1. health and fitness
2. disease
3. aids and hiv

UNIVERSITY OF FLORIDA
Moderator: Donna Wegner
04-14-10/10:30 am CT
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UNIVERSITY OF FLORIDA
Moderator: Donna Wegner
April 14, 2010
10:30 am CT
Dave Ashkin:
Good morning, everybody. We’re really so, so happy to have you all here with
us today. We’ve been doing grand rounds for quite some time, and I know you
guys are tired of me saying this but we really, really, really have an exciting I
think presentation today and something that I’m very, very sure that at the end
of today you’ll be able to take home with you and definitely I think will
influence your practice and that’s always been the goal.
Over 120 years ago, Robert Koch discovered tuberculosis and as all good
scientists know, discovering the organism is not good enough. You have to
find the cure. And he set out to try to find the cure by taking TB, heating it up
and killing it, making it into old tuberculin and injecting it into people to try to
cure them.
And the story goes that one of the people who was working with him was Sir
Arthur Conan Doyle and as guys know, he was the writer for Sherlock
Holmes and at the time, he was a physician and he was working with Koch
and he realized that as a cure, old tuberculin was terrible.
UNIVERSITY OF FLORIDA
Moderator: Donna Wegner
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But actually interestingly enough as a diagnostic tool, it actually may be a
good way to know who was infected with TB and that was the beginnings of
the PPD.
And since the 120 years that we’ve been using the PPD, most of us at least for
myself, I’ve at times felt it to be very, very helpful in trying to figure out
who’s infected. But once you’ve used it for a little while it becomes quite
evident that it has a lot of let’s say limitations and those limitations have really
frustrated a lot of us for a long time.
And for a long time, we’ve had to deal with the limitations of the famous 20%
had a false negative, 20% had a false positive, the interactions with other
NTMs, BCG and many of us for a long time have wished it would be a better
test.
And what’s pretty amazing over the last couple of years is some new
technologies have come out that now maybe hold the promise that once and
for all we may be able to better assess who may truly be affected with
tuberculosis and that’s what our grand rounds is about today.
It’s about interferon gamma release assays and we are so lucky to have today
three speakers who are going to talk about the backgrounds on interferon
gamma release assays, possible applications and again possible limitations and
then after we’re going to have two speakers talk about their experience with
the different tests.
So without any further ado, I want to introduce a good - somebody I consider
a good friend - Phil LoBue from the CDC who is going to talk to us about
interferon gamma release assays yesterday, today and tomorrow.
UNIVERSITY OF FLORIDA
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Phil is the Associate Director for Science with the Division of TB Elimination
and he’s with the National Center for HIV, Viral Hepatitis, STD and TB
Prevention with the CDC.
Most importantly what I really like about Phil, he’s a clinician and what I
really like is he’s always been able to take very, very complex subjects and
explain to even people like me so without further ado, I really want to
introduce Phil. Phil, thank you so much for being here today. Thanks, again.
Phil LoBue:
Thank you, thank you, Dave. Thanks for the invitation and this is
unfortunately a somewhat complex topic but we will go through it and
hopefully you’ll have a better understanding of IGRAs and how they can be
applied to diagnosis of TB infection.
So let me just say I’ve no conflicts of interest to disclose and for the overview
of my talk today, I’m going to start and talk about the development of these
tests, talk about the currently FDA-approved IGRAs, recommendations for
use.
The CDC has had two prior sets of guidelines and we have another one which
is actually at the publisher waiting to be published and I will talk about those
guidelines.
I’m going to categorize those recommendations as provisional because they
haven’t seen print yet but nothing has changed so far as we go to publication,
talk about some research questions and future possibilities for use of these
tests.
So development of IGRAs. As Dave told you in the beginning, there was a
tuberculin skin test and as most of you are familiar with this, it involves the
UNIVERSITY OF FLORIDA
Moderator: Donna Wegner
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injection of .1 mls of five tuberculin units of PPD and then you read
induration in millimeters at 48 to 72 hours after the injection.
But it was not completely perfect and as most of you know, these limitations
of the TST have been categorized very well. There are technical problems in
terms of administration and reading.
You really need practice to do this well. You need more than one patient visit.
You get false negative responses as Dave mentioned usually due to
compromised immunity but just with waning immunity with AIDS, you can
see TST reversions to negative.
Because of the possibility of boosting, you need to do two-step testing for
persons who are going to have serial testing and then especially in a lowincidence country like the U.S., false positives are really a major issue and
particularly due to cross-reactions to Non-Tuberculous Mycobacteria or NTM
or people who have gotten BCG vaccination.
So people obviously raise the question, is there an alternative way to approach
the diagnosis of TB infection and in this next slide, what I show you is if you
look at the top part, what really happens when we do a tuberculin skin test?
So after this, you inject that PPD material over the next 48 to 72 hours, what
happens is a delayed-type hypersensitivity reaction which involves multiple
chemical cytokines and cellular responses which ultimately produces that
swelling or bump that you measure as induration.
But another alternative is just to look at one component of that response. In
particular, an important component is interferon gamma which is very
UNIVERSITY OF FLORIDA
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important in the immune response to tuberculosis as has been demonstrated in
multiple studies.
So the IGRAs are going to look at one component of the immune response to
TB, specifically measurement of interferon gamma so the underlying principle
is as follows.
If you take blood and you expose the peripheral blood lymphocytes of a
person you suspected to have infection, if you take that blood and expose it to
antigens from tuberculosis, if a person’s infected they’re going to have an
immune response and you can measure the interferon gamma that’s made by
lymphocytes in response to that.
There are two approaches that I’m going to talk about a little more. One
approach is that you just measure the amount of gamma interferon that is
made. The other approach is you actually measure the number of cells that are
producing interferon.
So a little background history, this assay was actually initially developed for
cattle testing and marketed as Bovigam. At that time, they’re interested in the
bovine tuberculosis which is generally caused by Mycobacterium bovis and
the antigen that they used and understand that PPB isn’t really a single antigen
but is a whole bunch of proteins that they’ll talk about.
So they started out with using the M. bovis PPD and they actually had a pretty
good motivation in addition to all the problems with skin testing. Many of you
may say well, how do you skin test a cow and I know Dave Ashkin spent
many sleepless nights wondering so I’m going to reveal the answer.
UNIVERSITY OF FLORIDA
Moderator: Donna Wegner
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What you have to do is you have to lift up their tail and inject the PPD into a
rather sensitive area and then you have to measure it in a place where most
people do not want to measure induration.
So that’s how they did it in cattle and it was a difficult test to do and so they
had really wanted an alternative to do that - and they came up with this
bovigam test which was to measure interferon gamma responses.
That was subsequently modified in human use and later marketed as
QuantiFERON TB. That initial test actually used basically a proprietary M.
tuberculosis PPD, which was not Aplisol or Tubersol, which we generally use
in the skin testing. That was substituted for the M. bovis PPD and so that’s
how they made it essentially into a human test.
And there was a study published initially I think in 1997 and we did a trial at
CDC which Jerry Mazurek headed and then there was subsequent FDA
approval in 2001.
However, if you look at the original QuantiFERON test, you see some
advantages but you see something that’s not particularly different from the
skin test so QuantiFERON is a blood draw, one patient visit, TST two patient
visit. Again, you’re measuring interferon gamma so potentially more
objective because you have a machine which is quantitating it as opposed to
having to have people measure the induration, which is somewhat more
subjective, but the antigen was basically the same. They were different
versions of PPD, but they were PPD.
So just to review and Dave mentioned some of this, what is PPD? So you start
off with the old tuberculin, which is basically a sterile solution of concentrated
UNIVERSITY OF FLORIDA
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filtrate of M. tuberculosis and culture, so you’re culturing M. tuberculosis,
you’re filtering the solution that it’s growing in and you’re concentrating it.
But you want to make it more purified so they just actually just purified the
protein fraction of that so you just get a protein concentration and that’s PPD.
It’s purified protein fraction.
But it’s not a single antigen. You have many antigens and proteins in that mix
and the problem is that some of these are also found in BCG and nontuberculosis mycobacterium so any IGRA that uses PPD really doesn’t
address this issue of false positives due to cross-reaction.
So people thought more about this and said well, what would we really like to
do? What we’d really like to do are find these antigens which are specific for
M-tuberculosis, so in this scheme that I show here, if you look at three
overlapping circles, our target area is just this pink area. We want antigens
which are only found in M. tuberculosis. We do not want antigens found in
these overlapping areas. We do not want these cross-reacting antigens.
And there is such an area which is actually if you look at the M. tuberculosis
genome which I show in this slide, you see that it’s about 4 million base pairs.
People looked at the genetic region and it turns out there’s this region of
difference 1 which is actually quite useful for our purposes because in that
genetic region, that region is not found in BCG or most NTM.
There are now I understand four exceptions based on a recent paper that I read
so M. kansasii, M. szulgai, M. marinum, and M. riyadhense which I just
learned about in the paper that there are these four where there isn’t - always
have this region of difference 1 - so there’s a potential for overlap.
UNIVERSITY OF FLORIDA
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This region codes for nine proteins and two have been found to have a very
strong immunologic response in persons infected with M. tuberculosis and
those are 10 kilodalton in culture filtrate protein which I will call CFP-10.
And another one is a 6 kilodalton in early secreted target antigen which I will
refer to as ESAT-6 so two very promising antigens.
So in the newer generations of IGRAs, the way the test is generally set-up...
Man:
(Unintelligible).
Phil LoBue:
Okay, okay - there’s a negative control which is usually saline and Heparin.
You don’t expect any response to that. There’s a positive control or what they
call a mitogen and that’s some non-specific immune stimulator
phytohaemagglutinin or PHA is frequently used and then you have these M.
tuberculosis specific antigens. And unlike PPD used in TSTs, these generally
do not cross-react with - they don’t cross-react - with BCG and generally do
not cross-react with NTM except for the exceptions I mentioned.
And it actually turns out that this actually works better when you use
simulated - when you simulate - the antigens by using overlapping peptides as
opposed to using the total protein as a recombinant of protein and that was just
determined empirically by the people who developed the test.
So that these antigens actually are these overlapping short chains of linked
amino acids or peptides that simulate these antigens.
So what are the currently FDA-approved IGRAs? Well, there’s the original
QuantiFERON TB which I mentioned already. That’s no longer available and
UNIVERSITY OF FLORIDA
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obviously had some disadvantages that TST had so really isn’t as useful
anyway as the newer versions that I’m going to discuss.
There’s a QuantiFERON TB Gold, which was FDA-approved in 2005.
There’s the Gold In-tube approved in 2007 and, finally, the newest approved
test which is the T-SPOT TB.
So I’m going to talk about each of these individually so you have some idea of
how they work. With the QuantiFERON Gold you will start by drawing
blood. You then take that blood and you aliquot it into wells and there’ll be
four wells for the blood sample. One is the no-control as I mentioned then
you have one well where you’re going to add ESAT-6, one where you add
CFE 10 and one where you add your mitogen - so negative control, two
separate wells for the TB antigens and then your positive control.
