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- This is Lab Medicine Rounds, a curated podcast
for physicians, laboratory professionals, and students.
I'm your host, Justin Kreuter, the bow tie bandit of blood,
Transfusion Medicine Pathologist at Mayo Clinic.
Today, we're rounding with Dr. Jeff Winters,
Chair of the Division of Transfusion Medicine
and Professor of Laboratory Medicine and Pathology
at Mayo Clinic.
And we're gonna be talking about the new AABB guidelines
for convalescent plasma.
Thanks for joining us today Dr. Winters.
- Hey, it's my pleasure.
So a bit of an update since it's the last time
we chatted back in 2020.
- Yeah, it's been some time.
Some of us may have lost track
of the convalescent plasma conversation.
And I was wondering if you could kind of give us
an update about what's been happening
regarding convalescent plasma.
- Well, you know, we had all hoped that maybe this
would all become moot and things would go away,
but it hasn't happened.
So since the last time we chatted, there was discussion
about really a review of the literature.
And at that time, there were 14 trials,
a mix of randomized controlled trials and controlled trials
that I chatted about.
Now, since then, we're up to actually 33 randomized
controlled trials as of January of this year, 2022.
And so utilizing that information,
AABB, which I'm gonna say the new name for everybody, right?
The Association for the Advancement
of Blood and Biotherapies, formerly known
as the American Association of Blood Banks
has published some new guidelines.
So back since last time we talked,
there were some consensus guidelines published in 2021.
Now those were based solely on the opinions
of people involved in the field.
So these newer guidelines, however, are really using
meta-analysis, really critically examining the data
with a very structured format using the grade methodology.
So that's happened.
I think the other thing that's happened just
sort of overall, when we talk about convalescent plasma
is that we've seen a decrease in its utilization.
And that came about in part because of recommendations
that came out from the National Institutes of Health
as well as the Infectious Disease Society of America
and others that sort of recommended against it.
We saw a substantial drop off.
Okay, now that happened.
And there was some evidence that was published
that actually suggested, again, not randomized
controlled trial, but more anecdotal case series,
case report evidence that suggested that that decline
in the use of COVID convalescent plasmas may have actually
been associated with increased mortality amongst patients.
So that was one of the real drivers behind AABB
wanting to go ahead and really go back
and look at this literature and make new guidelines.
In addition, there were recommendations from, again,
the Infectious Disease Society of America.
Not that COVID convalescent plasma should be utilized
in everybody, but that it should be considered
in immunosuppressed individuals.
And there were also some guidelines that came out
from the European Conference on Infections in leukemia
that again, similarly recommended the use
in immunocompromised individuals.
So really, that's been sort of where we're at.
So utilization has dropped, but we've gotten more evidence.
We're starting to look at it critically
and we're starting to see some fine tuning
of some of the recommendations
- Right, yeah, it's great to put that in context that
what we had for data and what we were using
for our recommendations, how that has increased
how we have been learning.
So can you kind of take us through what are some take home
points from this new AABB guidance or guidelines
that are out?
- Sure. First, just to mention for the people
that are watching this, you can see the guidelines,
you can download the document from the AABB's website,
so aabb.org, and eventually it should appear
in the Journal Transfusion as a published document,
but for the time being from the AABB's website.
So again- - And we'll make sure
to put it a link to that in the show notes
as well for listeners. - Sounds great.
So again, this represents a more critical analysis.
So we'll talk about the key points
but I wanna talk just briefly about how we got there.
So basically AABB worked with the people with regard
to the Cochrane Database to have them actually
begin to abstract data and have people from Cochrane
actually do the data analysis to begin
pulling this together to do a formal meta analysis.
Now, before that occurred, there was a committee set
up with a bunch of different people, myself included,
that either had been involved in research in this area,
had been involved in the collection in this area.
There was an attempt to get representation, not only
from the blood banking laboratory medicine community
but from the infectious disease community
and other individuals, including critical care.
We voted on what were the questions that we wanted to ask?
