Voiceover: This is Charles Proburg.
Voiceover: And I'm Morgan Theiss.
Voiceover: And we're going to be talking about
the diagnosis of tuberculosis
and the reason that we're talking about
the diagnosis of tuberculosis is that it's,
as we've said before, a very important infection.
It's estimated that there are about 9 million
new cases of tuberculosis recognized, RECOGNIZED
each year around the world.
There's also estimated that there's another
3 million or so cases, about a third additional,
that are not diagnosed.
So our goal is to increase our diagnostic
abilities around TB.
The picture, the x-ray that's shown,
is from the Centers For Disease Control
and this was a patient who had pulmonary TB.
You can see the arrows pointing in the lung
to a round lesion, which appears like a cystic lesion
and this is actually a cavity.
So this is cavitary TB.
So, how would you start suspecting somebody
might have a pulmonary infection with TB?
Well, first of all, they would typically present
to the physician with symptoms, respiratory symptoms;
coughing, for example, shortness of breath,
inability to do exercise the way they used to do it before.
When they're coughing, they might be
coughing up sputum, which is of an odd color,
maybe yellow or green or oftentimes
the sputum has blood in it, so-called hemoptysis.
So, you would see such a patient.
You would think they have a pulmonary process.
You'd do a chest x-ray and this is what
you see on chest x-ray and then you, the astute clinician,
would say, "This might be TB."
So the first thing you then would do
is a tuberculin skin test, which is shown
in the picture of the skin, also from the CDC
and the arrows indicate, the arrows pointing
at the ruler, indicate that the area of swelling,
the area of induration with this TB skin test
is about 10 millimeters and that's
a positive reaction.
There's also surrounding redness,
but that doesn't count in terms of
measuring the size of the reaction.
So, we now have a person
whose got a positive chest x-ray,
consistent with tuberculosis
and a positive TB skin test and that suggests
that, "Gee, this might really be TB."
But the diagnosis is not made at that point.
One needs to then try to isolate,
to find the organism in the lung of the patient.
And what's done as a first step to that
is to obtain a sample of the patients sputum.
So, to induce them to cough up some of their sputum
and then to send that sputum to the laboratory.
And in the laboratory, the first thing that they will do
after you've told them you're suspecting TB,
is they will do a TB specific stain
looking for AFB, acid-fast bacilli.
There are several TB specific stains.
One, for example, is called the Ziehl–Neelsen stain,
which is abbreviated the ZN stain
and these are good staining techniques,
but they're not hugely sensitive
meaning that even when TB is present
the stain may only be positive about half of the time.
So, that's not good enough.
The next thing that the laboratory will do
is to take that specimen, actually whether it's
positive on a TB stain or negative
and set it up on culture media that facilitate the growth
of the tuberculous bacilli and there are some very
specific culture media that the laboratory
will use for that purpose.
The only problem with culture is that
it takes a while.
So, it takes 4-8 weeks for a culture to become positive
if TB is actually present, but it's important to do
because culture is much more sensitive,
much more reliable in detecting the TB
if it's present, than the stain was.
So, instead of 50%, it's more like 80%
and also, you need to grow the TB to confirm it's identity
and also test whether it's killed
by a variety of different antibiotics,
antibiotics directed against the TB
and that actually, that's called sensitivity testing,
meaning determining whether the particular
TB isolate is sensitive, is killed by,
different kinds of antibiotics.
Voiceover: Okay, and so this is often
a point of confusing because we're using sensitive
in two different ways.
So, when we say sensitivity testing here,
we're actually talking about how sensitive
is my patients tuberculosis bug to all the antibiotics
we have, right?
Voiceover: Exactly.
Voiceover: Okay and sensitive up here,
sensitive ... The sensitivity of a test
is just of all the people who actually have this disease,
how often are we going to get a positive test?
Voiceover: Exactly and a very important distinction
because it is the same word with very different meanings.
Voiceover: Right.