You have to get this done - this blood to the lab - and start this within 12
hours. Then you incubate this overnight and you’re going to have interferon
gamma made if you have lymphocytes from someone who has been infected
with TB.
After that it’s an incubated overnight then you want to harvest the plasma
from those wells and you then subject that to an ELISA which is a type of test
which allows you to measure the amount of interferon gamma and then you
have a computerized interpretation that tells you what the results of your
interferon gamma test is.
The Gold In-tube is a little different. In a Gold In-tube you have three blood
tubes. Again, you have a nil tube which has heparin in it, you have the
positive tube which is the PHA tube - that’s got your positive mitogen which
you expect just about everyone should react to once they are immuno-
UNIVERSITY OF FLORIDA
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suppressed - and then you have this MTB tube and that tube is actually
contains your three antigens. All three in one tube so there’s ESAT-6, the
CFP-10 which I talked about and the third antigen, TB 7.7 which is another
specific antigen for tuberculosis. The advantage of this test is that you can
actually leave the blood in these tubes for up to 16 hours before you start your
incubation so it can help logistically if you have to do work in the field for
contact investigations.
But once you get it back into the lab, you then need to incubate at 37 degrees
for 16 to 24 hours, you need to centrifuge the tubes because you want to
separate your plasma, take off your plasma. And then you do the same thing
as you did with the QuantiFERON Gold test, which is you’re going to
measure how much interferon gamma is made and if someone is infected with
TB, you expect they’re going to respond to those TB antigens in the middle
tube, that MTB tube.
And T-SPOT ,which uses a different platform which we’re now looking at,
actually counting cells that make interferon gamma, in this again you start out
by collecting blood in you use a different tube - a cell preparation tube or CPT
tube - and you need to actually recover, wash and count the peripheral blood
mononuclear cells. So you need to actually isolate these cells, count them,
wash them, and then you’re going to aliquot the cells to a standard
concentration 250,000 to four different wells. And this is similar to the Gold
in that you can have four different wells, one with your negative control
saline, one with your ESAT-6, one with CFP-10 and one with PHA, your
positive mitogen.
Wash away the cells and then you use antibodies against interferon gamma
and if it’s there, those antibodies are going to test the interferon gamma that
it’s made.
UNIVERSITY OF FLORIDA
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And if positive (doesn’t show up this well on this screen) but if you look at the
bottom, as you can see if you have - the saline which is the negative control you shouldn’t see - there shouldn’t be cells making interferon gamma at all
and so you don’t see any spots.
Let’s move all the way over to the PHA. PHA is your non-specific immune
stimulator. You expect anyone with a healthy immune system to react to this.
As you can see in this example, there are just tons of spots so this person’s
lymphocytes are just reacting like mad and making lots of interferon gamma.
You have lots of cells making it. You get lots of spots.
In the middle, these two are actually positive reactions for someone who is
infected with TB because both ESAT-6 and CFP-10 both have a fair number
of spots developed in reaction to those antigens. So this would be considered
a positive test. I’m going to tell you some more about the details of how you
go through determining what’s positive and what’s negative.
So just to summarize these tests in comparison, if you look at the format in
QuantiFERON Gold, you must get the vial to the lab and stimulate by 12
hours. With the Gold N-tube, you have 16 hours before you can - you can wait
up to 16 hours - before you get it and start that incubation at 37 degrees.
With T-SPOT you have to start the stimulation within eight hours of drawing
the blood. The TB antigens, QuantiFERON Gold and T-spot both use ESAT-6
and CFP-10 and they both use separate wells so you’re measuring the
individual reaction to each of these antigens. With the Gold In-tube you have
a single tube. It contains all the antigens that you’re exposing the lymphocytes
to.
UNIVERSITY OF FLORIDA
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The Gold and Gold In-tube QuantiFERON test measure the total amount of
interferon gamma. T-spot counts the number of cells which is shown by the
number of spots that you see. And in terms of the possible results that you get
for both QuantiFERON tests, you can get a positive result, a negative result or
an indeterminate result.
However, for T-spot there’s a fourth category which is borderline and I’ll
explain what those are. So what’s considered positive? Well, it depends on the
test but basically it’s based on a calculation of your interferon gamma
response to these TB antigens relative to the interferon gamma response to the
negative control.
Unlike the tuberculin skin test, this is not risk-stratified so remember that in
the tuberculin skin test, we have a five-millimeter cutoff for the highest-risk
people, a 10-millimeter for people with some risk and a 15-millimeter cutoff
for people with basically no risk.
There is no stratified interpretation for this. It’s either positive, negative or
indeterminate and it’s still somewhat complicated when you think that there
are all these calculations that you have to make but there’s software that does
this for you so there’s computerized software so you don’t have to manually
do these calculations.
What about indeterminate and borderline results? Well, indeterminate
basically occurs for one of two reasons. Either your negative control result is
too high, which means for some reason this person has a lot of background
interferon gamma being made, and that’s going to be a problem in terms of
interpreting the results.
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The second one, and this is probably more common, is that you have a
positive control result, your mitogen result which is too low and this is
something you might see in someone who’s immuno-compromised with
advanced HIV infection for example where they just can’t respond to the
mitogen.
And finally for the T-spot, you have this borderline result where the result
falls within what’s called a borderline zone, which is close to the negativepositive cut line. And so within that range it’s really hard to know should this
be positive or negative and the FDA decided that there should be a borderline
because they really feel you cannot tell if it falls in that zone that’s so close to
the cut line.
Now I’m not going to go through this in great detail. Just to show you that this
is kind of complicated if you look at how to interpret and this example is for
QuantiFERON Gold In-tube, how you interpret these tests because there are
multiple calculations that have to be made, and you have to look at these
different wells and the different responses.
So for example if we look at a positive, what’s a positive test for
QuantiFERON Gold in-tube, well first of all it’s got to be greater than or
equal to .35 units in the TB well - in the TB tube - and also that you’ve got to
have a - it’s got to be greater than 25% of the null response but then you have
to look at the nil well and that’s got to be less than or equal to eight and then
the mitogen response can be anything.
And so you’re looking at this and going wow, this is kind of crazy, how am I
going to figure this out? Well, the computerized software does that for you but
I just wanted to give you some idea of what’s involved in these calculations,
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kind of what’s under the hood and when you get this positive and negative
result.
However, as I talk about with the guidelines, you can’t ignore the actual
numbers because we’re still learning about these tests and actually knowing
what the numbers are, especially in people who have results which are close to
these cut-off points, is important in terms of potentially making clinical
decisions.
Although we don’t really understand that well enough, we think it’s really
important for people to capture that information so we do learn more about
what the actual quantitative numbers from these tests mean as we are very
careful about using quantitative numbers for this tuberculin skin test
induration.
Okay, so CDC guidelines. So in 2003, we published the original guidelines.
That was for the original QuantiFERON TB test and since that’s no longer
available, those are really irrelevant.
2005 we published the guidelines for the Gold QuantiFERON TB Gold test,
and those are the existing guidelines in print. But we have new tests and
there’s been a lot of information published since those 2005 guidelines so we
felt it was, and I think everyone would agree, that it was time to readdress this
question of how these tests should be used.
So in terms of the new guidelines, to begin with we wanted to focus on the
data from the two tests which have been improved since 2005 which were the
QuantiFERON Gold In-tube and the T-spot.
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We assembled a domestic and international expert complication panel which
was convened in August 2008 and the other issue is that we needed really to
coordinate with professional societies particularly American Thoracic Society,
Infectious Disease Society of America, American Academy of Pediatrics
because we didn’t want, you know, it’s confusing enough. We didn’t want
different organizations saying completely different things about how to use
these tests so we worked hard to harmonize what the guidance is from these
different organizations.
The draft by CDC staff were reviewed by our peer experts. We revised them
based on their feedback and the guidelines are actually at the MMWR
editorial office awaiting publication. They have been there for awhile, longer
than usual and we’re hoping that they will be published soon but I cannot as
of today give you an exact publication date.
So when we look at the data, there were over 150 published articles that we
looked at. In the August consultation, we did have some unpublished data
presented which was also looked at, but in the guidelines you will only see
published articles used and cited as the evidence basis for the guidance.
So I’m just going to summarize briefly with data that we reviewed and our
interpretation of it. Understanding that there are still, you know, since that
time, there are always papers being published every week on this but we
haven’t really seen anything - well, there may be some nuances really has we
feel changed what we think and how we interpret these data in terms of use of
these tests.
So the first question is sensitivity of these tests and the problem that we
struggled with from the beginning is that there is no gold standard for
determining who has latent tuberculosis infection.
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So tendency has been to use TB disease as a surrogate and obviously that is
problematic for a number of reasons and the obvious one is that people with
TB disease are sick. They have a very different organism burden and so it’s
probably and I think there’s evidence to say that this is not really a great
surrogate for latent TB infection but it’s kind of what we have and so that’s
what’s been used in most of the studies.
So when you look at that, I would say our interpretation was that overall these
tests need to be comparable. Now I’m going to cautiously say that there is
somewhat of a trend for increased sensitivity with T-spot; however, I think
you need to be very careful with that because this is limited by a really lack of
good, large head-to-head comparison trials.
So this can be very biased by the fact that if you have one study which only
looks at T-spot and one study that only looks at QuantiFERON, the
populations may be so different that it’s really not fair to compare the
sensitivity so I think you need to be very careful with that.
And just looking at the data that we looked at at the time, if you look at
different studies and different types of studies, if you look at studies where
you just had QuantiFERON Gold In-tube only, the sensitivity - again this is
for TB disease - was about 82%, T-spot alone 93%, studies which compared
tuberculin skin test and QuantiFERON Gold In-tube, you had 89% for TST,
83% for QuantiFERON Gold In-tube.
TST versus T-spot, you can see they’re both about the same 91% and very
limited data on studies which had all three tests. Actually TST was quite
sensitive overall, QuantiFERON Gold a little less, and T-spot in-between. But
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just again, you need to be very careful because it doesn’t make sense that for
example TST sensitivity should vary quite a bit and it does in these studies.
It’s because you’re looking at different populations so unless you’re - only in
these studies which really compare all tests in the same population - I think
can you really get a fair idea of comparison. You have to be careful about
making comparisons using data from different studies but we had to go with
what existed.
But nevertheless, we don’t think there’s a huge difference between
sensitivities. Specificity, same problem. No Gold standard so what do you
use? Well, generally you measure the results in persons with low or no
identifiable for M. tuberculosis infection.
But if you look at these studies, there’s quite a variation in the population
from study to study and again, being very cautious about this, we thought
there was somewhat of a trend towards increased specificity with
QuantiFERON Gold In-tube but you had the same problem of not having a lot
of large head-to-head comparison studies. And in fact certainly at the time,
and I really don’t think there’s been a lot more - there’s been at least one
larger study, there really were very limited specificity data on T-spot at the
time.
So again if we looked at kind of the pool data -- and this is not a formal meta
analysis so you have to also interpret this with caution -- that if you look at
studies where the tuberculin skin test was compared to QuantiFERON Gold
In-tube, you use that QuantiFERON Gold In-tube was quite specific, 99%
compared to the skin test which was only 84%. And when you look at T-spot
versus tuberculin skin test, they were fairly comparable, about just under 90%.