What did we wanna look at?
And we voted on those before we had access to the data.
So again, this is not to bias us.
We had the Cochrane people go together,
do this data abstraction, apply the grade methodology,
and then give us the results.
The committee met, and we began crunching through
these numbers and making decisions.
All the decisions were consensus decisions.
Everybody had to vote.
And some of the committee members were actually excluded
from voting, including those people that had done
the data analysis, but others were excluded
if they had been involved in clinical trials in the area
where the particular question
that we were discussing was involved.
So, to lay the groundwork.
Now, what were the findings?
So there were some recommendations that came out,
there were five recommendations.
And so I don't mess them up,
I do have them written down here.
So forgive me for breaking eye contact,
but I wanna get this right.
So recommendation number one is dealing with outpatients.
So AABB suggests that CCP,
so COVID Convalescent Plasma Transfusion,
in addition to the usual standard of care
for outpatients with COVID 19 who are at high risk
of disease progression.
So there was a recommendation to provide it
to outpatients with a high risk of progression.
Now, this recommendation was a weak recommendation based
on moderate certainty of the evidence.
So again, not very much of a strong recommendation,
and basically this was derived from the fact
that there were three nice randomized controlled
trials that provided us data.
Now, two of those controlled trials actually showed evidence
of benefit in this context, right?
One of them did not.
Now the problem is that the one that did not
had the most patients, but that particular trial
actually used methylene blue treated plasma.
And the issue is that there's some evidence
in the literature that suggests
that methylene blue treatment alters some
of the glycosylation of the antibodies
and may make them ineffective.
So even though that much larger trial did not show benefit,
there may be a reason why it didn't show benefit.
Hence the fact that this is a weak recommendation
with moderate certainty of evidence.
Second recommendation.
Second recommendation is in the inpatient setting.
And they recommended against, so against,
transfusion for unselected hospitalized individuals
with moderate or severe disease.
And this was a strong recommendation
with high certainty of evidence.
One caveat here, this recommendation did not apply
to immunosuppressed individuals or those who had a lack
of antibodies against SARS-CoV-2.
So really this was coming out
of what we had talked about back in 2020,
those randomized controlled trials that were
treating patients that were
in the ICU, that were on the ventilator,
and it really wasn't suggesting any efficacy.
And if you think about it, it makes sense, right?
The damage has been done by the viral infection.
So why would administering passive antibody
to those individuals be of any benefit?
In addition, many of the trials demonstrated
that those individuals, by the time they got
to that stage of the game, yeah,
they already had antibodies.
They had their own antibodies.
So adding a bit more was not gonna be particularly helpful.
So again, if you're in the hospital, you're severely
affected, you're on the ventilator, you're in the ICU,
really, there's not a role and again, strong recommendation,
high certainty of evidence.
So that's pretty good.
Third one.
Third one is back to inpatients, and AABB suggests
for transfusion, in addition to the usual standard of care
for hospitalized patients with COVID-19,
who do not have antibodies to SARS-CoV-2
detect it at admission.
So in other words, those individuals who have failed
to have an immune response, yet are not as severely affected
going forward.
Again, a weak recommendation with low certainty of evidence.
Okay, so.
- I'm sorry, just to clarify that one.
So inpatient, in addition to the usual care
was the recommendation for using or against using?
- For using, for using it in the setting of individuals
who haven't developed an antibody yet.
So again, we're attempting to provide passive immunity
to hopefully help intervene in the infection
and prevent them from progressing to more severe results.
So that was the third one.
Fourth one was an inpatient,
and they suggest CCP transfusion.
So this sounds like the other one.
Suggest CC transfusions, in addition to the usual
standard of care for hospitalized patients
with COVID-19 and preexisting immunosuppression.
So these would be individuals again.
So that recommendation three,
they didn't have any evidence of antibody.
Recommendation four is they may not be able
to form any antibody
because of their underlying immunosuppression.
And again, there were studies that had looked
at this population and suggested that there may be
actually some reduction in the relative risk
in immunosuppressed individuals.
