The Big 3: Tuberculosis Part 3
It's time for our third and final post on TB, or at least for the time being. Part one and part two are here if you haven't read them yet.
In my last post, we talked about the course of a tuberculosis infection. Now let's dig into how we've treated TB over our history.
Did collapsing someone's lungs work? The answer is that I don't know. I was unable to find modern commentary on it. But people did it until antibiotics became a thing.
The four core drugs of choice when combatting tuberculosis are isoniazid, rifampin, ethambutol,
and pyrazinamide. These are our first-line drugs, which means that they're the first things we try. Those four drugs are not our only drugs. There are a few others we mix in, and sometimes when they don't work as well as hoped we turn to our second-line pharmaceuticals. This post is already too long to single out the mechanism of action for each of these agents, but together they work to neutralize tuberculosis. In cohort, these medications prevent TB bacteria from maintaining their membranes, stop their division, and impair their metabolism. However, these have substantially more side effects than popping an aspirin.(5,13,15,17)
While taking TB drugs, it is not uncommon to experience anorexia, nausea or vomiting, and weakness or fatigue. People taking rifampin will find their body fluids turned orange, including their urine and tears. This can lead to permanent staining of contact lenses. Patients may also feel tingling, numbness, or burning around their hands or feet. Their bodies will bruise more easily, and they may experience blurred vision.(2)
Compared to the past when we collapsed people's lungs, these drugs are a step up. However, getting people to follow through with the full course of treatment is a problem. Just making sure patients take all of their antibiotics when they have strep throat is difficult, and now they have to commit to a nine-month regimen of intense, powerful drugs with nasty side effects. And remember, if they have a latent infection, they are not showing symptoms so this is a step down in quality of life for about a year. Not taking the right dosage and all of your medication can lead to drug resistant TB, a nasty subject we'll talk about in a few sections below. Due to the public health threat of tuberculosis, it is understandable that countries have a vested interest in their citizens completing treatment.
Here in the United States, some communities have a system called Direct Observed Therapy. What this means is that a health care provider comes to your house with the medication and watches you swallow them. DOT became a thing when US public health officials looked around the world and realized to their embarrassment that some of the poorest nations in the world had better TB treatment completion than the wealthiest country in the world. So we adopted similar programs. Mozambique and Tanzania kept their tuberculosis under control with methods similar to DOT at low cost until the AIDS crisis overwhelmed their public health systems.(8)
Now, there is a new form of TB test which has been in use now for a couple years. This is called an interferon-gamma release assay (IGRA). Unlike PPD, this is a blood test which directly checks if your immune system has encountered tuberculosis before. The test has fewer mistakes, and most importantly, will not give a false positive to someone who has received the BCG vaccine. The downside is that IGRA is very expensive, so from a fiscal policy standpoint, PPD is where it's at.(2)
In my last post, we talked about the course of a tuberculosis infection. Now let's dig into how we've treated TB over our history.
Treatment
Antiquity
A disease as old as tuberculosis has endured many treatment regimes over the centuries, some worse than others. Hippocrates prescribed milk, food, and exercise for his patients. The Roman physician Galen recommended fresh air and sea voyages in addition to the milk. It also appears that he and other doctors of his time advised that their patients eat wolf liver and drink elephant urine. Our ancestors treated their tuberculosis with bloodletting as well, which isn't a surprise because bloodletting is a terrible treatment that was used to treat everything back then. Other treatments included: inhaling smoke, licking limestone, consuming animal fat, and eating butter boiled with honey.(6)
In the Middle Ages, scrofula became known as "the King's Evil" because it was believed that it could be cured with the touch of a king.(6)
Sanatoriums
The sanatorium came into vogue in the 1800s. If you were rich, it was a luxury resort in the mountains and other pleasant, airy places believed to help people with their infection. There were also sanatoriums for the poor with less pleasant food and a greater resemblance to nursing homes or hospice centers. From a public health stand point, sanatoriums were a good way to remove your TB patients from the rest of society. There is some really interesting history behind these places, so sanatoriums will probably get a blog post at some point.
Pneumothorax
In the late 1800s, physicians noticed that tuberculosis patients whose lungs collapsed seemed to have a better prognosis. Some doctors began to wonder what if they collapse the lungs before TB could? An Italian physician came up with a procedure that did this and then filled the lungs with nitrogen. It seems to have been all the rage for a while, despite the risk of additional infections.(7)Did collapsing someone's lungs work? The answer is that I don't know. I was unable to find modern commentary on it. But people did it until antibiotics became a thing.