But again, because of the lack of head-to-head comparisons, we really didn’t
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feel we could say there’s actually clear differences between the IGRAs at this
point.
So what about special situations and populations that we’re interested in?
Well, let’s start with contact investigations. So, if you look at the studies done
in close contacts of patients with tuberculosis, what you tend to see is that the
exposure characteristics associated with increased risk of infection tend to
correlate better with IGRAs than they do with the TST.
And the types of things I’m talking about in terms of these characteristics that
are associated with infection would be the duration of exposure to the
infectious patient, the infectiousness of the patient, the things that are kind of
surrogates for the likely that the people who are in close proximity are going
to get infected.
Where this really I think this difference really becomes the most obvious, and
clear-cut, is if you look in contacts who have been BCG vaccinated and based
on what I’ve told you. I think that’s what you would expect since we know
that BCG shouldn’t be an issue with the IGRAs but it does have potential for
the TST.
Children, this is a difficult one. Fortunately they’re a lot more data are being
published but we still relative to adults we have limitations with the amount of
data that we have to review for children, especially young children, those who
are less than five years old. So, some of the studies tend to show an increased
percentage of indeterminate results in young children. All of you who are in
pediatrics know, it’s more difficult to draw blood from very young kids.
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It’s more difficult to confirm the diagnosis of TB disease in children, so all
these things make it much more difficult to do these studies, and have caused
limitations in interpretation of the data.
But really, what we refer to as the million-dollar question or I guess in current
economic times maybe the billion or trillion-dollar question, is which test is
the best at predicting who will get future TB disease? That’s what we really
are interested in. And at the time and there’s not been a lot that’s come out
since then, there were just a very limited number of studies that looked at this
question. So there were two studies in particular, one that was done in
Germany in close contact with TB patients, another one done in Austria which
in HIV-infected persons. And both of these suggested that QuantiFERON
Gold In-tube was better at the TST at predicting future TB disease. However,
there are really a lot of cautions. The number of TB cases that there were any
studies was quite small, and because the number of these cases was quite
small, the confidence intervals even though the actual raw data said that they
QuantiFERON Gold was better, statistically you’d be hard-pressed to say that
was a strong finding because you were very limited by this small number of
TB cases and there was overlap so it’s theoretically possible that it was not
really statistically significant in terms of the ability to predict TB disease.
Now there’s another study from the Netherlands which found actually that a
tuberculin skin test with 10-millimeter cut-off was actually better than
QuantiFERON Gold or T-spot at predicting TB in immigrant contacts. But
they had a similar problem. They only had nine cases of TB and not all of
these differences were statistically significant so you had these first two
studies which showed IGRA was better, this other study which showed TST
was better. None of them are really large enough to make us feel confident
about it and so I think this is really an open question.
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Finally I’ll just mention a study which was done in Gambia which showed no
difference between the Elispot assay and this Elispot assay is not the
commercial T-spot but very similar. You have to understand that that’s
another limitation and there’s no difference between that assay and TST in
predicting future TB so really mixed results without a really clear answer to
this question which is an extremely important question.
Another important group that we’re always concerned about are immunocompromised patients. It doesn’t appear to be that there’s significant
difference in the number of positive QFT Gold In-tube and TST results in
HIV-infected. You get similar results in terms of percentages of people who
will test positive. Of course there’s still discordance so even though you may
get 20% of people testing positive to Gold In-tube and 20% testing positive
TST, they’re not the same people, and so there’s always discordance, and it’s
often high in these studies when you look at immuno-compromised
populations.
Indeterminate results tend to be associated with a low CD-4 count for QFT
Gold N-tube. When you look at T-spot, there is a tendency to see more
positive test results for T-spot across these different types of immunocompromised populations. And overall I would say there’s more
inconsistency in the study results when you look in these different populations
so this area is one that’s very difficult to interpret exactly with certainty
whether one test is better than the other.
A population that’s important in the U.S. are healthcare workers because there
are a lot of them and generally they’ll require at least a baseline screening for
TB. The problem with periodic screening is that we really need to understand
more about test variation over time with some of these assays, so if you look
at some of the studies that have been done, you see that the interferon gamma
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response varies in people over time. And the thing that we don’t really know
about is what magnitude of change in a result is really caused by a new
infection versus just variation in the test over time. Because one day your
immune response may be somewhat different from three weeks from now
depending on various things, if you’ve got a cold or a viral infection or
various other things that can affect your immune response.
So it really raises questions about what the significance of conversions (going
from a negative to a positive) and reversions (going from a positive to a
negative) which occur especially when the initial test result is near these
cutoff points for these tests. Are these really conversions or is this just natural
variation in the test?
There’s a possibility that certainly as we have decided what a conversion is
now since we haven’t really developed other criteria that’s simply going, if
you just say a conversion is simply going from a negative to a positive, you
may get more false positives because of the less-stringent criteria that are used
compared to a TST. We’ve got a pretty high bar for the tuberculin skin test.
You need to have a change of at least 10 millimeters. If we don’t set the bar
quite as high for IGRAs, is it possible you’ll actually see more false
conversions because you have a lower bar in terms of the amount of change
you need. This is a question which I think is open to discussion and we really
don’t know the answer to that.
So another question obviously faces health departments and hospitals and
anyone else who wants to consider using these tests is what about cost? I think
you’re going to hear some examples from the speakers who follow me about
what their experience is and I think that will be very helpful. From our
perspective looking for really a large evidence base, we were not able to find
really good cost-effectiveness data. If you look at some of the studies that
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have been done, the non-U.S. studies, and they have suggested for example
that if you limited IGRAs to testing of persons who are only TST positive,
that that’s actually the most cost-effective strategy. But it turns out that that
really depends on the population that you’re testing and it can vary quite a bit
depending on whether you’re dealing with foreign-born people who are likely
to be infected, or a low-risk people, so there are a lot of assumptions that go
into these. It’s not clear to us how they would affect applying this to a hospital
which generally deals with low-risk people.
What we do know is that the cost of IGRA materials is greater than the TST
but that can easily be offset by labor costs or the fact that you get fewer
positive test results so you don’t have to worry about following-up as many
people.
So let me just quickly go through the provisional recommendations as they
stand and hopefully will be published shortly. So number 1 is that the skin test
or IGRAs are used and should be used as aids in diagnosing infections with
tuberculosis. And we really encourage as with the skin test that you have a
qualitative test result, you know, positive or negative or indeterminate
borderline but also that you do maintain the quantitative assay measurements.
Because for people where there’s uncertainty, these quantitative
measurements over time we may learn a lot more about how to use the
quantitative measurements just as we learned about using quantitative
measurements for tuberculin skin test.
As with the TST, you should not be testing people who are at low risk for
infection and a low risk for disease. So don’t test people who don’t need to be
tested, because you’re going to end up in many cases with quandries about
what to do when you get positive results so really reserve these tests for
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people who you think are likely to be infected, or are really at risk to have TB
disease.
You need to decide what to do in terms of what is the context of your testing,
what is your situation, so select the most suitable test or the combination of
tests for detection. It really should be based on what are the reasons that
you’re testing, what’s the context, how easily available it is and what is the
cost for you because the cost is going to vary. I mean, like with many other
things, the cost may vary from setting to setting so these are all the things that
you need to keep in mind when you decide which test you’re going to choose
for a specific population.
So IGRAs we say may be used in place of - not in addition to - the TST. In all
situations in which CDC recommends tuberculin skin testing as an aid to
diagnosing TB with some of the preferences and special considerations which
I’m going to talk about, okay. So the general rule is they are used in place of,
not in addition. I’m going to talk about some potential exceptions to that and
the other thing is despite the fact that I’m going to talk about some
preferences, we think it’s still appropriate to use an alternative test. It’s still
acceptable and it’s still considered good medical practice, even if you don’t
use what we consider the preferred test, if you have good reason to use the
alternative tests and cost and availability may play into that.
So what are the populations and situations in which we think IGRAs are
preferred? One I think that would be obvious to most people is people who
you know historically have poor rates of return for TST readings. You really
run the problem because you spend a lot of time and effort trying to get these
people back and most people are negative and so you waste a lot of effort on
people of negative tests so it could be really cost-ineffective in these groups to
use TST.
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So in this case, IGRAs really are a nice advantage because you only need to
get the blood - get the test results - and if it’s negative, you don’t need to
really spend a lot of time worrying about chasing after these people. Also I
think the data clearly and people who have received BCG, there is, you know,
BCG is a vaccine for cancer therapy, you see an advantage because of the lack
of cross-reactivity of the antigens using IGRAs so that’s a second population
that we think the IGRAs are preferred which is if you’ve had BCG
vaccination or for cancer therapy.
The situation where we think the TST is preferred is testing children younger
than five years old and the major considerations there are we still think we
need some more data and there are issues, logistical issues, I think with
getting enough blood which can be a problem in some of these very young
children.
Populations, since we really can’t that there’s a preference, recent contacts of
persons with infectious tuberculosis or for periodic screening that occurs in
occupational settings such as with healthcare workers. We really couldn’t say
based on the data that you could strongly say you prefer to do one or the other.
Either one would be equally acceptable.
So I also said that we don’t recommend using both tests, generally stick with
one or the other; however, there are two situations where you may consider
doing there sequentially. So if you’re really worried about someone being at
risk for tuberculosis infection, you really want to be certain whether this
person, you know, if this person is not infected, you may decide to do both
tests. You do one, if it’s negative then you move on to the other. If they’re
both negative you say I’m happy this person is not infected. If either one is
positive, then you’re going to say well, I’m so concerned about the risk of
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infecting this person, I will accept that if either one is positive it’s positive and
I’m going to treat them. So in groups where the risk of infection, the risk of
progression and the risk of poor outcomes from TB is so high that you’re
really concerned, you may think about doing both tests on a case-by-case
basis, in a sequential manner. Similarly if you’re using this as an aid to
diagnose TB disease then understand these are not tests to rule out TB disease.
You cannot rule out TB or your TB infection based on one or both tests, but if
you think this would provide more information from you from a clinical
standpoint on making a decision, then doing those tests may be helpful.
Conversely, if you’re looking at the other situation where someone shows up
with a positive test result and they should have never been tested because they
really have no risk factors. This is a situation where doing a second test may
help you if you’ve decided unless they’re both positives, this person really
shouldn’t have been tested. Unless they’re both positive, I don’t really think
this person’s infected so I will take a negative test on either one to say I just
don’t think this person’s infected.
Conversely, having in some people who really should get LTBI treatment but
are reluctant, particularly people who have had BCG vaccination, let’s say
healthcare workers, who really won’t believe a skin test that’s positive,
confirming it with an IGRA in an individual person may help get you to
encourage you and reinforce the need for LTBI treatment.
So either people who are really low risk who have a positive result which you
really don’t believe or people who you - reinforcing the information with a
second positive result - these are two situations on a case-by-case basis, you
might consider both tests.