It wasn't getting to the point of being
statistically significant compared to others.
However, relative to the overall population
of patients examined in those studies,
these were much smaller numbers, and therefore
there is possibly a signal there, again,
weak recommendation, low certainty of evidence,
acknowledging the weakness in the data.
And then number five.
Number five is with regard to prophylaxis.
So AABB suggests against, so against, don't do it,
prophylactic transfusion for uninfected individuals,
uninfected individuals who have a close contact exposure
to a person with COVID-19.
So this was a weak recommendation
with low certainty of evidence.
So really those are the three recomme-
or excuse me, three, five recommendations that have come out
from AABB from looking at the sum total literature.
And there was also some clinical good practice
recommendations that came out or rather,
a clinical good practice statement that came out.
And that was that when you give COVID convalescent plasma,
it appears from the total data that it is most effective
when transfused with high neutralizing titers.
Because again, that was what we talked about back in 2020.
A lot of these clinical trials, they hadn't measured
the antibody levels in the plasma, in the donors.
And in retrospect, many of these did not have high titers.
So high titers are important and infected patients
should be transfused as early
after the onset of symptoms as possible.
So again, if you're out weeks, days to weeks out,
those individuals probably have already responded,
have generated antibodies, and the total amount of antibody
that you're giving is probably irrelevant
to the total body production.
The other caveat, the one other thing I think I mentioned,
I probably should have mentioned with your first question
is another reason why I think there was a discussion about,
yeah we need to go ahead and push out these new guidelines
is that with the Omicron variant,
what we found is that the monoclonal antibodies
that were being utilized were essentially ineffective,
and that as the variants have proliferated
and new variants have appeared, the monoclonal antibodies,
which are directed towards a specific epitope
on the spike protein, if there's a mutation in that epitope,
are no longer effective.
On the opposite the benefit of the COVID convalescent plasma
is that it appears that at least in the high titer stuff,
usually individuals who either were infected
and then vaccinated or vaccinated and then infected,
the very high titer broad specificity
does appear to retain efficacy
against some of these variants.
- Wow, thank you.
It really kind of, I think for the student listeners
of this podcast, you highlighted,
this is a great case example in kind of evidence-based
medicine and the way that this is done in a proper way
with the consensus voting on questions ahead of time,
looking at data, making sure people that are conflicted
are not participating in that ultimate recommendation.
And for our clinician listeners, I think you're
also highlighting
it kind of put some explanation behind some of that
kind of earlier, do we use this tool?
Do we not use this tool?
And after gathering this data, I think what I'm hearing
from you is we really have developed some sophistication
on when and how do we really use this tool?
- Right, it's really focusing this tool
down into a population of patients where it's going
to potentially have an effect, right?
Sometimes people say, "Hey when you're a hammer,
the entire world looks like a nail."
And I think that's sort of what we were doing
with our hammer initially, which was
the COVID convalescent plasma, it was like,
"Hey, everybody gets it."
Even though you could argue
from a rational scientific basis, there were a lot
of patients that were receiving it that,
yeah this sort of doesn't make sense.
Now, I should make one comment
that I think is also important, and that is from giving this
to all of those broad range of patients,
at least we do have a signal from the clinical trials,
from the expanded access program
that it does appear that COVID convalescent plasma is safe.
Meaning that it is not any, there's not a greater risk
in giving that as opposed to giving just regular old plasma.
We were not seeing enhancement
with regard to the infections.
We were not seeing other complications due
to it beyond what we would normally see.
- So with the data, and we're getting this more
sophisticated understanding, sometimes the data and science
is one place and kind of the practical use of it
might be in the other the sort of how in implementing this.
And so I'm curious, what challenges,
were there challenges discussed or things
that you see applying these guidelines,
either domestically or internationally?
- Yeah, so a couple of thoughts there.
Number one, I think we're still a bit
of mixed messages coming out from different things.
So at this point in time, NIH has not updated
their guidelines and they are still recommending
against this, the same with the World Health Organization.