Modern Antibiotics
Tuberculosis is a tough, resilient organism from the primal mists of time. It is hard to kill these bacteria because of that thick fat layer. Even when we have modern day antibiotics, you're still facing nine months of drugs to clear the infection. And these aren't fun drugs.The four core drugs of choice when combatting tuberculosis are isoniazid, rifampin, ethambutol,
and pyrazinamide. These are our first-line drugs, which means that they're the first things we try. Those four drugs are not our only drugs. There are a few others we mix in, and sometimes when they don't work as well as hoped we turn to our second-line pharmaceuticals. This post is already too long to single out the mechanism of action for each of these agents, but together they work to neutralize tuberculosis. In cohort, these medications prevent TB bacteria from maintaining their membranes, stop their division, and impair their metabolism. However, these have substantially more side effects than popping an aspirin.(5,13,15,17)
While taking TB drugs, it is not uncommon to experience anorexia, nausea or vomiting, and weakness or fatigue. People taking rifampin will find their body fluids turned orange, including their urine and tears. This can lead to permanent staining of contact lenses. Patients may also feel tingling, numbness, or burning around their hands or feet. Their bodies will bruise more easily, and they may experience blurred vision.(2)
Compared to the past when we collapsed people's lungs, these drugs are a step up. However, getting people to follow through with the full course of treatment is a problem. Just making sure patients take all of their antibiotics when they have strep throat is difficult, and now they have to commit to a nine-month regimen of intense, powerful drugs with nasty side effects. And remember, if they have a latent infection, they are not showing symptoms so this is a step down in quality of life for about a year. Not taking the right dosage and all of your medication can lead to drug resistant TB, a nasty subject we'll talk about in a few sections below. Due to the public health threat of tuberculosis, it is understandable that countries have a vested interest in their citizens completing treatment.
Here in the United States, some communities have a system called Direct Observed Therapy. What this means is that a health care provider comes to your house with the medication and watches you swallow them. DOT became a thing when US public health officials looked around the world and realized to their embarrassment that some of the poorest nations in the world had better TB treatment completion than the wealthiest country in the world. So we adopted similar programs. Mozambique and Tanzania kept their tuberculosis under control with methods similar to DOT at low cost until the AIDS crisis overwhelmed their public health systems.(8)
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| Tuberculin skin test. Image credit to Greg Knobloch. Content provided by CDC/ Gabrielle Benenson. |
TB or not TB: Detection and Prevention
If you have ever worked or volunteered in a health care setting or served in the armed forces, you have received a purified protein derivative (PPD) test. There's a picture of it right above this section: they put a bubble in your arm, then they look at it a couple days later. The purpose of the test is not to see whether or not you have tuberculosis. What the test is actually doing is seeing if your immune system has ever been exposed to M. tuberculosis.
When they stick that needle in you, you are being injected with a protein called tuberculin. This is made by tuberculosis bacteria. If your immune system has ever been in contact with the bacteria, it will freak out and make the skin around the area swell and turn red. As soon as the health care provider sees this reaction, they will order a chest x-ray and a sputum test to confirm if you actually have TB. The chest x-ray is to see if you have any granulomas in your lungs, which would imply a latent infection. The sputum test is to see if you are producing live TB bacteria. If they find TB there, you are infectious.
In the United States and many other parts of the world, the tuberculin skin test is a major part of our detection system to find TB cases. I mentioned in my first post that there has been a vaccine for tuberculosis since the early 1900s. This is the BCG vaccine, which is made from Mycobacterium bovis, a cousin of M. tuberculosis that causes TB in cows. The vaccine is popular in other countries, particularly those with high rates of tuberculosis, but here in the US, we don't typically use it. Now I'm going to talk about why.
A vaccine primes your immune system to kill pathogens. If your immune system is ready to attack TB, it will also react with the tuberculin skin test. That means the test will give a false positive. From a public health stand point, we're left in a bit of an awkward either/or kind of situation. If everyone receives the BCG vaccine, the PPD test is useless.
So why doesn't everyone get the vaccine?
Well, the BCG vaccine provides about 80% protection against tuberculosis. That means that 20% of people who have received the vaccine will still be infected if they are exposed to the bacteria. That makes it just an okay vaccine. There are also different strains of the BCG vaccine because over time the cultures grown by different countries and manufacturing facilities have diverged. That makes efficacy variable. So from the viewpoint of the United States, the BCG vaccine is not worth it because our tuberculosis numbers are so low and PPD has been sufficient to detect cases. That doesn't mean we never use it though. The BCG vaccine is given to children in homes with endemic TB as well as healthcare workers working in high-risk facilities. Also, it appears that the BCG vaccine is a treatment for bladder cancer. Go figure.
When they stick that needle in you, you are being injected with a protein called tuberculin. This is made by tuberculosis bacteria. If your immune system has ever been in contact with the bacteria, it will freak out and make the skin around the area swell and turn red. As soon as the health care provider sees this reaction, they will order a chest x-ray and a sputum test to confirm if you actually have TB. The chest x-ray is to see if you have any granulomas in your lungs, which would imply a latent infection. The sputum test is to see if you are producing live TB bacteria. If they find TB there, you are infectious.