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Okay, the other thing is that repeating an IGRA or performing a TST may be
useful when the initial IGRA result is indeterminate, borderline or invalid.
You know, especially if you really think you need to get this test result, so you
get an indeterminate result, you can repeat the IGRA or you can consider
doing a skin test.
So each institution TB control program really needs to evaluate their situation,
decide what is likely to work best for them based on the populations that
they’re dealing with and then decide which test to use and prioritize. If
they’re going to use multiple tests, maybe they can only use limited IGRAs or
we would only use it in certain populations in their setting.
So it’s important to remember that a diagnosis of M. tuberculosis infection
and decisions about medical management and public health management
really need to look at the complete picture. You need to look at the epi
information, historical information, other test results. You can’t always base
everything on a single test or even these two tests, so you know that for
example, you could have a contact to a very infectious case. If that contact is
HIV-infected, low CD-4 count, so why if both tests are negative? They very
well could be negative and this person could be infected because they’re so
immuno-suppressed and their risk is so high that you just can’t base
everything on one test. You always need to consider all information available.
So, I want to close by talking about some of the needs for additional research
because I think as I’ve gone through this it’s been obvious that there’s still
some major questions that need to be answered and in the guidelines, there are
actually 16 research questions which we posed. I’m not going to go through
all of them but just a few of them to give you an idea of what we think some
of the important ones are. I already talked about what’s better at predicting
subsequent TB disease which is really a crucial question.
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Are the IGRAs better at predicting TB ultimately someone who get TB
disease? Are they better than the TST? Another big one, what change in an
IGRA is from negative to positive? What magnitude of change from a
quantitative standpoint is really indicative of new infection? What tests
variability? How long does it take for an IGRA to become positive after
infected? We really don’t know the answer to that question.
And we’re still having some questions about IGRA performance in children as
compared to adults, and why do we see this? What is really the reason for a lot
of the discordance we see and we don’t really have a great handle on why. If
you were to take some of these people into all four tests on them, you might
get two positive and two negative. It doesn’t make sense and why do we see
that? We need to have a better understanding. What are some of the possible
future directions thinking beyond the current tests?
So when I showed this slide at the beginning, I focused on interferon gamma
but if you remember from the slide, there are other cytokines that are involved
in immune response and do we know for certain that really interferon gamma
is the only one? Is that the one that we should be betting on? Well I mean,
there are good reasons why interferon gamma was chosen. It is very important
in the immune response to TB but as I show here, you have things like TNF-α
and IFN-γ. There are numerous others that potentially could be looked at so
another direction could be to look at other cytokine responses, not just
interferon gamma.
So tests implying cytokines other than interferon gamma, perhaps
combinations or some kind of cytokine profile. Maybe it’s really looking at
CNF alpha and interferon gamma, or some combination that gives you a better
answer.
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What about other antigens? There are very good reasons why ESAT-6, CFP10, TB 7.7 were chosen but there are many other TB antigens that are
potentially specific and maybe we need to look at other combinations of
antigens. And the other thing is that a lot of these tests is being done
manually and there are a lot of steps and so ways to do better automation may
actually help improve some of these tests.
Just to give you an example of the potential for doing these multiple cytokine
tests, they have these types of assays called Multiplex Bead-based Immuno
assays where you have different beads and each bead will have antibodies to a
different cytokine. So it could potentially allow you to detect three or four
cytokines in a person from one blood sample and you could actually have this
profile. Now I don’t know this will be better. It may not be any better at all
but it’s something that could be looked at to see if actually a profile of more
than one cytokine other than interferon gamma is actually better at answering
these questions than interferon gamma. So that’s one thing that I know a
number of people are interested in looking at.
Let me thank everyone, especially the TB controllers in the U.S., all the
professional organizations that work with us, there are other co-authors who
I’ve listed here from CDC on the guideline,s and the expert consultant panels
from August, which quite a few of, you know, you will recognize these names
as being really a wonderful group of national and international TB experts
who had input into this.
Thank you very much. I know we’re going to go into the next presentation
now so we’re holding questions until the end, so we can forget about that
slide. Thank you.
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Dave Ashkin:
Thank you very, very much. That was outstanding. Thank you so much.
Thanks, Phil. As Phil indicated, if it’s okay with you, we’d like to hold the
questions until after the next two presentations and then this way we can ask
our questions to a panel.
So first Phil, thank you very, very much and as promised, you did exactly
what I thought you were going to do which is really take a very complex
situation and really explain it so that somebody even as simple as me, very
simple, could understand and thank you.
What we’d like to do now if it’s okay is we’d like to actually take two
different public health perspectives and go over some experiences using these
tests in a practical manner and our first speaker is going to be Thomas Dobbs
and Tom is a District Health Officer with Public Health Districts 7 and 8 in
Mississippi and he works for the Mississippi State Department of Health and
he’s going to talk about some of his experiences using the QuantiFERON so
Tom thank you so much for joining us here today.
And for you guys, Tom speaks with a little Mississippi accent and for us
Northerners, I don’t understand a word. There’ll be an interpretation on the
bottom if you need it, you know?
Thomas Dobbs:
I’ll try to talk faster so you can understand it. I’m Thomas Dobbs from
Mississippi State Department of Health and I’d like to thank the Southeastern
National TB Center for having me. It’s been great and I’m going to talk really
about our experience with QuantiFERON and how we’ve integrated
QuantiFERON testing into public health practice in Mississippi.
Let’s get started and so just a quick background. Mississippi has a population
of about three million so we’re a lot smaller than New York City for the
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whole state. We had a TB case rate of approximately four per 100,000, 118 in
2008. We rank 15 overall in case rate. We rank number 2 in native-born case
rate. We don’t have much foreign-born disease. We have an additional four
and five suspects in 2008 and the majority of our acid fast that come through
our state lab likes to (atypicals) so we have a lot of NTM in our area and we
follow about 1800 LTBIs for that year.
There we go. We have 68% TB above African-Americans, 93.2% of cases are
U.S.-born, 14% are homeless and 15% are HIV-positive within this age range.
We have two different diagnostic tests we use for diagnosing latent
tuberculosis. Of course we’re using tuberculin skin testing but also too we’ve
incorporated QuantiFERON and right now we’re using the QuantiFERON
Gold In-tube assay for certain groups routinely through our state protocol for
actually for TB suspects who are using preferentially QuantiFERON testing.
We use it for HIV-positive individuals and a lot of that is because we’re a
rural state. We actually have a regionalization of HIV care and most people
don’t actually live in the town where they’re seen. We had a very low rate of
return for reading TB skin tests and so we’ve instituted QuantiFERON testing
for HIV-positives and we’ve had a marked increase in getting results back.
Also too we use QuantiFERON for those who may not return for a reading
and also those with prior BCG exposure.
Basically we used In-tube assay using the tube system. Each tube will
automatically fill to one cc. It has a preloaded vacuum so if you draw it, it will
draw to one cc without a problem. Basically we have our nil tube, our
positive control and our TB antigen and basically, if we have appropriate
controls and a negative TB antigen, it’s interpreted as a no TB exposure. And
then if we have the same appropriate controls and then a positive TB antigen
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tube which contains three different antigens mentioned above, we took that as
a positive TB exposure and then if we have inappropriate controls, we can
interpret either as an overactive immune system or underactive immune
system in a real basic sort of model.
However, the interpretation’s a little bit more complicated. There is a
relatively thorough algorithm that was designed to optimize performance
characteristics of the assay. And so it’s not quite so simple, but it’s become
quite apparent that it’s very important for us to have the actual ELISA values
available to us when interpreting this test, and some of this will be relevant
and you’ll understand why it’s important because a TB antigen of .8 or 4 is
very different and it may have severe implications for your management of the
patient.
So in 2008, we started using QuantiFERON Gold In-tube assay. We had tried
with QuantiFERON Gold initially but there were a lot of logistic problems
that really prevented us from implementing it, so our first year we did 554
specimens of which 20% were positive. Now a lot of these were actually TB
suspects and TB cases so that’s why you have such a large number, 77%
negative. We had 18 indeterminates, about half of which were known to be
HIV-negative and two were HIV-positive and the 14 culture-confirmed TB
cases that we did have QuantiFERON performed, 11 were QuantiFERONpositive, three were QuantiFERON-negative, consistent with published
studies.
One of the things that really good about Mississippi is we have a centralized
public health infrastructure. Each county has a county clinic and they all
answer to the state health department in Jackson.
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We also have an incubator in each county clinic and so each county can
incubate QuantiFERON through the In-tube assay on-site. They draw the
blood on-site. They incubate it overnight and then they will transport through
an in-state courier system that goes through every day and does night
deliveries into Jackson where they do two to three runs per week on an
automated ELISA platform.
The other thing that’s been good about the state is we have an automated
platform that minimizes human error and the In-tube assay really is critical to
keep folks from not having to process the specimen for analysis.
The other thing is with the In-tube assay because of the new design, after it is
actually drawn, it can sit for 16 hours prior to incubation. But assay incubation
actually can sit for several days before you actually have to get it to the central
lab and I think I’ve got some things in here so we collect them at the county
health department, incubate them overnight, actually can centrifuge them onsite or we can centrifuge them at the central lab, you have three days.
We have an overnight courier and then after the specimens are processed,
they’re basically good for three days at room temperature, up to four weeks
refrigerated and maybe even up to eight weeks according to the package insert
and then for four months or longer if frozen to low temperatures.
So one of the rationale that we use either in Mississippi, well similar, and
probably not improved sensitivity versus TST, we also would like to use it for
its enhanced specificity versus NTM exposure and also too for BCGvaccinated folks. We don’t have a lot of BCG-vaccinated folks but we have
some. Single site visit is required which has been very important, objectivity
of readings. This is actually fairly important because most of our positive TST
reports that we get are from communities, not from people who are TB nurses
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or TB experts, but from people who do it periodically maybe at healthcare
screenings or for infection control at small hospitals maybe because there may
be some better correlations, exposure and risk of developing active disease
and also too, it may be cost-effective and we’ll look at some of the details of
that in our experience.
So clearly we have enhanced specificity versus TST for NTMs, particularly
MAC. We have a lot of MAC in our area. BCG, although we have few
foreign-born cases in Mississippi, we do have a large immigrant presence in
certain local industries and also too we have some military bases. We’ve had
some folks from Afghanistan and Iraq.
There’s kind of a soft body of evidence that supports the possibility that a lot
of your positive TB skin tests in the south may be due to MAC and NTMs in
low-risk folks, and this is just a study from a group that has actually a small
body of work using MAC sensitin which one of the things that MAC sensitin
is, it’s not standardized and so you have to take it with a grain of salt. But
basically one of the conclusions you can find is that the majority of folks,
healthcare workers who had a 5 to 14-millimeter PPD reaction were actually
not due to exposure to tuberculosis but were more likely due to MAC
exposures. And in our area, we do have a lot of MAC, and even in the state we
had a lot of Non-Tuberculosis Mycobacteria, but in my area specifically, we
actually have probably twice as much as the state overall as far as clinical
isolates of AFB’s.
