test. I don't want anyone  who's positive to not be detected as positive

but actually, if you look at the reality from more  of an epidemiological lens speed becomes a much

more critical factor and what I'm showing here  in this sort of busy slide but i'll break it down

there's the identical scenarios on the top of the  side and the bottom of the slide but on the top

you're using a PCR test that's 100 sensitive and  on the bottom you're using a rapid test that is 80

sensitive this test used on the top takes  two days to return the test using the bottom

takes minutes. So in the top scenario, you have five  infectious people, in both scenarios, you have five

infectious people walking into a workplace and  I have them in black and boxed in but the color

of the box represents how much viral load they  might have, so all five of those are infectious.

All five of them get a PCR test, but then they  don't get a result back for two days so they spend

two days walking around work not knowing that  they are spreading the virus, because they're

waiting for their PCR results to return and so  with this scenario you have collectively five

infectious individuals who walk around for two  full days before finding out that they're positive.

All of them find out that they're positive  at the end of the day, at the end of two days.

But it took 10 person days of walking around  positive and spreading to other people in the

workplace be before they found out so that's  10 person days of infectivity in the workplace

before they get discovered and that causes them to  infect numerous new people and send 20 odd people

to quarantine or more now on the bottom we have  the exact same five people walk into a workplace

but they have a 15 minute turnaround  time on their antigen test the rapid test

but it's only 80 sensitive and so the person  is probably going to miss so it catches for the

people immediately and one person 20 of five one  person ends up getting through without detection

that person was probably very low amount of viral  load in the first place and so they were so they

probably were not highly, highly infectious but  they were able to, they squeaked by, but ultimately

they get caught but the important thing was four  of them were caught immediately so eventually

at the end of the day you have two person days  walking around infectious so the 80 rapid test

leads to only two person days of infectivity  in the workplace versus ten so it's the fast

test regardless of its sensitivity that ends up  becoming much more critical to limiting spread

and in fact you'd have to have an abysmally bad  rapid test to be as bad as a PCR test that takes

two days to return which but but speed is just  generally not really considered in our metrics at

the CDC and at the FDA and I think it's been a big  failure of of scientists and sort of the medical

industry to not recognize how important speed is  when we think about the qualities of a test. Yeah,

it's been really frustrating actually. Having  understood what you said a very long time ago

so, right, so my next question is a very important  aspect of pandemic management that is omitted for

most public health information is the topic of  viral load and the role viral load plays in the

virus cycle. By way of example for our audience,  let's compare two scenarios example one. A person

infected with a coronavirus, but not contagious  and example two, a person infected and contagious

with the ability to transmit or spread the virus  to others this is a major aspect of testing that

you have just provided an excellent medical and  scientific information side about and it's been

very confusing and contradicting for non-medical  people. So can you please talk about these two

examples in the context of viral load and how  rapid antigen tests work in comparison to PCR

tests within this framework? So what I'm getting  at Michael is CT values really, ultimately.

Absolutely! And this is one of the most  misunderstood aspects of this pandemic. I think

especially by physicians oddly and it's there's  some history there of why physicians have had such

trouble thinking about viral load. Doctors aren't  generally trained to think about transmission.

Now when the only time we normally think about CT  values or the number of cycles it takes for PCR to

turn positive, so the more cycles it takes for PCR  to turn positive, means the more times you had to

amplify the starting amount of RNA which means  the lower the viral load was at the beginning

normally when we're thinking about CT values in  viral diagnostics we're usually thinking about HIV

and with HIV it's kind of a binary question  oftentimes for diagnostics are you HIV positive

or negative and so it doesn't matter if you even  have one molecule the infectious disease physician

diagnoses you as having HIV and of course if  you have a lot of molecules you might really be

even sicker but the point is you're HIV positive  either way but we actually do think about even in

the HIV world we say that yes somebody might have  HIV we know that they probably have molecules of

