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In this episode of “Lab Medicine Rounds,” Justin Kreuter, M.D., sits down with Jeffrey Winters, M.D., and discusses the new AABB guidelines for convalescent plasma.
A Mayo Clinic podcast for laboratory professionals, physicians, and students, hosted by Justin Kreuter, M.D., assistant professor of laboratory medicine and pathology at Mayo Clinic, featuring educational topics and insightful takeaways to apply in your practice.
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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,
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