And so what disadvantages do we have to worry about? Well, there’s a cost to
the lab program. We’ve tried to minimize that but it is considerably more
expensive to the lab compared to TST. There’s a logistics with blood draw,
transportation infrastructure but we’ve actually overcome a lot of those
barriers just because of the way our state is organized and also too, lack of
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experience with IGRAs actually has been quite a problem because it’s taken
awhile particularly for local physicians to get used to the proper way of using
it. But also too we have to worry about our judicious application of
resources. These are some of the county clinics in one of my districts and
they’re relatively small clinics and on some days, there’s only one nurse there,
particularly if one has been told to do something else. And they have a lot of
responsibilities from immunizations to helping pregnant women to a whole lot
of things and if they’re having to track down a bunch of LTBIs, which is
really the vast burden of work for our health department, they can’t get done
what they need to do specific to fit the community and their needs so we
really need to use our resources very judiciously.
So this whole next section entitled Primum Non Nocere, which we all know
means First Do No Harm and Bayes’ Theorem, because we’re in a low
incidence area for tuberculosis, you know, we’re testing a lot of people who
really are not going to have disease.
I take Isoniazid toxicity very seriously. I know it’s rare and it’s probably very
safe and certainly is effective. Real hepatitis is perhaps 20 per 1,000 persons
treated and rarely we see fatal hepatitis. But in Mississippi, we’ve had one
death in one liver transplant over the past four years from Isoniazid and so it’s
something that we take very seriously and I really don’t want to treat, as a
clinician, treat someone for latent tuberculosis if they really don’t have it.
So we want to take good care of these people not just from a population
perspective but also from an individual perspective. So one of the things that
we’ve done in my area is we’ve tried to use QuantiFERON in a limited way to
look at people who were low risk for actually having latent tuberculosis. And
a lot of these people as Dr. LoBue had mentioned before, people that we
shouldn’t have checked in the first place or maybe we checked because we’ve
got a system in place that automatically checks folks who really would not
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have otherwise been assessed. As an example, we have seen several people
who would go in to volunteer in a hospital to work in the gift shop and they
would all be tested and they would have positive skin tests. Based on a state
policy and other states have similar policies, anything over 10 millimeters is a
positive. Well, these are people that would not normally have been tested and
now they’re sent to our system to be treated for latent tuberculosis infection.
And we’ve identified quite a number of people who kind of fall into this
category so we wanted to look at folks who were TST-positive, low risk for
tuberculosis, were not at risk or increased risk for progression to disease and
we’ve performed QuantiFERON Gold In-tube testing on them and if they
were positive, we would treat them for latent tuberculosis infection. If they
were negative, then we would not treat them and we would monitor them so at
this point, we’ve identified 56 low-risk individuals in our area thus far with an
age range of 13 to 82 years of age, the majority African-Americans. Majority
were females and the female predominant tested mostly with healthcare and
nursing and people going into that field in our area. The TST range was five to
20 millimeters so there were some people who came out of that 10 to 14millimeter range that we were considering and most of them were health
sector screenings. There were some who were screened for adoption and
foster care. If you want to adopt a foster child at one of developmentally
disabled schools, you actually have to get a skin test, for nursing home
admissions and special circumstances, military, congregate settings, child
care, nursing school, etc.
And so one of the things that we discovered when we checked these folks, of
the 56, only seven were positive by QuantiFERON which was a lot lower than
I had anticipated, but really I’m cherry-picking a population that’s going to be
naturally low-risk for having a positive test. So we did treat these folks for
latent tuberculosis and I felt very good about it. I felt like I was doing the best
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thing for the patient and then we also identified another 48 who were negative
by QuantiFERON and then we had one who was indeterminate.
Not surprisingly when you broke it down by TB skin test, there was some
difference that actually is statistically significant that in the low range 10 to 14
millimeters, there were only 8% of people actually had a positive
QuantiFERON. In the higher TB skin test range which we think really is the
more specific skin test range, it was higher at 21% but still was not even half
of the folks who came in and we did have one person had a five-millimeter
skin test actually had a positive QuantiFERON and we did treat that person.
Funding issues, these are the cost breakdowns that we’ve done on internal
analysis of what it costs for us to treat folks for latent tuberculosis. TB skin
testing is about $4 including materials and applications. QuantiFERON is
$21. That’s pretty low when I talked to other folks but one of the things is
through volume and automation and we incorporated it into an ELISA
platform that we used for other things, it’s $21 a test so it’s really not that bad
and we batch them, too. This includes lab tech time, materials, transportation
and everything. The most expensive parts are X-rays which we did on all of
these folks, just based on the way that we do our TB controls. Isoniazid
treatment is not very expensive. Lab, actually our lab would be more than that
because I’m more compulsive about LFT orderings and our nursing time
actually $190 per nine months. Actually this is a little bit low because this
doesn’t account for people who have problems, people who have nausea or
elevated liver function.
And so when we look at that, the cost that it would have taken if we had just
followed the TST would have been about $24,000 for this cohort of folks. Our
cost was $14,000 but if you exclude the cost of the chest X-ray, actually
which primarily is placed on the patient or on their insurance provider, the
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total cost for QuantiFERON testing for this whole thing for all these patients
was about $2800 and saved us about $2000. I asked for that $10,000 in a raise
but they turned me down. But also too, when we follow these folks, in about
60 patient-years of follow-up so far, we haven’t had any development of that
disease. I’m going to knock on wood right here.
Also too we’ve used it in some outbreak settings. We’ve had periodic chicken
plant outbreaks or exposure in contact investigations we have to do in our
area. We recently had a 54-year-old gentleman who worked in a chicken plant
had cavitary pulmonary disease, 49 employment rated contacts. Instead of
using TB skin testing which we traditionally had done, we used
QuantiFERON. Chest Xrays were performed on those who had symptoms or
positive QuantiFERON. Of initial screening. It took a total of two days which
was very good. Usually it takes us a lot longer to get hold of everyone so it’s
a lot of shifts. We had people who had to work shift. We got all the employees
in a two days. Three nurses were required. One thing that we were surprised
about is 12 of the tubes did overdraw when we hooked it up on the automatic
vacuum. The Celestis folks told me that that was impossible but I told them to
bring extra tubes anyway in case it happened again so that was one thing we
just had to kind of watch out for. And so of the 49 folks, we had 8% positive
by QuantiFERON, 19 were foreign-born, a total of QuantiFERON cost was
$931 and our LTBI treatment costs were about $1000.
In comparison, we compared it to a 2005 chicken plant contact investigation
with the 21-year-old gentlemen with cavitary disease, 229 employees and they
used TB skin testing. Now these are a little bit apples and oranges. This
earlier chicken plant outbreak actually had more foreign-born individuals so
you can’t make dread comparisons and also obviously you can’t say one
person was particularly more infectious than the other but there were 229
screened. Twenty-seven percent were TST-positive, 52 were treated for latent
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tuberculosis infection that was either holdouts. 209, the majority were foreignborn and total LTBI treatment costs were about $11,000. We broke it down
by individual. You can see QuantiFERON we had an 8% positive rate in the
recent outbreak, 32% in the other but when you look at the cost, we tried to
break it down and see what was the cost to us for QuantiFERON versus TST
screening and final results and basically it was cost-neutral.
For the U.S.-born, it was about $19 a piece total cost and for the foreign-born,
it was slightly more for QuantiFERON but again, we’re talking apples and
oranges.
Also too we’ve had some anecdotal issues come through. We do have some
folks with BCG. Our experience is that in most of our foreign-born folks,
BCG have a very strong distrust of TST and the majority of them actually
refused LTBI treatment.
Two a one, the people that we’ve done QuantiFERON on that were positives
that had a positive TB skin test, they all agreed and were anxious to take LTBI
treatment because they believed it. They didn’t believe the TB skin test.
Also too we have seen some false positive QuantiFERONs in healthcare
screenings. We do have a large hospital that does about 3000 screening
QuantiFERONs in their health system every year.
We did have a pseudo-outbreak one summer where they had a baseline rate of
1% and this includes people who previously were known TST-positives and
also had a 9% one month. We went back and looked at them. A lot of them
were low-risk. We went back and repeated the QuantiFERON on a recollect
draw. Almost all of them were negative and we’re monitoring them but we did
not treat them.
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This is another situation where looking at the actual values was very important
because when we looked at the TB antigen result, we would see that it
actually was very low. They would just be barely above the cutoff value for
positive interpretation and so we’ve kind of noticed anyone who has TB total
antigen readout of less than one, these were folks that were questionable. And
all of these folks actually on recheck were negative and we’re talking about
people who have a positive mitogen of greater than 10 and maybe a null
control of 0.35 and then a TB antigen of 0.7 so they’re really close to the nil
and just above the cutoff. We also had some initial skepticism by our public
health nurses. In TB control we’re kind of wedded to tradition a little bit and
can be kind of slow to embrace technology but we’ve had rapid acceptance
from our nursing staffs and our professionals and now there’s a lot of
preference because they’re seeing some of the benefits. It’s not a panacea. It’s
a useful tool. You got to take it with a grain of salt because some of the things
- it’s just a test. It’s not perfect and if it doesn’t make sense, we don’t need to
kind of hang all of our decisions on it.
And that is all that I have and I would like to thank you all very much for
letting me be here and share our experience in Mississippi.
Dave Ashkin:
Tom, that was outstanding. Thank you very, very much. That was fantastic.
That was great. Thank you. Now for all you guys on the West Coast because
who knows what Tom said just now, we actually have notes, no. Mike
Stacey’s coming here and he’s going to talk to us about his experience with
the T-Spot.
Mike is the Deputy Health Officer and TB Controller for Solano County in
California. Mike came all the way from the West Coast to the East Coast to
join us. Right now Mike’s coming to us about four in the morning and no, but
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Mike I can’t thank you enough for being here and thank you for sharing your
experience. Thanks a lot, Mike.
Mike Stacey:
Yeah, good morning or good afternoon. I’m happy to be here and thanks to
the Southeastern National TB Center for putting together this webinar and for
inviting me to speak with you.
Again, I’m from Solano County. We don’t know how to use computers in
Solano County.
Man:
The easiest way to do this is just click on this little icon right here.
Mike Stacey:
Okay. Great. So where is Solano County? Solano County is in the San
Francisco Bay area. We’re very close to San Francisco. Here’s a map and you
can see in red is Solano County and this little point here is San Francisco so
right in that area.
And I should say Solano County is a mid-sized county. We have about
425,000 residents. The county is very racially and socioeconomically diverse.
Our TB rate for 2009 was 5.3 per 100,000 which was actually very low and
much of the country saw drops in TB this year and we certainly did.
Our rate the previous year was 7.6 per 100,000 and the year before that it was
actually in the eights. We have two public health clinics and we have a public
health laboratory which performs a whole spectrum of TB testing including
interferon gamma release assay testing.
In our lab, I have chose the T-Spot and today I’m going to talk about my
experience with that test and although it’s not really time to throw out the skin
test altogether, the skin test still continues to, and probably will for quite some
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time, have a lot of uses. There are some definite advantages to using the
IGRA test and some of the advantages that I’ve seen are really this mistrust of
TST readings that’s been talked about, particularly in some populations from
countries where BCG vaccination is used.
