So, tuberculosis. What's the epidemiology of tuberculosis? Well, 30% of the population of the world are infected with tuberculosis.
Fortunately, most of those patients have what we call as latent infection. That is, the bacteria is present in the body, but it's not causing active disease. Subtitles by the Amara.org community Of those 30% of the population of the world, it's estimated about 10% will actually have reactivated disease from that latent disease over a lifetime.
What that means is that the dormant bacteria start replicating and actually start to cause an infection. At any one time, there's about 10 million people across the world with active tuberculosis infection, and that causes deaths in about 10% of them. So we're talking 1 million deaths per year, and that makes tuberculosis the first or second commonest cause of bacterial infectious death across the globe. What's tuberculosis caused by? It's caused by the organism Mycobacterium tuberculosis.
Now this is quite an unusual bacteria. So unlike the bacteria that cause normal acute pneumonias, it's quite slow growing. It takes several weeks to culture in the laboratory. It has a very unusual cell wall full of lipid, and there is no environmental source. You cannot catch tuberculosis from the environment.
You catch it from somebody else who's already infected with the bacteria. There are a couple of subspecies of Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanus, and there's also the BCG. Now that is a Mycobacterium bovis that has been cultured in the laboratory and is now not pathogenic, doesn't cause disease or rarely causes disease.
And we use that as a vaccine to try and prevent M. tuberculosis infection. As I've already mentioned, there are environmental Mycobacteria which are related to M. tuberculosis. This is...
And these are called the non-tuberculous mycobacteria, and there's quite a large range of different species. And they can cause a similar disease to tuberculosis sometimes, but they are far outweighed by patients infected with M. tuberculosis.
So the pathogenesis of M. tuberculosis, like influenza A, requires being infected by somebody with active disease. So if somebody has active lung disease, with tuberculosis, they will cough, and in the cough, there will be infected droplets carrying the bacteria that can be inhaled by somebody else. Once the bacteria is inhaled, it goes into the lung, and there it actually invades your normal mechanism for protecting the lungs against bacterial infection, which are the alveolar macrophages. It actively seeks out and invades these macrophages because it's able to prevent the normal macrophage killing mechanisms.
So it diverts the normal fecal isoan pathways. and that allows it to survive in the macrophage and it can be latent in that macrophage for decades. In addition, the macrophages, because they move, will allow the bacterium to spread all across the body and this is one of the reasons why sites of immune function such as the lymph nodes often get infected with tuberculosis.
Long-term persistence within the macrophages is what latent disease is. In addition, there's a certain inflammatory response to this infection which causes a very distinctive histological appearance called granulomas. And that is one of the hallmarks of tuberculosis infection, is the presence of granulomas in the infected tissue. So, to talk about the disease, there's two main forms.
There's pulmonary tuberculosis, which is TB affecting the lungs, and there's extrapulmonary tuberculosis, which is TB affecting outside the lungs. Just to describe the pathogenesis in a bit more detail, what happens is you're in contact with somebody of open pulmonary tuberculosis, and what we mean by open pulmonary tuberculosis is that if you look at the patient's sputum, you will see the bacteria present when you stain it with a special stain called acid far-specialized stain. So their sputum AFB positive is the description that's used.
The tuberculosis reaches the lungs, invades the macrophages, but in fact... Quite a lot of the time, 50% of people, it will be killed and removed from the lungs and not cause any problems at all. In some people, it will actually start to cause primary disease or replicate enough to cause infection in the lung. And that's classically described as a gone focus, where you have a mid-zone patch of abnormal shadowing representing the replicating bacteria and the inflammatory response to that infection at that point.
In the middle, what we have is patients with latent disease. So the invasion of the macrophage does not lead on to active disease, but the bacteria becomes dormant and stays within the macrophage for a very long period of time. And in fact, if you're infected as a child, it is quite likely you have latent infection present at the point when you die, even if that may be 70, 80 years later.
So the majority of people will fall into the cleared infection or perhaps having a latent infection. So what can happen with the small minority with the active infection is that that can progress and it can progress to affect other parts of the body. So as well as having pulmonary tuberculosis, it can spread to affect the lymph nodes, the pleura, affect the brain with the TB meningitis and perhaps other parts of the body as well. With latent disease, over a long period of time, that may reactivate. And that occurs in about 10% of people with latent disease, as I've mentioned already.
And that reactivation is a situation that occurs more often than not. more likely to occur when immune surveillance is weakened against the bacteria. So as you get older, your immune response becomes weaker. If you are malnourished, then your immune response also becomes weaker. And that may allow the bacteria to reactivate.