Voiceover: Thank you for that clarification.
Another test that can be done on the sputum
or the specimen from the patient is actually
molecular testing and a molecular test
that may be used is something called PCR,
Polymerase chain reaction, and this is
a laboratory based test that looks for some DNA
and then puts it through a process
that augments the amount of DNA present
in the laboratory, it does that.
So, if there's even a very small amount
of DNA present, this PCR test may be positive
and the advantages of this test are that it's quick,
results can be present in hours rather than in weeks,
in terms of saying that TB is present,
but the disadvantages are that, first of all,
it's expensive, it doesn't allow you to determine
the sensitivity, the antimicrobial sensitivity
to that particular organism
and you can have false positive reactions.
So, you can have a positive PCR
and actually TB really isn't there.
So, it's not routinely used, but under
special circumstances, PCR may be used.
There's a test, however, that is used
and endorsed by the World Health Organization
as being an important rapid diagnostic test
in the developing world and this test
is also based upon molecular techniques
in trying to detect the parts of the tuberculosis
and it's called the expert, meaning it's
an expert kind of test I suppose, MTB,
which stands for the micro-bacteria, tuberculosis.
Voiceover: Okay.
Voiceover: ... /RIF and RIF stands for rifampin,
which is one of the important drugs to treat tuberculosis.
And what this test does is it allows
the rapid detection of the presence of TB,
for example, in sputum.
Concomitantly, it allows one to determine
whether that TB that's present is rifampin resistant,
that's the RIF part.
Very important, again, especially in
the developing world.
Results may be present.
You may get results in, again, a few hours
like the PCR test, so it's actionable quickly.
The downside is that it really is quite expensive.
None the less, because of the World Health Organization
endorsement and it's wide deployment,
this test is now available in about two-thirds
of the countries where TB is of a very high burden,
where there is a lot of disease
and about half of the countries worldwide
where highly resistant TB is present.
So, it's been a very important, so-called point
of care test under those circumstances.
Voiceover: And so the advantage that the
Expert MTB/RIF has over just your regular PCR
is that it can actually figure out if the TB
in my patient has rifampin resistance or not?
Voiceover: Exactly.
Voiceover: Oh, that's good.
Voiceover: And if it is rifampin resistance,
when we talk about treatment, there needs to be
a modified therapeutic strategy.
Voiceover: Got it, so it's good to know that quickly.
Voiceover: Exactly.
So, there may be a circumstance where, on your table,
the chest x-ray is positive, but the tuberculin
skin test is negative and this may be because
the chest x-ray is not representing TB
or it may be that the skin test is falsely negative,
either because it's an overwhelming infection
and then the immune system may not be kicked in enough
to cause a positive skin test, or it may be
that it's so early in the infection
that the skin test is not yet converted.
So, if you're still suspecting TB
based upon the clinical presentation,
the positive chest x-ray, but the skin test
isn't positive, you still may want to go through
the diagnostic testing that we've spoken about.
Now, in the diagnostic testing, I've talked
about sputum all the way along.
I'd like to say one thing about children
who don't produce sputum typically.
Well, they produce it, but they immediately swallow it.
So, when trying to diagnose pulmonary infection,
lung infection caused by TB in children,
instead of using sputum, we often use gastric aspirates,
that is samples from the stomach,
typically obtained in the morning after
there's been a chance to collect a lot
of what might be coughed up from the lungs
and swallowed, so gastric aspirates are used
in place of the sputum.
And I also should say, in some patients,
you can't get a good sputum specimen.
They just don't produce it.
It may mean the infection is very distant
in the lung and for those patients, sometimes
doing a brochoscopy, putting a tube down into the lungs
to sample the fluid, is used as the specimen
to send to the laboratory to do the testing
we've spoken about.
Voiceover: Okay, and then just looking back
at this table here, what about the situation
where you have a positive skin test,
so I'm thinking TB is somewhere,
but then you actually have a negative chest x-ray.
