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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.