And there are drugs that we can give people that may allow the reactivation as well. Corticosteroids, antitumor necrosis factor treatment. Specifically, it makes you much more likely to reactivate latent tuberculosis.
infection of HIV is a very important reason why people may get reactivated disease and is associated with quite a high proportion of cases of tuberculosis across the globe. A slightly unusual and the reason why this occurs is not known is that if you emigrate you actually also increase the risk of reactivated disease. So in the United Kingdom, for example, we have quite a lot of people emigrating from countries with high risk of tuberculosis who have latent disease.
And within four or five years of arriving, they frequently develop reactivated tuberculosis. So overall, if you look at the epidemiology of tuberculosis in the United Kingdom, the median age of diagnosis is in the mid-30s. There's a slight male preponderance, but essentially it's a disease that's split relatively equally between men and women. The chance of having infection is dictated by what happens as a child, whether you're likely to have developed latent infection or not.
And that is dictated by the prevalence of tuberculosis where you live. and therefore people who are brought up in countries with a high prevalence of people with open tuberculosis, and that's sub-Saharan Africa, the Indian subcontinent, and parts of the former USSR, then you are likely to have latent tuberculosis, much more likely to have latent tuberculosis, and therefore develop reactivation disease as you get older. The mid-risk countries are other Asian countries, the north parts of Africa, the Middle East, South and Central America.
In addition, People who are at the margins of society are also quite likely to get exposed to tuberculosis. The homeless, alcoholics, drug addicts, people who have been imprisoned. So this defines the patients most likely to have tuberculosis.
Where they were born and if they've been born in the West, whether they have the situation of being homeless or alcoholic or drug addiction. And that means the ethnic breakdown of people with tuberculosis in the United Kingdom is heavily biased towards people who were born abroad. And that's why 35% of people with tuberculosis in the United Kingdom are of South Asian origin.
And another 18% are from sub-Saharan Africa. With Caucasians only making up 25% of the population. So just to go over the risk factors of disease in a bit more detail, recent emigration as we discussed for some reason makes latent tuberculosis very likely to reactivate. Vitamin D deficiency has the same effect because vitamin D is an immune modulator and deficiency of that weakens your immune system protecting you against tuberculosis. The same for HIV infection, which is present in 8% of cases of tuberculosis.
And this problem of HIV allowing TB to reactivate or become a problem is actually before the patient has become heavily immunosuppressed. Smoking, diabetes. And the elderly being elderly are all examples where your immune system has been weakened to a degree and allows potentially the infection to take hold and cause a problem. We've already discussed homelessness, drug abuse and alcoholism. And there's the other immunosuppression, steroids after transplantation, tumour and necrosis factor treatment.
All these will make you more likely to reactivate latent disease. So the clinical manifestations of tuberculosis are lung alone, pulmonary, which is nearly half of people, a combination of lung plus outside of the lung disease, which is only about 10% of people, and then there's just extra pulmonary disease, disease that's not affecting the lungs, and that includes the mediastinal lymph nodes, because they're not actually part of the lung, they're in the mediastinum. and also includes pleural tuberculosis, because pleura, the infection is actually of the pleura itself. Again, that's not the lung parenchyma.
Now, an important distinction here is that infective disease are those patients with pulmonary disease, and all the extrapulmonary forms of tuberculosis are essentially not infective. You can see there's quite a big list of different sites that can be affected by extrapulmonary disease, and the frequency is given here as well. The commonest being nodes, lymph nodes. metastinal lymph nodes being the commonest sites. But it could be pleural, can have bone and spine disease, you can have myelocubic tuberculosis, which is a very specific form where the TB has been spread by the blood throughout the body, affecting mainly the lungs, the liver and the bone marrow.
Meningitis, which is a very serious form but relatively rare fortunately, and then the various parts of the abdomen can be affected as well. So the classic symptoms that somebody presenting with pulmonary tuberculosis is very simple, they cough. and they may cough with blood present in the sputum, haemoptysis.
And with that, they'll have systemic symptoms because it's an active infection, and these systemic symptoms are prolonged because the patient presents with several weeks, even several months'worth of history. So over that time, the patient's feeling ill, they're not eating, and they have fevers and night sweats, and they'll be losing weight as well. And that's very important for identifying somebody who may have active tuberculosis, the presence of the systemic symptoms.
Now the other areas within the thoracic cavity that may be affected are the mediastinal nodes, as we've mentioned, but really that doesn't normally cause symptoms of the nodes themselves, and is visible on the chest x-ray. And that sort of patient will present with the systemic symptoms, but no necessarily respiratory symptoms. And pleural disease, that causes an exudative pleural fusion, and that presents largely with breathlessness and the systemic symptoms that we've described already.