HIV inside them but if they are undetectable  at such a low level we know that they don't

transmit so this idea of transmissibility has  started to enter into the medical thinking

but with regard to Covid, the issue is really, do  we need all of the sensitivity do we need to be

detecting somebody who has a very low viral load  or who has a very high CT count. CT counts, a very

high CT count say 38 or 40 is implies a very, very  low viral load they're inversely correlated and so

the fact is we don't need to find people with  very, very low viral loads if our interest is

to detect people who are going to infect others  and it turns out that different tests do better

at different things so a PCR test will detect you  as positive across the whole gamut of viral loads

an to a rapid test will only detect  you when you're at a high viral load

and that actually impacts the sensitivity so the  sensitivity of a test is is absolutely related to

the amount of virus that you're trying to  detect so i'll share a graph that I made

quite a while ago and this is from this is  from a manuscript from tim keto in the uk

who looked at seven different rapid  tests and asked what is the sensitivity

of each of these tests to detect virus at  different amounts of viral load and different

amounts of viral load indicate that you have  different levels of infectivity to others

and so we found was that at for all seven of  these tests they were all able to perform with

pretty much a hundred percent sensitivity when the  viral load was the highest meaning over 10 million

copies or even moderately high meaning 1 to 10  million copies all of the tests still had 100

sensitivity and it wasn't until you got to  pretty moderate, or low viral load that the tests

start to drop in sensitivity. So 100,000 to  1 million you're still moderately infectious,

but not highly infectious and then the tests are  to get to 90% to 95% sensitivity and as you drop

below a hundred thousand viral load you start to  no longer be infectious you just aren't infectious

PCR will still keep being positive but you're  you're not likely to be infectious and so finding

detecting you as positive at that period of  time is much less important than detecting as

positive and you have a very high viral load if  your goal is to stop somebody from transmitting

so on average a test that is across all  of the viral loads that might happen

in a population at any given time you might have  a test that's only 50% sensitive versus PCR but if

you look at what are the viral loads we actually  care about that very same test might be 97% or 95%

sensitive so the sensitivity is absolutely  essentially it's essential to look at sensitivity

stratified by what you care to ask which  is am I infectious or do I have any virus

and we see that the sensitivities differ markedly  what has happened in the medical literature

and that has caused so much confusion is most  papers discuss just what is the sensitivity of

the antigen test against any viral load and that's  what you see here in this white bar in the middle

which is any RNA detection that test might only  be 50% or 40% sensitive sometimes even only 30%

sensitive so people think oh what an  abysmally bad test but it's because

you're looking you're starting to look for  viral loads that are not relevant anymore

so if you really key and just  on the high viral load people

then you see oh wow that same test does very very  well and I was being distracted by it not catching

people who I no longer care about because they're  no longer infectious now an important piece of

this is that a lot of people will say well what  if that low viral load was the virus on the way up

and that's actually something we care about  you want to actually detect somebody very early

so if their viral load is only a thousand but  they're on their way up and they're about to

hit a million the next day then that's critical  to know the problem is if you you again have to

take time into account so I showed this other  slide here the time frame in between that it's

just very unlikely that you're actually going  to swab somebody in that short duration of time

when you're in between the two sensitivities  so it actually is much less relevant and most

of the time that you see PCR being a very low  viral load and antigen test being negative is

after the infectivity is done and so that's why we  really have to be paying attention to virus load

when we ask what is the sensitivity sensitivity of  the test and I've advocated very strongly to the

fda and others unfortunately to a fairly you know  have made only moderate headway over the two years

is that we should always stratify sensitivity by  virus load and that is what would actually give us

a better understanding of how good is this test  because you could take an abysmally bad test

and if you only detect people when they have more  than a billion viral particles you could actually

make the test look like it's 100% sensitive  if you only recruit people into your study

who have a billion viral particles or more so  you could actually make a really bad test look

very good or if you only recruit people who are  on day 10 to 20 of their infectiousness or of