IGRA testing only requires one visit which is a huge advantage. TST readings
are often very subjective - thank you - and TSTs do not perform very well in
certain high-risk groups. So this is an issue of sensitivity really among certain
populations and TSTs are known to affect BCG vaccination results and BCGvaccinated subjects, we know that TSTs are not very reliable or you get a lot
of false positive results and that finishes specificity in that population.
So I’m going to focus mostly on these latter two points and specific why I
chose to implement IGRAs into Solano County. I did this about a year and a
half ago and because as I mentioned before in Solano County, we have a
number of foreign-born residents and many of these are BCG-vaccinated. We
have two public health clinics and our public health clinics really serve as a
safety net for a lot of people that have a lot of medical risk for TB. And in
addition to our regular primary care clinics, we have HIV clinics and also
within our county we have two large state prisons and these are both
populations at high risk for TB.
The FDA clinical trial for T-spot, one of the things I found really encouraging,
was that they included many patients from the ATS-CDC risk factors that are
listed in the guidelines from the American Thoracic Society and CDC joint
guidelines. And among other things, those included HIV-infected patients,
children, diabetics and patients from congregate settings or subjects from
congregate settings and that included prisons.
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When and what they did in this part of the study basically was compare rates
of TB-positive to TST-positive responses and their findings in that study was
that there was not an association between T-spot-positive and immunocompromised status. And they also found that the T-spot was not impacted by
age although also within the FDA, they did state that there was not enough
studies done in children and the test was - there was a limitation placed on the
test for use in children - as with all IGRAs at this point.
There have been several studies that again with lack of head-to-head studies
we have to take with some caution the results but there have been several
studies that have demonstrated that T-spot is a very sensitive test. And it is
thought that this sensitivity comes from the step of washing and counting a
standardized number of personal blood mononuclear cells. And this is
something that is done for every single test or each test is run essentially with
250,000 peripheral blood nuclear cells which is thought to correct somewhat
for patients with lower immune function because you’re actually not just
running the test on whole blood and may be a factor in increasing specificity
of the test.
And along with that to go along with that point is really that the level of TSTs
or the results of TSTs don’t appear to be affected by CD-4 levels so this again
is thought to be a factor of this isolating the 250,000 peripheral blood
mononuclear cells. One study that was done recently and there have been
other studies that have demonstrated this is that the first white columns here
are T-spot results. They compared to QuantiFERON and TSTs with cutoffs at
15, 10 and five millimeters found that the T-spot results were consistent
across levels of different CD-4 levels. So at levels of less than 100, 100 to
250, greater than 250 and then in the healthy control population. Some of the
limitations of the study were that in the very low CD-4 levels, there were only
10 patients.
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So in Solano County, we have implemented the T-spot into our HIV clinics.
We currently do not have sufficient data to do a meaningful analysis of the
data with the HIV patients but I can say however that we have had more
positives using the T-spot in this population than we did with TST.
Another thing that we have found in our limited experience is that sometimes
more blood is needed in this population. So instead of drawing one tube, you
may need to draw two tubes of blood and that’s really again thought to be
because you need enough blood to get this standardized number of 250,000
purple blood mononuclear cells to run the test.
In the future, I would like to also implement the test for newly-diagnosed
diabetics and also for rheumatology patients who are before they start TNF-α
blocking agent.
So one question that I often get because of the possibility and the studies that
showed this high sensitivity of T-spot is that is the high sensitivity of this test
coming at the expense of low specificity. And my answer to that question
really is I don’t think so and the reason for that is again some of these
complications in determining specificity. Doing specificity studies as Dr.
LoBue also mentioned is complicated because you’re basing this test on
finding a very low-risk population that is determined not to have TB but of
course whenever you do that, you don’t really know because latent TB
infection is a silent infection whether or not the people are really infected with
TB.
I do think that some of the studies that have been done in these groups have
identified possibly low-risk populations but not the low-risk risk populations
and so when you do that, if you’re not identifying the low-risk or at-risk
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population and you get a positive result, that’s going to affect the test
measurement of specificity. Because the right answer when you’re doing
those tests is to have a negative test because you’re presuming that all of those
people are negative and the percentage of people that have a negative test is
determined to be that test specificity.
Although there’s lacking data for really head-to-head analysis - there was a
recent large study in a truly low-risk population that were recent Navy boot
camp graduates and this was a large study, larger than most of the other
studies that included 326 subjects. And when this group was tested, they were
tested as part of screening just having come out of Navy boot camp, they were
graduates. The specificity of the test was found to be 98.9% and with a 95%
confidence interval at 96.9 to 99.8. And this is consistent with the test results
that were found in the FDA clinical trial and also with other studies that have
been done in truly low-risk populations but again, what we really need in this
data are more head-to-head studies done of these tests in the same large
populations that are truly low-risk populations. And one other point is that if
you’re doing these studies in not truly low-risk populations, the test that
would be the most sensitive may actually suffer in that sort of a study because
it would be more likely to find any underlying LTBI that might be in that
population.
Now the biggest way that the T-spot has affected my practice really is in the
BCG-vaccinated people. In our county, we get a lot of patients who are
coming from countries where BCG vaccination is done. And what I’ve done
is looked at the data of our children that have immigrated to Solano County
with BCG vaccinations and the number of patients that I looked at with this
was 104 and I found that of those that came in BCG vaccination and then
repeating a T-spot on these patients, 69% of them had a negative T-spot.
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And that’s huge - and the cutoff for that TST is generally 10 millimeters and
69% of those patients with 10 millimeter or more readings on their T-spot
were found to have negative T-spot - with their 10 millimeters or more on
their skin tests - were found to have negative T-spot. And that is a huge
impact to the way we’ve typically practiced medicine. Their recommendations
in the past have been with skin testing that you ignore the BCG vaccination
history and go with the skin testing result. But we can see and I can see
specifically in my population that there are a large number of these patients
who are likely not latent TB infection and to see if that really made sense,
what I did is broke these groups also down into age group. So of the patients
from 0 to 4 years old, 5 to 9 years old, 10 to 14 years old and 15 to 17 years
old, I found that there was an increasing amount of positive T-spots and that
the pink area here is a positive T-spot and the blue area here is negative. So
we see increasing positive T-spots with increasing age which makes sense
because as we increase with age, you’re more likely to actually have been
infected with TB. The other thing that I was able to tell with this data was that
larger TST responses were associated with positive T-spot so the data made
sense to me as far as that goes.
And one of the big questions always is what is the cost of the test and is it
really cost-effective. And it’s difficult to put actual numbers on this, but I can
say that savings that we do see are increased latent TB treatment as we find
less and less people that we need to treat, we’re saving on the cost of that
treatment. We’re seeing a decreased progression. If the test is trusted more
which I also find anecdotally people are more likely to believe the blood test,
where more people are actually going to complete their treatment and then we
may actually be decreasing the progression of latent TB infection to active
TB.
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And one visit for testing is a huge labor savings as well. We all know that
with skin testing, it’s often times very difficult to get that person to come back
for reading. And if you don’t, it’s even more difficult to get them to come
back to do the test again, so some of the costs involved are that the per-test is
more expensive than the skin testing and lab implementation can be a burden
as well. Any lab that’s trying to implement a test is going to have some costs
involved with that and they may be hesitant to do it and there is some - since
the tests have some manual steps as well - there’s a labor cost to the lab as
well. One thing that you can do is with Oxford immuno tech, they have a
diagnostics lab located in Massachusetts and specimens can be sent there. It’s
basically sent there through FedEx on the same day that you draw the
specimen.
So in conclusion, T-spot has really been an excellent test for us. The benefits
in - we do see benefits - in using the test in high-risk patient groups, such as
our HIV clinics, although again what we really need to know is this, what are
the long-term outcomes of these patients? So although we’re using the test in
these patient groups, we have to interpret the results with caution because we
really do need longitudinal studies to determine the predictive value of
interferon gamma release assays.
There has also been significant reductions in latent TB diagnosis and
treatment for individuals with BCG vaccinations, and that’s been a huge
benefit for us. And the cost savings, they still really need to be quantified with
cost-effectiveness analysis, and those are very difficult to do because some of
the costs associated with TB treatment and TB diagnosis are very difficult to
quantify.
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But I’m currently doing that for our program to determine how much we
potentially are saving with using the interferon gamma release assay and
specifically T-spot in our county.
And I guess it will be time for actually taking questions so my content is over.
Dave Ashkin:
Thank you very, very much. Thank you very, very much. We really appreciate
it. What I’d like to do now first is we’re going to start taking questions so first
of all, let me just go over the procedures for taking questions but if the three
speakers can join me up here on the stage, that’d be great. But if you guys
remember, there’s a couple of different ways to ask questions. First my
audience that are present here at Holley, please raise your hand. That’s always
a difficult thing and what will happen is somebody will bring a mike to you
and please ask the question.
Remember, please speak into mic. I know we feel uncomfortable about that
but the advantage of that is this way our guests on the webinar can hear us.
For those of you on the phone, if you’d like to ask a question, if you just ask
the operator and tell them that you want to ask a question, we’ll put you on
live.
For those of you on Web you can either - if you’re on the phone - please just
ask the operator or you can type in the question and we will be able to answer
it here.
And right now what I’m going to do is I’m going to allow the operator to give
instructions to our speakers - I mean to our participants - so you guys know
exactly how to ask the questions. Operator, are you there?
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Operator:
Yes. Thank you. Ladies and gentlemen, if you’d like to register a question,
please press the 1 followed by the 4 on your telephone. You will hear a threetone prompt to acknowledge your request. Your line will then be accessed
from the conference to obtain information. If your question has been answered
and you’d like to withdraw your registration, please press the 1 followed by
the 3. If you are using a speakerphone, please lift your handset before
entering your request. One moment please for the first question.
Dave Ashkin:
Well, thank you very much, operator. I appreciate that very much. Our first,
you know, as part of our tradition here at Holley, I always get to ask the first
question so if it’s okay with you Phil, I’m going to ask you.
One of the questions that always comes for us, it was early on there was
always this issue of when do you do the skin test, when you do the IGRA, like
there was always this issue if you did them too close together, was there a
possibility to get false results.
Would you be kind enough to comment on that as far as what is the proper
timing, so go ahead, please, Phil. Come on, you don’t have the lapel on - guys,
I screwed that up.
Phil LoBue:
So that’s a really good question because let me start with the easy part. The
easy part is that IGRAs do not boost IGRAs because you’re just drawing
blood from someone so if you do serial IGRA testing, there’s no issue with
that. But there is concern and there are some data suggest that so the skin test
may affect an IGRA result. I think it’s still somewhat controversial but it is
possible and so if you were going to - ideally - if you’re doing both tests, you
would draw the blood for the IGRA first.
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But sometimes that may not actually be - there may be issues with that because suppose that you for some reason you’re doing skin testing as your
primary test and for some reason you wanted to follow it up with an IGRA
result - so then how long do you wait before you can say that there would be
no effect of the skin test on the IGRA and that’s also a difficult question. I
mean I think that there’s some feeling that maybe a couple of weeks or so out
and probably lose the effect, but I don’t think you can say definitively.