Now, if you have extrapulmonary disease, how you present depends on the site of the disease, clearly. So, cervical lymph node involvement is very common, and those patients will present with a lump palpable in the neck that they can feel or see themselves. That lump tends to be smooth, it's firm, it's not particularly hot.
If they have mediastinal or abdominal lymphadenopathy, then that will be identified by x-rays. Gastrointestinal disease will cause pain, bloating and ascites. Pericardial disease is caused by constrictive pericarditis and pericardial effusions.
Meningitis presents with chronic headache, focal neurology and eventually coma. And it's a very serious problem with a high mortality. And even if you do survive it, you're likely to have a neurological defect as well.
Millery TB I've mentioned is where you have blood-borne spread across the body and actually that's very difficult to diagnose because the patient has very few in the way of localizing symptoms they just have the systemic symptoms and weight loss but the chest x-ray is often characteristic showing very small nodules throughout both lungs if you have bone and joint TB that will present with a mass and pain of that bone or that joint that's been affected And if you have nodal TB and bone and joint TB, then what can happen is that the infection can penetrate through the skin and cause what we call a discharging sinus. We have a hole going into the infected area that oozes out fluid and tuberculous organisms can be seen in that fluid. So just to give you a couple of case histories to give a feel for what this disease, how this disease presents.
This first patient is a man from India. He's had three-month history of the systemic symptoms of weight loss and night sweats and feeling not very well. And with that, he's had a cough. And if you can see the chest X-ray, what you can see is biological apical disease here.
And there's cavitation present. And this is a very classical presentation for somebody with pulmonary tuberculosis. Systemic symptoms, cough, and a chest X-ray showing upper lobe changes with cavitation. And given the man...
was born in India, this is almost certainly going to be tuberculosis because he's from a high-risk group with a very classical presentation of what pulmonary tuberculosis looks like. And his sputum should show acid fast bacilli because this is a high bacillary load, high bacterial load disease. This is a different presentation. This is a Somalian who has moved to London and now is presenting with two months history of back pain and again systemic symptoms of sweat, feeling not very well, a bit of weight loss. Now the back pain is the localizing symptom for where the problem is and you can see this on this MRI scan.
There's an area of high density, high signal density occurring in the thoracic vertebra and in fact if you look closely there's destruction of the edges of those vertebra. and there's some soft tissue swaying around those bones. And you can also see that there's an angulation occurring there. And this is spinal TB, and the MRI appearances there are very classical for tuberculosis.
So again, we have somebody from a high-risk area, sub-Saharan Africa, so therefore has been exposed to tuberculosis as a child, quite likely to have been. Recent emigration, which is a risk factor. Systemic symptoms, which are very indicative of active inflammatory or infective disease.
tuberculosis being one of the common causes, and a characteristic radiology. So just to reiterate that, to recognize tuberculosis, really you need two things, systemic symptoms plus a high-risk group. So somebody who's got weight loss, fatigue, fever, sweat, who has been born in a high-risk country, sub-Saharan Africa, Asia, or is homeless.
intravenous drug abuser, alcoholic, has been in a prison, or is HIV positive. That combination, you must think about tuberculosis. And the localizing symptoms will help as well, because if somebody has classic localizing symptoms, that will also make the disease much more likely. A family history of exposure to tuberculosis is sort of helpful. If somebody says, yes, my aunt had TB when I was a child, then that means they're quite likely to have latent tuberculosis.
But we don't often get that history. How do we confirm the diagnosis? Well, frequently the diagnosis is clinical only. If you're in a developing world where you don't have access to investigations that we have in the industrialized countries, then you may have to rely on clinical diagnosis. Confirmed diagnosis requires seeing or culturing the bacteria in a sample from the patient.
And for lung disease, what we do is we send free morning sputums for culture and microscopy. For extrapulmonary disease, we may be able to get a sample. So for example, genital urinary disease, the urine might be positive. Meningitis, the CSF might be positive. But we often have to do biopsies of the affected tissue as well.
because that will give us an example for culture and also for looking histologically for the characteristic granulomas that I mentioned earlier. So microscopy, what we're looking for is acid fast bacilli. There's a special stain used for mycobacteria and if they're present they will be positive for that stain and show up on microscopy and that shows that there's a mycobacteria present in that sample and so 95 times out of 100 that mycobacteria will be tuberculosis although occasionally it is one of the non tuberculosis mycobacteria that I mentioned earlier in this talk. Culture is very important because it confirms that that mycobacterium present on us in microscopy is M. tuberculosis.