their infection you could make a very  good antigen test look like it has 20%

sensitivity so it really depends on where  people are in their course of infection

and we should know that and think about viral  sludge when we think about sensitivity of a test

yeah so to really clarify it for the audience  high viral load means that you're infectious and

contagious a CT value is a logarithmic measurement  that which makes it inversely proportional to

viral load so a low CT value means that you have  loads of virus in you and you're really contagious

and a high CT value say above 30 or 40 means that  you have very little contagious virus in you and

probably won't spread it and my contention  is is that we have PCR machines that can

give a CT value so when people get their  their test repeat from a PCR really they

should be given a CT value to say where they  are in infectivity what do you feel about that

I 100% agree it was actually a paper that  I published in April of 2020. I believe

in I think it was clinical infectious diseases  it was one of the earlier papers on PCR testing

in this pandemic and I at that time you know  over two two years ago now I was advocating

for using the CT value if we're going to  ever tell somebody they're PCR positive

give them the CT value because what was happening  was we had all these patients in the hospital

that were positive and they were staying in  isolation wards for two months, because they kept

being PCR positive and I kept saying you know we  should be looking at the CT value and if somebody

has a CT value on one day of 38 and on the next  day of 38 then they're done

with their infection they're no longer infectious  their body just hasn't finished clearing that last

little bit of RNA but if on the first day of  hospitalization they have a CT value of 38 and

on the second day they have a CT value of 20. then  in that 24 hour period of time they they massively

expanded their viral load they definitely need to  go into isolation and so or if you just take one

PCR CT value and it is a 17 and the first time you  take it you know that they're currently infectious

they have a very high viral load so the  use of the PCR if you're going to use such

a profoundly sensitive test that can scale over  many orders of magnitude then it is so critical

for the physician or public health expert to  know well where am I in the course or where

is my patient in the course of this infection  are they massively infectious and spreading the

virus and have a billion viral particles in  their nose right now or do they have almost

no viral particles and they're probably past  their infection and the CT value gives you that

information i'll show an interesting slide that I  think is just really illustrative of this concept

what we normally show for CT values is  what I show on the top here actually let me

let me rewind here so i'll show a slide to put  this all into context what we normally show for CT

values is on the top here this is what we normally  see for viral loads in a person they go from sort

of undetectable levels of virus and then once they  pass maybe a hundred viral copies per milliliter

that might be in some PCR instruments a CT value  of 40. they then go up really quick maybe they get

to a CT value of 18 and then they drop down again  and finally become undetectable after three weeks

or four weeks so this viral load makes it look  like you should probably be detecting people

out to 20 days for example but if we actually  look at what do these CT values actually mean

and like you said CT values are logarithmic they  actually are on a log scale and so if we take this

this same viral load curve that I'm showing  and this is sort of that this is a depiction

of what somebody's virus might do inside their  body since infection so they go from zero they

go to really high viral load and back down again  to undetectable if we put this on a linear scale

how we normally think about virus load as an as  any individual might think about virus load the

same graph these two graphs are identical they're  just changing the scale on the Y axis to one is

logarithmic which accentuates low viral numbers  and on the bottom it's how we actually think of

like how much virus is actually existing and so we  can see is almost all of the virus that somebody

has in their body occurs in a very short amount of  time 99%+ of all of the virus you have

occurs from like on this particular person, day  four to day seven, you know and after day seven

they have pretty much you know very very they've  cleared 99 of their virus or more and so this is

just so critical to recognize that CT values we  we count you know one might think CT value to 40

to 30 to 20 it's kind of the same from 40 to 30  and 30 to 20. but actually it's not it's it's a

massive difference and that's what happens when we  we try to think on logarithmic terms most people

in their brain think that it's a linear scale but  actually on the bottom here is what virus loads

really look like for how people should be thinking  about when is when is somebody most infectious

great and I must confess to the audience I  learned everything I know about this subject