Dave Ashkin:
Right, because that’s what usually happens to us. Somebody comes - as we’ll
talk about in a second - but somebody comes to you with a positive skin test
and now you’re stuck. You want to do the IGRA and the question always
comes out when, I mean, you know, we always in the beginning when we first
started hearing about it, I think we all fretted about it, but I think one of the
statements that all of us have made is that this is only a test. And you have to
take the results of that test in context of the whole patient and we have not
seen at least we can’t prove it again because one of the biggest problems is
there’s no Gold standard. You really don’t know who’s truly infected with
tuberculosis but clinically, it seems that with time, that’s become less of an
issue. I remember when this was first coming out, we were debating and that’s
why I asked that question.
I guess if I can do one more and then I’m going to just switch over but the
other thing that I think is kind of always important is that you don’t think
about it, the diagnosis of TB infections is the smallest part actually. The real
thing is once we have somebody who is infected with TB, do they take their
meds? Do they complete their meds and something I think all three of you
have talked about and I was wondering is, you know, something that’s always
interested me is that does the IGRA influence compliance?
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And the instant part is is that the gut that I have is that people who believe in
the test will actually take their meds. You know, but (unintelligible) to the
best of your knowledge, are there any of you - has there been a study that
patients who have a positive IGRA complete INH or complete their LTBIs
more than patients with a positive skin test because that’s the bottom line.
That’s the most important thing we need to know. It may not be that important
if the test is accurate. The question is if you have a group that’s a high risk, do
they complete because that’s the bottom line. Are we going to prevent
infection? Do you know of any tests with adherence?
Phil LoBue:
Let me say a few things. One is anecdotally I have heard both. I’ve heard
people who say in my experience, the people who have IGRAs are much more
likely to believe them especially if you’re going foreign-born healthcare but
BCG, they will believe the IGRA, they won’t believe the skin test. I’ve also
heard other people’s experience say it doesn’t make a difference. no matter
what you must have - it doesn’t make a difference - they won’t take the meds.
In terms of published studies, I’m not sure all these have been published. I’m
aware of three. What I know isn’t published because it’s still ongoing so
actually we’re doing a study in healthcare workers. The main aim in that
study is to look at serial testing and what happens over time. We just test
variability but part of the study is does this make you more likely to - do you
like this test better? Are you more likely to take it so we don’t know the
results of that yet. That’ll probably be the biggest study because it’s 2500
healthcare workers and that may help. There are two others that I’m aware of
and I don’t know whether they’ve been published or not and my recollection
is they have conflicting results. One where the people were positively
influenced by the IGRA results and preferred it, the other one where they
didn’t so I don’t think we have an answer to that question. You intuitively
would think yes, but I don’t know that there’s good evidence base to say
definitively.
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Dave Ashkin:
And it seems most of the population, you know, like again, I think a lot of my
bias is in the healthcare workers where it’s truly hard to get them to believe
the tests in the first place. You know as healthcare workers, we’re all
skeptical, you know, and we’re also by nature for the most part folks are
pretty non-adherent. So the bottom line comes down to in healthcare workers I
think especially foreign-born healthcare workers, I think where there was
really this lack of trust of the TST because in many countries, they don’t give
TST and they’ve been told when they got the BCG, the skin test is always
going to be positive. Don’t bother getting it. That’s what they go into this test
believing and I guess the results would vary I guess by the population I test
but thank you very, very much.
There’s a flip side to that argument and I think it’s not just the patient’s
compliance, it’s the provider’s compliance because if I have somebody who’s
got a positive QuantiFERON, I may be more compelled to push them and not
cut them off at INH if they have side effects or switch them to rifampin or
something like that. And my nurses too may have stronger buy-in and I
started seeing that is in my nurses if they have somebody that has
QuantiFERON they say hey, this person, we really need to address it with
them and they’ll hound them more so there’s a lot of interplay that goes just
beyond the patient’s acceptance but also our acceptance.
Phil LoBue:
I totally agree with you, you know.
Dave Ashkin:
You know what I’d like to do is we have some questions on the Web I’d like
to turn to so the first question is from (Yvette) and she’s asking us regarding
BCG vaccinations, is the TST contra-indicated? And she goes on to say I’ve
read that a severe reaction can slough off and require surgery. Is this correct
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and should anyone that reports having had the BCG vaccine avoid a skin test?
Any of you like to go ahead?
Phil LoBue:
No, that’s really - you can see people who have had prior positive - if a
person’s had a severe reaction to the skin test initially, I would not give
another skin test but just because they’ve had BCG vaccination, that’s not a
contra-indication. You wouldn’t expect to see that.
Dave Ashkin:
I agree and you know but going back to this whole thing of compliance again,
I’ve heard a lot of patients who have had the BCG who may have had the skin
test before say I’m not taking another one and that is maybe another role again
but I think we agree that it’s not a contra-indication.
But the second question we have on the Web is from Kay and she’s asking do
live virus vaccines affect the IGRA test results? Also, because interferon
gamma levels can vary over time, can you comment on the IGRA conversion
after LTBI treatment, so I guess the question is after somebody’s treated, what
happens to IGRA. So Phil, you’re on again.
Phil LoBue:
Two excellent questions. I think the answer to both is we don’t know with
certainty. Our approach though has been to for IGRAs is to use the same
approach we do with TST in terms of live virus vaccines because it’s an
immunologically-based test. And it’s theoretically possible that the live virus
has a lot of the same issues in terms of their effects on immunologically-based
tests where there’s TST or interferon gamma release assays so we’ve used the
same strategy which is either you get the test at the time you give the vaccine
or you wait at least I think six weeks. The effect of treatment is a really
interesting question. There’s not I think there’s not as much data actually on
looking at LTBI treatment as actually people with TB disease and the ones the couple of studies - or at least one from India I know that’s well-
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documented is really interesting in that what they found was that about 70%
of the people were skin test positive - I’m sorry, IGRA positive - at the start of
their TB treatment and about 70% were positive at the end but the same 70%
so you had some people whose reactions went up, some who went down and
some who stayed the same. But there is at least theoretically reasons to think
that LTBI treatment as you eliminate the organism with LTBI treatment, it
definitely could affect the results but I think we don’t really have good
longitudinal data in a large enough population to answer that question but
theoretically it’s a concern.
Dave Ashkin:
Tom, you said that you did - did you have anything more to comment? I say
you kind of - okay, oh come on, this is...
((Crosstalk))
Dave Ashkin:
You’re way too laid back there. We got to rile him up. Hey, a guy like a
comment that somebody just wanted a clarification and I think Mike, this is
both you or actually Phil either one. It says just a comment on explaining the
null control in the T-spot, exactly what does it mean? And it says there, you
know, what I guess they’re getting at is the nil tube or well I guess really it
contains a cell culture medium, it contains the cells but I guess it’s missing the
antigen or it’s missing the - what do you call it - the antigen. Is that correct or
if we could just explain it? Go ahead.
Mike Stacey:
I mean, that’s essentially it - you shouldn’t see any reaction in the nil, so...
Dave Ashkin:
So it’s just actually the negative control.
Mike Stacey:
Or negative control, right.
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Dave Ashkin:
Just to make sure that the person just added their cells itself or not having a
high amount of positive and/or reactions, you know, without any antigen
added that you’re not seeing activated cells just naturally.
Mike Stacey:
Exactly, yes, so that’s all it is, really.
Dave Ashkin:
Okay. Actually just for a second, I think we have a question in the audience.
Dr. Kumar, hold on one second. I’m coming to you so go ahead so go ahead.
(Kumar):
Thank you. My question is finance. Is for the two of you. Did you have the
accounting departments or the state, was this test billable and the insurance
company with that? We do see some patients who don’t come to us who have
insurance so we were trying to see and we were very close to implementing I’m am actually by the way, I am from the Palm Beach County health
department - so I just wanted to see what your experience has been.
Thomas Dobbs:
For us it is billable and we can. Now we don’t have an infrastructure built-in
to do third-party except for Medicare and Medicaid. We actually do farm
some out though some doctors actually send people over and if they pay, we’ll
do it like as a service. It’s about 120 bucks I think is the Medicare
reimbursement so we clear about 100 bucks per test but most time we just do
it and lose money.
Woman:
(Unintelligible).
Mike Stacey:
Right and California, too, it’s covered in some but it’s not covered in children
or the immuno-suppressed or HIV-positive so that is - I mean, it’s a problem
as far as being able to get billed. We do bill for the tests but not in those two
populations because it’s not - the FDA approval for children is not there so we
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don’t get medi-cover reimbursement and there’s still some question about
immuno-suppressed and we still are not getting reimbursed for those.
Woman:
(Unintelligible).
Mike Stacey:
We’re not able to get reimbursed for that.
Dave Ashkin:
You know, one of the things that I think was a common theme that’s coming
out of this and I just want to comment on this is you know, it’s almost coming
out. It seems like, you know, listening to all three of you that we may be
coming to a point that we’re maybe using the right tests for the right
population. You know, like in the point they’re like, you know, Mike, I think
you made a great point in like those populations where traditionally we’ve
been somewhat skeptical that the TST may not be functioning as well as we
would like, you know, due to the immuno-suppression that the T-spot actually
may show some advance and again it’s a little early. And I think on the other
hand among healthcare workers where you really need a high - you’re really
looking for a low-risk population where we still support the test - that a test
with a higher specificity like potentially the QuantiFERON - not that I’m
saying the T-spot’s any different, maybe more. So do you think we’re coming
to just where as healthcare providers that we may have a variety of tests that
we’re picking the right test for the right situation, so what do you think about
that?
Mike Stacey:
Yeah, I mean I think you know, to sum it up you have essentially four
different tests. None of them is perfect but each has advantages and
disadvantages and they may very well be population-specific. I mean, that
does make it very difficult though from a health department standpoint or a
facility because you really practically are only going to be able to do one or
maybe two. And so one of the approaches we may have to take or look at is
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what are the most common types of people that we deal with, what’s the
majority of the people that we deal with and try to aim for that.
Dave Ashkin:
But in some ways you almost feel that you may want - while I agree that you
may have that maybe for your general - that you may want these other tests at
your availability for certain situations. And it may come a time -- and
obviously it’s way too early and I think we need a lot more information -where you’re actually picking different tests for the situation. And of that
same role if I may, we got a question here that says what testing would you
recommend for patients already on TNF-α inhibitors that were not screen prior
to find a treatment which is always an issue?
And then for what patients with indeterminate QuantiFERON results should
the test be repeated and if so, when should you repeat the test? Any of you
guys want to handle that one or first luckily you’re getting paid a little extra
for this one, right, or do you want their salary, like they got one?
Phil LoBue:
So TNF-α, there have been some limited studies done in them and they
variable, I mean, again I think is either a call. What you tend to see with the Tspot is you tend to see more positive test results. I don’t know whether that
actually - whether that means - those people are really infected or not without
a Gold standard. I don’t know. Does that mean it’s the better test? I don’t
know. I think at this point we would have to say we can’t say there’s a clear
preference. T-spot or QuantiFERON or a TST, I think we would consider any
one of those acceptable in that population.