What are you thinking there?
Voiceover: So, there's a couple of possibilities there.
The positive skin test will indicate a prior infection
and we know a third of the world is infected
with tuberculosis and the negative chest x-ray
may indicate that the patient doesn't have TB at all,
or at least doesn't have pulmonary TB,
but the patient may have TB somewhere else
other than in the chest.
So-called extra pulmonary TB.
So, if you have signs of infection outside of the chest,
for example, swollen lymph node or a problem
in the genital urinary tract, or the bones
and you're thinking TB as a possibility
then you may see that positive skin test,
negative chest x-ray and then your sampling
will not be sputum because they don't have anything
in their lungs as far as you know.
You may be sampling the lymph node if they have
swollen lymph nodes.
You may be sampling the bone if it's a suspected
bone infection.
You may be sampling the urine if you think
they've got infection that might involve
the genital urinary tract or there are other
body fluids that might be sampled.
They go through the same testing procedure
in the laboratory, but it's just a different
kind of fluid.
Voiceover: Okay, and then I guess,
just to complete all the possibilities here,
what about someone who, you're suspicious
they may have TB based on something clinical
and then they actually have a negative chest x-ray
and a negative skin test?
Voiceover: So, that's also an important circumstance
to recognize because TB is still possible
even though you've got those two negatives.
So a negative chest x-ray, again, may simply be
because their TB infection is not involving the lungs,
so it's a negative chest x-ray
and the negative skin test may be a false negative
skin test.
They may, in fact, have TB, but either
because the infection is overwhelming them,
including their immune system, or because it's very
early on in the infection and they haven't converted,
they may not have a positive test.
So, you still, you can't rule out TB on the basis
of both of those being negative
and if you have a clinical scenario
that still makes you think of TB and perhaps
they're a very high risk host, such as,
an immunodeficient host, for example,
somebody infected with HIV, you still may want
to pursue diagnostic testing even under
those circumstances.
The two terms that I'd like to finish with
and we haven't spoken about except when we talked about
antimicrobial sensitivity testing, or related
to sensitivity testing.
So, you check to see if the tuberculosis
is killed by the different drugs you want to use,
such as, INH and rifampin and so forth
and if the tuberculosis is sensitive to all of those
antibiotics, if it's killed by those antibiotics
then you're in good shape in terms of treatment,
but sometimes you will encounter strains
and they're becoming more common, where the bugs
are resistant to INH and rifampin.
Voiceover: Oh, dear.
Voiceover: And those are called MDR-TB
and MDR stands for multiple drug resistant
and then TB stands for tuberculosis.
And by definition, MDR-TB are resistant,
as I mentioned, to INH and rifampin.
And then you have to use different drugs
other than INH and rifampin to treat them.
Another term that is important to recognize
with regards to TB diagnosis in sensitivity testing
is x, little xDR-TB.
The x stands for extreme drug resistance,
the DR, drug resistance TB and these are strains
that are becoming more common,
especially in the developing world, so they
also are resistant to INH and rifampin,
like MDR-TB, but they're also resistant
to several other anti-tuberculous agents.
And it gets a little complicated,
but I'm going to say it because it's important
for people to know about these xDR-TB.
They're resistant to all of the fluoroquinolones,
which are a whole family of antibiotics, the quinolones.
So these xDR-TB are resistant to all of those
and they are resistant to one of, at least
one of, the following three antibiotics
that I'm going to mention.
One antibiotic is amikacin.
Another antibiotic is kanamycin.
Both amikacin and kanamycin
are so-called aminoglycosides.
And then the third one that they may
be resistant to is capreomycin.
So, again, these xDR-TB strains are resistant
to INH and rifampin.
They are resistant also to the fluoroquinolones
and they're resistant to one of the three
other drugs that is written.
Voiceover: And that sounds like a challenge
for treatment. (laughing)
Voiceover: Indeed it is and we'll come to that.
Voiceover: Okay.