Diagnosing active TB

this is Charles prober and I'm Morgan theis 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 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 but it's also estimated there's another three million or so cases about a third additional that are not diagnosed so our goal is to increase our diagnostic abilities around TB now 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 cavity TD so how would you how would you start suspecting somebody might have a pulmonary infection with t v-- well first of all they would typically present to the physician with symptoms respiratory symptoms coughing for example shortness of breath inability to do the 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 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 in the area of induration with this TB skin test is about 10 Melanie 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 who's got a positive chest x-ray consistent with tuberculosis and a positive TB skin test and that suggests that gee this really might be TD 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 patient's peuta 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 TV specific stains one for example is called the zeal Nielsen 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 TV 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 four to eight weeks for a culture to become positive if TB is actually present but it's important to do because culture is much more sense of much more reliable in detecting the TB if it's present then the stain was so instead of 50% it's more like 80% and also you need to grow the TB to confirm its identity and also test whether its 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 his sensitive is killed by different kinds of antibiotics 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 exactly and sensitive up here the 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 exactly and a very important distinction because it is the same word with very different meanings 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 per limb 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 in the laboratory 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 routine we used that under special circumstances PCR may be used there's a 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 bacterial tuberculosis okay / RI f & RI f stands for f Thampan 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 concomitant ly it allows you to want 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 nonetheless because of the World Health Organization endorsement and it's wide deployment this test is now available in about 2/3 of the countries where TB is of a very high burden where there's a lot of disease and about half of the countries worldwide we're highly resistant TB is present so it's been a very important so-called point-of-care test under those circumstances and so the advantage that the expert MTB rif has over just your regular PCR is that it can actually figure out if the if the TB and my patient has rifampin resistance or not exactly oh that's good and if it is rifampin resistance when we talk about treatment there needs to be a different there needs to be a modified therapeutic strategy get to know that quickly 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 maybe that it's so early in the infection that the skin test is not yet converted so if you're still suspecting key being 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 view them typically what were they produce immediately swallow it so when trying to diagnose pulmonary infection lung infection caused by TB and 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 that in some patients you can't get a good sputum specimen they just don't produce it maybe the infection is very distant in the lung and for those patients sometimes doing a bronchoscopy 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 Lee spoken about 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 test x-ray what are you thinking there so there's a couple of possibilities there the positive skin cast will indicate a prior infection and we know a third of 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 a swollen lymph node or a problem in the genital urinary tract or the bones and you're thinking TB is a possibility then you may see that positive skin test negative chest x-ray and then your sampling will not dispute them 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 suspect 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 their other body fluids it might be sampled they go through the same testing procedure in the laboratory but it's just a different kind of fluid 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 that clinical and then they actually have a negative test rate and chest x-ray and a negative skin test so that's also an important circumstance to recognize because TB is still possible even though you've got those two negatives so negative chest x-ray again may simply be because their TB infection is not involving the lung so it's a negative chest x-ray and the negative skin test may be a false negative skin test then they 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 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 are 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 that the two terms that I'd like to finish with that we haven't spoken about except when we talked about antimicrobial sensitivity testing are are 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 refampin and so forth and if the 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 this the bugs are resistant to inh and refampin and those are called MDR TB and MDR stands for multiple drug-resistant than in T V stands for tuberculosis and by definition MDR TB are resistant as I mentioned two inh and refampin and then you have to use different drugs other than inh and refampin to treat them another term that is important to recognize with regards to TB diagnosis in sensitivity testing is X little X BR 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 inh and refampin 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 floral quinolones which are a whole family of antibiotics of quinolones so these xdr-tb are resistant to all of those and they're resistant to one of at least one of the following three antibiotics that are gonna mention one antibiotic is Ana cases another antibiotic is kanamycin both amikacin and kanamycin are so-called aminoglycosides and then the third one that they may be resistant to is Caprio my son so again these xdr-tb strains are resistant to inh and refampin they're resistant also to the fluoroquinolones and they're resistant to one of the three other drugs that is written and that sounds like a challenge for treatment indeed it is and we'll come to that okay