Mike Stacey:
And really ideally you would be doing the test at the start of treatment but
even still in those patients, lots of times they’re on long-term steroid therapy
so I mean that affects it as well. So the T-spot, there have been some studies
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that have shown that the T-spot functions well in this population, again with
more positives.
Thomas Dobbs:
But clinically does the presence of a positive control make you feel better
using that than the TB skin test, even though there’s no data, would it make
you feel any better?
Phil LoBue:
You know, it’s a great question. I don’t know. You used to put a lot of
emphasis on anergy testing to the skin test and it turned out that wasn’t very
helpful.
I mean, there’s such a thing as selective anergy to PPD and it’s
theoretically possible you could deal with some of the same issues with these
tests so I don’t, theoretically it’s nice, but I don’t know if the evidence basis is
there to say that’s true. I think there was a second part to this question.
Dave Ashkin:
Don’t worry about it. I think Mike you had a...
Mike Stacey:
Would you repeat it?
Phil LoBue:
Would you - yeah, I think and I’ll ask my other two colleagues to comment on
this since it’s experience, because they could tell you. But from what we can
tell, that it’s actually quite useful to repeat indeterminate tests because very
frequently you will get a positive or negative result if you repeat it so it’s
worth repeating it. And you can do it whenever because one test result
doesn’t affect the other but I’m curious to hear their experience.
Mike Stacey:
Yeah, I mean, with T-spot what you end-up getting is basically a positive, a
negative or just borderline or the indeterminate is really an invalid test where
either you have a bunch of - not enough reaction in the mitogen plate - or
you’ve got to much in the nil plate. And those ones you should repeat because
the test result is not really valid. When you get the borderline result, this is
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something that’s been established with T-spot around this cutoff point.
They’ve determined a borderline zone which lets you know that it’s anywhere
from five to seven spots and when you get that I repeat it and see if I can get a
positive or a negative.
Thomas Dobbs:
It’s both, indeterminates go too, I think there’s a component for human error
in there because there’s some things particular to the In-tube if when you
shake the tube up, you have to shake it quite adequately for like the mitogen to
get adequate coverage within the plasma. And then if you shake it up and put
it down and wait some period of time before you put in the incubator, you
have to shake it again and so there’s little thing like this that if you mess up,
you’re not going to interpret properly so there’s a lot of things in there. And
actually almost every indeterminate I’ve repeated except for in severely
immuno-compromised person, they’ve all come back definitive as positive or
negative.
Dave Ashkin:
Okay. We’re getting a bunch of questions on the use of the IGRAs in
pregnancy and as you know, that’s always the population that especially here
in a lot of areas where we have a lot of foreign-born individuals where they’re
have positive pregnancy pre-natal care, they require a TST. And I was
wondering what you guys, we’re getting some questions about what’s the role
of the IGRAs maybe in this population?
Phil LoBue:
Yeah, I don’t think we have specific data that we could - but we don’t have a I mean, obviously pregnancy does affect immune system, etc., but there’s no
reason why I think it’s going to have more of an effect on IGRAs than the
TST and so we don’t have any reason to think that you shouldn’t use it. And
so for now, even though we don’t have a lot of data, we would say it’s used
the same as a TST.
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Dave Ashkin:
Right, you know, we’re getting a question here from Edna and she’s saying
one of the points which has been raised is that the TST IGRAs testing is really
not indicated in low-risk individuals. How would this be interpreted for nonpatient contact healthcare workers in a low-risk non-TB endemic area? The
CDC seems to indicate that anyone employed in a healthcare institution
should be tested. Is this accurate?
Phil LoBue:
So the - yes - so the guidelines say for healthcare workers, that they basically there are two classifications of facilities so the facilities which pretty much
have low risk, they don’t see TB patients. In that case, the only recognition is
that people get a baseline testing and assuming that no TB cases occur in that
institution, there’s no reason to do serial testing and either an IGRA or a TST
either one would be equally acceptable to use for that baseline testing.
The facilities which have kind of medium or moderate risk or those that do see
a certain number of TB patients and there you have serial testing which is
recommended and I think that again we say there’s no preference at this point
because you could make arguments for advantages and disadvantages of each.
I think there’s a lot less known about serial testing in IGRAs and again
because of the issue of what constitutes a conversion, I think it does make it
more difficult. I’m not saying you shouldn’t use IGRAs, but you need to
understand that was it really, you know, if you have a bunch of people whose
tests go from just below the cut point to just above the cut point, does that
mean you have to be concerned about there’s some undiagnosed TB case in
your office - I don’t know because I don’t know whether that’s really a
conversion or not.
Thomas Dobbs:
And I think there’s a policy issue too where policy doesn’t make
recommendations. Some accreditation standards for hospitals that shouldn’t
be testing people to test them and so we have people who come through that
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never should have been tested in the first place and so it’s not really making
translation into what we really should be practicing.
Phil LoBue:
The one other caution that I would say you got to be careful if you decide
you’re using one test and switching to another because you’re going to get
different results. So the one where you’re really - if for some reason you’re
using IGRAs and then you decide to switch to a TST - you’re going to see
likely more positive results but the opposite could happen too. I think you
have some good examples about particularly from Dr. Dobbs about we had
this institution where all of a sudden you’re seeing these positive IGRAs
where you don’t expect. You need to look carefully at the quantitative data
because we’ve seen some examples where there were some systematic issues,
probably you could be operator error, mixing up which tube or which well and
often you can actually tease that out if you look at the quantitative data
carefully. So with any of these tests, if you start seeing things that you don’t
expect, you really need to look at the results carefully.
Dave Ashkin:
You know, we’re running out of time, so I just want to kind of summarize a
bunch of questions that were asked. And I know Phil you kind of touched
upon it, but I think they’re asking for a little more clarification which there’s a
lot of questions about what happens to the IGRAs and I know you’ve already
touched with treatment for TB, treatment for LTBI, what happens over time
and I know you’ve kind of said we’ve had mixed. But I mean just to elaborate
on that, I mean, do you want to just talk about kind of any general like
statements that for the most part what is known?
Phil LoBue:
Okay, I mean, so part of the issue it’s hard without the data and I think we’re
really lacking the data especially in longitudinal measurement in LTBI. One
of the interesting things when we did - now understanding that this was the
first IGRA test, the QuantiFERON TB - which does not exist anymore but is
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clearly different from the others - but one of the things that we found, we
thought the greatest surrogate would be people who had had TB and had
completed treatment as being the best surrogate for LTBI when we did the
first study and it turned out that was not good and it was particularly bad for
IGRAs. The TST was great. About every one of those patients was TSTpositive but the QuantiFERON results, there were a lot of them that were
negative and so we were puzzled by that. And since then, the thinking has
been that when you eliminate the organism burden, you’re decreasing affecting the immune response - and you’re exposing antigen, and so that at
least theoretically, there’s a possibility that people who have received
treatment will not have the - their response will wane - and people who are
positive and infected, once they’re treated will be negative after treatment has
completed. Now I cannot say that definitively for LTBI treatment because I
don’t think the data are there to say that.
Dave Ashkin:
And interestingly enough, some of that data is actually out there. Dr.
Steadman now going back 20-30 years ago, you talked about people who
outlived their reaction and so you know that they had TB in their body for so
long and had it under control so long that there’s wasn’t enough T cells to
respond...
((Crosstalk))
Phil LoBue:
The data where people who were positive and there were contacts and their
infection was recent and they were treated with INH very quickly, where their
TSTs would revert when there were contacts who were treated very quickly,
we were guessing that you could get rid of even the TST response if you
killed the organisms and got rid of them quickly.
Dave Ashkin:
Well, I’m going to take - do we have any of the questions in the audience? I
have one more question and it’s from Jon Warkentin. If I don’t answer his
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question, you know, he’s the only person who has as long a hair as I do and he
always threatens me with haircuts and stuff. So Jon’s question and I’m going
to say this is specifically to you Phil. He writes in bold “for Phil” so we got to
get this so he says does the CDC plan to develop software for public health
labs and programs to aggregate both qualitative and quantitative IGRA results
for population-based TB surveillance?
Phil LoBue:
That’s a great idea. We don’t have plans to do that but it’s something I
certainly will bring back because I think that’s a really useful thing to do. I
think we’re thinking about some of the types of studies with our epidemiology
consortium about longitudinal studies and the type of thing that Jon is
suggesting might be the type of thing that would fit well into that.
Dave Ashkin:
As a matter of fact, I think Jon should do it. You know, let’s put him to work,
right, but I agree. I think it’s great. It’s good - the only way - since we’re
doing this all over especially with computerization and stuff like that - we
have better ways not to really collect data and really be able to analyze it.
You know, the only problem getting into these, you may be able to, you know,
it’s always the apples and oranges like you were talking about but on the other
hand, it’s a great idea. Jon, get working on it.
Hey, I want to thank everybody so much specifically Phil, Michael, Tom, that
was outstanding. Thank you very, very much. I know there is a bunch of
questions we were unable to get to on the webinar.
As in the past and I’m looking at Donna right now, what will probably happen
is for you guys who asked those questions, we will give those to our speakers
to go home with on their plane ride and to come up with some answers, and
we’ll get that back to the people who asked. And I want to thank you all for
listening in and thank you for asking questions.
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We really, really appreciate it. I want to thank the SNTC for sponsoring this. I
want to thank the AHEC for providing CME and remember please for all you
guys here, please fill-out your evaluations so you can get your credits and for
you guys on the webinar, please follow the instructions on the screen so we
can get you those CME credits. We want to make sure that you get them.
As far as upcoming events, in South Carolina we have the TB program
manager’s course. We’re going to be - we also have the address - I’m sorry Arresting TB which is addressing TB in correctional settings. There’s two
locations in Mississippi and one of them I understand that they got you Dr.
Dobbs - or two of them they got you - so they may actually be able to
understand what you said there. No, I’m sorry. It’s that Dr. Dobbs is
conducting with Ellen Murray of the SNTC.
In June, we have the Comprehensive Clinical TB Course here at A.G. Holley
and Tom, nobody understands a word I say here either for that week but we’d
love if you guys if you can out there to join us. It’s a great four-day course
and then on the last day on Friday’s we have the TST train-the-trainer and in
July we have Grand Rounds coming up and we’re actually in the planning
stages and you’ll hear more about that real soon.
In one-half hour we’re going to be doing M&M here at A.G. Holley and we’d
love you guys to join us on the web. Please, what you’re going to have to do is
disconnect and if you go to the - I know some of you have been e-mailed the
link - please just link on. If you haven’t been e-mailed the link, if you go to
the SNTC’s home page, go there and then click on the M&M and you’ll be
linked-on to the M&M page and we’d love you to join. We have two
interesting cases.
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Well with that again, on behalf of all of us here at A.G. Holley, all with the
SNTC and my speakers, we really want to thank you very, very much for
joining us today. Have a great day. We’ll see you real soon. Thanks again.
Bye bye now.
END