from michael I've read all of his research papers  time and time again so we're running out of time

yeah I know it's true you're fantastic I've got  two really important questions I need to ask you

the first is about Omicron so the original  SARS-CoV-2 symptom onset was around four

to six days after becoming infected with  the Omicron variant we have experienced

an acceleration of symptom onset to the first few  days of becoming infected the rapid antigen tests

were registering negative and not turning positive  until several days after symptom onset for Omicron

as a result many scientists have stated that rapid  antigen tests do not work for the Omicron variant

what is your opinion of this new adaptation of  the virus as it relates to rapid antigen tests

now this has been one of the most difficult pieces  for many people to understand and that's because

immunology and testing and virus kinetics these  are these are a lot of different areas of science

and medicine that most people don't bring together  people who understand testing don't usually think

as much about immunology and people think about  immunology might not think about viral kinetics

and actually understanding what's happening here  takes synthesizing all three of these together

and so what we found with Omicron it's it's one  of the most interesting aspects I think that

has happened during this pandemic is that people  are now starting to get symptomatic with Omicron

really early and you might get exposed today and  you might become symptomatic tomorrow which is

really fast if we think about two years ago with  the original variant we would say oh if you get

exposed today don't expect to see any symptoms  for seven days you know don't even bother testing

yourself for five days but now we're seeing people  get symptomatic at one day and so people ask the

question well is this just because Omicron is  so much more aggressive and replicates so fast

well that's a little bit of it but it's actually  not the majority of it the majority of it is

what's happening is Omicron is really good at  infecting people who have pre-existing immunity

so I've been vaccinated and I got Omicron and  that means I had a breakthrough infection and what

that means is that I actually had some immunity  clearly not enough to stop myself from getting

an infection but I had some immunity built up so  when I got exposed my body re started to recognize

the virus early and it actually created symptoms  but the symptoms are different than they were

two years ago the early symptoms of Omicron are  things like a fever and congestion and those are

actually symptoms of your immune system turning  on whereas two years ago or even just seven months

ago the symptoms of Covid were loss of smell  and difficulty breathing and those were symptoms

of the virus destroying your body so people  can have symptoms for very different reasons

and so what's happening with Omicron is that an  individual gets infected and their immune system

creates the symptoms the next day their body is  like sending all kinds of red flags up saying

whoa whoa whoa you know I recognize this virus  because I've been vaccinated and boosted so then

people are becoming symptomatic before the virus  even has a chance to grow up and be detectable

in that you're still in that incubation phase  of the virus when your body is turning on red

flags and saying hey I think I'm infected so we  should actually use that as an early warning sign

but unfortunately what's happened is people  then use a test during that period of time

and the test register is negative and they  say what the heck you know I thought that

tests are supposed to be positive when I'm  symptomatic because people have equated symptoms

with being infectious and having high virus load  but that's not true in an era of Omicron and

breakthrough infections symptoms are oftentimes  a reflection of your immune system turning on and

actually I'd be almost more worried about somebody  who doesn't have any symptoms who's infected and

because their their immune system clearly is might  not be doing what it's supposed to be doing to

really stop spread so we actually saw evidence of  this where well so to go back what this

is showing in the population now is people are  using antigen tests on the first day of symptom

onset or PCR tests and they're getting a negative  result and then they're getting a negative result

on day two and day three they might be turning  positive and so they say oh these tests don't

work anymore for Omicron well that's actually  not true if we go back to the recommendation

a year ago it was don't even bother testing  yourself for four to six days after you've been

exposed so the same thing holds still the virus  hasn't changed to make its replication much much

faster it's that your body is just identifying  the virus faster sending up warning signals

in the form of symptoms trying to battle the  virus early before it even has a chance to grow

so for many people they might be symptomatic and  might never become antigen test positive because

their body did what it was supposed to do and  it actually beats the virus down you still might

detect it on PCR for other people they might turn  positive two days after symptom onsite because

the virus had a chance to grow up and become  infectious and we actually have evidence what

we found we looked at health care workers who were  infected and getting tested and returning back to

work at five days into isolation and what we found  was rather extraordinary we found that healthcare

workers who were recently boosted with a vaccine  were the most likely to still be infectious

at five days after symptom onset so they were  per CDC guidance, which I don't agree with.