And more importantly, it gives you the resistance profile, whether that bacteria is a sensitive M. tuberculosis or resistant to some of the drugs that we might use to treat it. The big problem with culture is that it's slow.
It takes three to four weeks. So you're often left with a patient who has given a sample, no acid-phar specificity has been seen in it, and you're waiting now for the culture to occur. And you need to make a decision.
about whether the patient requires treatment for TB because you're really sure that they may have TB. For example, in one of the examples I showed earlier, the Bengali man, he would be treated before we got the culture results back, even if he was AFB negative in his sputum, because the clinical presentation was so clearly going to be tuberculosis. But if it's not clear, then you're just left waiting.
Patients with pulmonary tuberculosis, their sputum will be culture positive for the mycobacterium in 60 to 70% of cases at least. However, for extra pulmonary tuberculosis, the chance of culture being positive is not so high for some diseases. Nodal disease, lymph node disease, pleural tuberculosis and TB meningitis, the yield from culture is much lower.
Recently, there's a pulmonary chain reaction which has been developed, a test which has been developed which is useful for identifying tuberculosis much more rapidly than culture does. And that's actually positive even in patients who are not AFB positive. And that has improved our ability to rapidly recognize patients with tuberculosis. We also use biopsies to try and prove that tuberculosis is present.
Now, this is particularly important for extrapulmonary disease. And what the biopsy will show is the presence of granulomas, which is that very specific histological appearance that reflects the immunological response to the presence of a mycobacterium tuberculosis. And in fact, with TB, there are very specific granulomas which have a central area of necrosis, and that's called caseating granulomas. And we use biopsies of the pleura, abdominal disease, the lymph nodes, to confirm the patient may have extra-pulmonary tuberculosis. Now, the main differential diagnosis when you have histology showing granulomas is of sarcoid.
Now, in most clinical circumstances, TB and sarcoid are not easily confused. The main exception being the presence of mediastinal lymphadenopathy. The difference between sarcoid and tuberculosis is that the granulomas in sarcoid tend to be non-caseating, and clearly you won't grow the bacteria M.
tuberculosis from patients with sarcoidosis. We also use immunological testing, and what we use that for is to identify patients who've previously been exposed or infected with tuberculosis, and this therefore identifies latent infection. And we have two different methods for testing for that.
One is the HEAF test or MAN2 test, where we inject a mixture of tuberculosis antigens into the skin. And in patients who've previously been exposed to tuberculosis, that will stimulate an immunological reaction and a painful lump will form there. The other test is a more recently developed blood test, where essentially we do a very similar thing, is that you incubate the patient's blood with a tuberculous antigen, and you see whether the white cells have a response to that.
And those are called the interferon gamma release assays. Their main advantage is that they're not confounded by previous vaccination with BCG. So, for example, I have a reasonably strong MANTU reaction because I was vaccinated with BCG as a child. And that means it's very difficult to use that skin test to identify patients who may have been exposed to tuberculosis. if they've previously had BCG vaccination.
However, the interferon gamma release assay will only be positive in patients with previous tuberculous exposure and is not affected by the BCG. The treatment of tuberculosis is actually relatively straightforward. It requires antibiotics. However, it requires more than one antibiotic, and the standard therapy is four antibiotics.
And it requires antibiotics for a long period of time. The minimum treatment period is six months. And if you have central nervous system disease or bone disease, it often goes on for at least 12 months.
So we'll ask the patients to take four drugs for two months. and then two drugs for four months at least. And the actual dose that we give the patient is dictated by their weight, the split being 50 kilograms. If they're below 50 kilograms, they get a lower dose. If they're above 50 kilograms, they get a higher dose.
And the four drugs that we use are isoniazid, rifampicin. Those are the most effective drugs and the ones that are kept going for six months. And for the first two months, we give the patient pyrazinamide and ifampitol as well.
Ifampidol can affect the eyes and therefore we test the eyes before we start that drug. There are other things we may want to do. One is that actually with patients with brain involvement of tuberculosis or pericardial disease, we give them corticosteroids. And the reason why we do that is that tuberculosis, as it heals, is a very scarring infection.
So you get a lot of fibrosis occurring where tuberculosis has been. And in the brain, that causes neurological deficits. And we know that if patients are given corticosteroids, then the chance of having long-term brain damage is reduced.