As I had indicated, the Infectious Disease Society
of America has carved out specifically
immunocompromised individuals,
and AABB obviously has issued new guidelines.
So there still is working towards a bit more
of a consensus opinion.
I do know that there has been a petition started
asking NIH as well as WHO to go back
and revise their guidelines because their guidelines
are also a bit out of date with regard
to the administration of monoclonal antibodies,
and also don't acknowledge some of the newer things.
So that's one thing, there's still a little bit
of who do we believe conflict out there
with recommendations and guidelines.
From a practical standpoint, with the decline in requests,
following the NIH guidelines, a lot of blood centers
backed off.
So they have stopped collections.
So there are people that are ramping it up.
So it can be hard to find if you are a physician
and infectious disease doctor making this request.
It may take a bit of time for your hospital
to obtain product.
I think given some of the guidelines that the FDA
has released with regard to eligibility for donors,
there are limitations.
You have to have been infected within so many days
in order to be considered eligible.
And so you're constantly looking for new donors
who are recovering from COVID-19 and bringing them in.
They did loosen some things up so that the order
of infection versus vaccination no longer matters.
So that's useful, but again, sort of hard
to do those collections.
And then again, I think identifying those appropriate
patient populations.
With regard to outside the US, one of the arguments,
again for utilizing COVID convalescent plasma,
let's say compared to the monoclonal antibodies,
is that in resource-limited countries,
it would be far easier to obtain and collect
convalescent plasma and cheaper than access
to some of the monoclonal antibodies.
So there could be a benefit there.
It gives greater flexibility.
It's a bit easier in resource-limited countries
to be able to do that compared to the monoclonal antibodies.
And as I've indicated, those have lost some
of their efficacy with the variants.
- Interesting, interesting.
Thank you for shedding that light on that
kind of the practical, how to.
As you were going through there, I was taking note,
I mean, there are some that do have high level of evidence,
some that have low level of evidence, those guidelines,
given that this is really,
the knowledge and science continues to evolve,
I'm curious, like you said, you've participated
in the formation of these guidelines,
this kind of rigorous process.
Is there an aspect that you would like to see
kind of addressed with more robust data
as we kind of go forward?
- Sure. More data is always better.
I think the real key is that as we've sort of talked about,
we're narrowing in our focus on who it is
that we're treating, and really it's those individuals
who are immunocompromised, who are likely not to be able
to respond with producing antibody
and clear their infection.
And so really there is a need to look specifically
at that patient group.
That is again, randomized controlled trials
that are looking at that group,
which are appropriately designed and powered.
And part of that design needs to be
making certain that the plasma that is administered
is high titer plasma, that there are the antibodies there,
that those patients by their definition,
we're gonna look at a population that doesn't have
antibody present, but measuring antibody before,
measuring antibody after and following them up.
So really that's what we need to focus on
is strengthening the evidence
in that immunosuppressed population.
Because again, that was a small subset of many
of these clinical trials aggregating the data says,
"Hey, there's a signal here, but really doing something
focusing solely on those patients is what's needed."
- So I just wanna highlight that for our student listeners
of the podcast, right, that this highlights
the importance of study design,
not just any study looking and putting something together
is going to add value, add information to our knowledge.
And so as you go through your journal clubs,
it really highlights the importance
of paying attention to study design.
And this is a wonderful case example of that.
Thank you so much, Dr. Winters for rounding with us today
and updating us with respect to convalescent plasma
and the new AABB guidelines.
- Yeah. I would encourage everybody to take a look at 'em,
a lot of information in them.
There's some really great forest plots for those
of you that have never seen those that really sort of
put it all into a visual, into a picture.
And I think can help you understand how
we came about those decisions
- And to all of our listeners,
thank you for joining us today.
We invite you to share your thoughts
and suggestions via email.
Please direct any suggestions to mcleducation@mayo.edu
and reference this podcast.
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And until our next rounds together,
we encourage you to continue to connect lab medicine
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