They were coming back to work at five days into,  after isolation, after isolating for five days

and the boosted people were much more likely to  still be infectious than the non-boosted people

so you could ask the question. Well that's weird.  Are boosted people somehow not clearing the virus

better? No that's not the right way to look at  it. What's actually happening is that boosted

people have so much immune activity that  their body recognizes the virus really fast

and so they start the isolation clock really  early. So they were starting the isolation clock

days before they even had a detectable viral  load, based on their symptom onset. So by the

time they were leaving isolation at five days,  they were at the peak virus load. Because their,

immune system turned on within  a day or two of becoming exposed and then they

didn't have their peak virus until four days later. So we actually see sort of circumstantial evidence

suggesting that breakthrough infections you  become symptomatic even before the virus really

has a chance to grow up and that's the primary  reason why so many people are still negative

on their first two days it's that they're  still in that incubation window. When

two years ago we knew that no test would turn  positive in that period of time and that still is

the case today. It's just the window of symptoms  has shifted, not the window of viral replication.

Right, so if you have Omicron, I'm going to be  very quick because we're three minutes over, if

you have Omicron and you are testing positive five  days into your infection and testing positive for

10 days or onwards, you're actually contagious.  So even though your symptoms might have gone

it's not that the antigen test isn't working,  because I think you've showed really that antigen

tests good ones validated ones are 100 percent  sensitive during the contagious period so if your

antigen test is registering registering positive  at day 10 to 15 to 20 you're actually contagious.

That's right. You should always expect that and  that just takes a little bit of understanding how

these rapid antigen tests work if you have enough  virus protein so that you can actually see a line

on a rapid test that means you have a lot  of virus protein there and the only way

you have that kind of virus protein is a virus is  actively replicating and you're likely contagious.

So my recommendation to anyone is, if you're  in isolation and you're thinking of leaving,

especially if you're leaving early. Test  yourself before you leave. If you're positive,

assume that you are infectious and if you're  positive, even if it's 13 days into your infection

into your symptoms, assume that you  are still infectious. An antigen test

does not stay positive if you're not likely  infectious and it's really important to know that.

My grandfather unfortunately is in a senior living  facility he's 96 and a lot of people just got the

BA.2 in his facility this is just last week and they  hit the 10-day mark and they said okay, nobody's

infectious anymore after 10 days of symptom onset.  You can take off your mask, stop quarantining,

stop isolating and even if people are positive  still, they were saying don't worry about it

you're not infectious. That is absolutely wrong.  We should not assume that just because 10 days

is up that you're not infectious. If the test  remains positive and it's a rapid antigen test,

assume you are still infectious. Thank you so much  for clarifying that because so many physicians are

going around saying that the antigen tests are not  working, ignore that positive result and re-expose

yourself to society and I know that your findings  have been replicated in Japan and Taiwan, so I

know it's not just your team that have that have  shown this. So we're out of time unfortunately,

I could talk to you for another hour. Thank you  so much for joining us. Thank you so much for the

work you do. I think I've said many a time you're  brilliant and I think your audience can see why

Dr. Mina's teachings have changed my whole  perspective of medicine. Thank you for taking

the time for being with us today and providing  such valuable and worthwhile information

and thank you for sort of striving valiantly  to help us to manage this pandemic properly.

Well thank you so much and I do hope that people  have learned something and certainly you know

if people want more information, my Twitter feed  is full of it. I'm sure we can put that in the in

the text here but yes, definitely I would highly  recommend you follow Dr Mina's Twitter feed. I do!

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