And the same for pericardial disease. We worry about the development of constrictive pericarditis, and the chances of that are reduced by giving the patient oral corticosteroids as well as their TB therapy. A very, very important point is that the cases of tuberculosis need to be notified and what we mean by that is that they need to be brought to the attention of the authorities so that there can be a screening process of that patient's close contacts usually the family the people they live with but if it's a school child it will also be their school class as well And what happens there is that if a patient with TB is identified, then who they live with will be tested to see whether they have active tuberculosis or latent tuberculosis as well.
And by this method, we can identify the source by which a patient has been infected and whether they've actually infected somebody else as well. And this is very important for the control of the disease. And the testing that we use is this immunological response to infection, the HEAF testing or the IGRA, and a chest X-ray to look for active disease. There are major problems with treating tuberculosis.
The first we've already mentioned is that diagnosis can be slow if it's relying on culture, where in fact it takes six weeks before you know somebody doesn't have tuberculosis in a sample that's been sent for culture, and the positive growth usually occurs within three or four weeks. The second is compliance. You're asking somebody to take...
quite a lot of drugs for six months and they don't like doing that and in fact when patients feel better they often think they don't need to take the medication and they feel better within a few weeks of starting the medication and within two weeks they should be starting to feel considerably better than they have been feeling for weeks and often patients will say well actually I'm feeling better now I'll stop taking the tablets. The third is toxicity. The drugs that we use for tuberculosis, unfortunately, several of them are liver toxic, and they cause an inflammation of the liver with an increase in the liver enzyme results.
And that can prevent those treatments being used. So we have to monitor the liver function test, and if they go too high, we have to stop the therapy and then restart the therapy, trying to identify which one of the drugs was responsible for causing the liver toxicity. And that's a complex process and delays treatment considerably.
And the last is drug resistance. This is a problem if the patient is given single-agent therapy. So when we first developed therapies for tuberculosis in the 1950s, only one agent was available, and treatment with that led to patients developing resistance.
these very quickly and this is a problem so this is why we give the patient four drugs to start with it is to prevent resistance developing and if resistance is present to one agent if you give somebody four four drugs, then that will prevent that resistance increasing to affect the other drugs as well. If somebody has resistant disease, you suddenly have a problem in that the treatment has to go on for at least 12 months. You may be using second-line drugs which are less effective, and they need very close monitoring to ensure that they're improving and that they're compliant with the drugs that are being used. If you have extensive resistant disease, those organisms that are resistant to rifampicin and isoniazid, and several other drugs, then actually you can get a situation where tuberculosis is not treatable, and there's a very high mortality in those patients. So what's the outcome?
Well, if you have non-resistant tuberculosis of 100 cases, you'd expect 90-95% of patients will be cured. So it's a very good outcome in most patients. And people should not really die of tuberculosis, and that only really happens if they have resistant disease or if the diagnosis is made late because the patient presents very late.
Or they have the more severe forms, such as meningitis or mineral tuberculosis. There is a problem with TB, and that... Once you've had tuberculosis, it can cause a lot of lung damage. Now this normally happens in people who have not been treated quickly or effectively. So this is not a common complication in the West, but it is very common in people who are born abroad.
And the extensive lung tuberculosis will leave extensive lung fibrosis, and that can have quite marked complications. You get poor lung function because there will be extensive pleural thickening around the lung. And also there seems to be a degree of areas of obstruction associated with extensive tuberculosis. You can get cavities formed by the tuberculosis and those persist after the bug has been killed and the patient's healed of TB.
And those cavities have been colonized by fungi to cause a mysotoma and that might cause haemoptysis. And sometimes it causes major haemoptysis. And often in the areas of the lung which have been particularly affected by tuberculosis, you get bronchiectasis. And in my bronchiectasis clinic, about 5% of the patients had previous tuberculosis causing their disease, and they present with recurrent bacterial infections of the lung. So this is a chest X-ray of somebody who had tuberculosis when they were much younger, and you can see there's extensive scarring occurring on the left-hand side, and the left hemidiaphragm is raised halfway up the heart, and that reflects.
the fact that the left lung is much smaller than it should be. It's about half the volume of the right lung. And that's partly because of the scarring within the lung, but it's also because there's a layer of pleural thickening around the outside of the lung, gripping it, stopping it being able to expand.
In addition, the right lung has quite a lot of scarring in the apices, and if you do a CT scan, you'll see that there's quite a marked areas of bronchiectasis and occasional small cavity in that area as well. And this is a very classic situation that occurs with people who've had extensive pulmonary tuberculosis when they are younger and leads to chronic lung disease and this patient has respiratory failure as a consequence of this with type 2 respiratory failure even when he's well.