In the United States and many other parts of the world, the tuberculin skin test is a major part of our detection system to find TB cases. I mentioned in my first post that there has been a vaccine for tuberculosis since the early 1900s. This is the BCG vaccine, which is made from Mycobacterium bovis, a cousin of M. tuberculosis that causes TB in cows. The vaccine is popular in other countries, particularly those with high rates of tuberculosis, but here in the US, we don't typically use it. Now I'm going to talk about why.
A vaccine primes your immune system to kill pathogens. If your immune system is ready to attack TB, it will also react with the tuberculin skin test. That means the test will give a false positive. From a public health stand point, we're left in a bit of an awkward either/or kind of situation. If everyone receives the BCG vaccine, the PPD test is useless.
So why doesn't everyone get the vaccine?
Well, the BCG vaccine provides about 80% protection against tuberculosis. That means that 20% of people who have received the vaccine will still be infected if they are exposed to the bacteria. That makes it just an okay vaccine. There are also different strains of the BCG vaccine because over time the cultures grown by different countries and manufacturing facilities have diverged. That makes efficacy variable. So from the viewpoint of the United States, the BCG vaccine is not worth it because our tuberculosis numbers are so low and PPD has been sufficient to detect cases. That doesn't mean we never use it though. The BCG vaccine is given to children in homes with endemic TB as well as healthcare workers working in high-risk facilities. Also, it appears that the BCG vaccine is a treatment for bladder cancer. Go figure.
Now, there is a new form of TB test which has been in use now for a couple years. This is called an interferon-gamma release assay (IGRA). Unlike PPD, this is a blood test which directly checks if your immune system has encountered tuberculosis before. The test has fewer mistakes, and most importantly, will not give a false positive to someone who has received the BCG vaccine. The downside is that IGRA is very expensive, so from a fiscal policy standpoint, PPD is where it's at.(2)
Drug Resistance
The mechanisms for why and how bacteria develop drug resistance deserve their own post, so I'm leaving the full discussion of that topic alone for now. When we talk about drug resistant TB, the CDC has some definitions for the different types of drug resistance. And they're all acronyms because science loves acronyms. If you have a strain of tuberculosis that is resistant to isoniazid and rifampin, then it is Multidrug-Resistant TB (MDR TB). Then there is Extensively Drug-Resistant TB (XDR TB), which is very concerning. This strain has resistance to isoniazid and rifampin as well as some second-line drugs and other antibiotics.(2)
Remember what I just said about how long you need to take drugs and their side effects? This is one of those cases where, in the mind of the unfortunate person subjected to that battery of drugs, the treatment may be worse than the disease. So people stop taking the antibiotics, or they take less than they're supposed to. They may not even have a choice for continuing their treatment. What if there's a civil war going on? What if there's a natural disaster like a hurricane or some other circumstance that prevents TB patients from finishing the therapy? The problem is that there may still be tuberculosis present in their bodies, and since the treatment regimen was not completed, it can come back with resistance to what was used before.
Drug resistance is one of the greatest threats to modern medicine because eventually, we will run out of viable antibiotics. What happens when we don't have the magic drugs anymore? Well, hopefully, we won't go back to sipping elephant urine.
Drug resistance is one of the greatest threats to modern medicine because eventually, we will run out of viable antibiotics. What happens when we don't have the magic drugs anymore? Well, hopefully, we won't go back to sipping elephant urine.
TB and AIDS
Since AIDS is such a pressing health concern and changes the way other infectious diseases function, I'm hoping to have a little section like this in every disease post I make. HIV is actually going to be the next disease we talk about so we will delve into some of its nuances pretty soon. But for now, we can talk about the TB side of the AIDS crisis.
Tuberculosis is the number one killer of AIDS patients. Where before we saw a patient, methodical killer, when paired with HIV tuberculosis roars through the body. Remember, tuberculosis was on the decline until HIV became a major problem. This pair goes together like two pathogenic peas in a pod.
When you throw drug resistance into the mix, you have a rapid onset disease that is difficult to treat. If you have drug resistant tuberculosis, you need to figure out what that strain is resistant to. How do you do that? Take a sample, grow it in the lab, and run some tests. But tuberculosis is a slow growing bacteria. That means those lab tests take some time. And unfortunately, when it comes to AIDS patients, that might mean that by the time you figure out what drugs will work on the TB, the patient is dead.(8)
Tuberculosis is the number one killer of AIDS patients. Where before we saw a patient, methodical killer, when paired with HIV tuberculosis roars through the body. Remember, tuberculosis was on the decline until HIV became a major problem. This pair goes together like two pathogenic peas in a pod.
When you throw drug resistance into the mix, you have a rapid onset disease that is difficult to treat. If you have drug resistant tuberculosis, you need to figure out what that strain is resistant to. How do you do that? Take a sample, grow it in the lab, and run some tests. But tuberculosis is a slow growing bacteria. That means those lab tests take some time. And unfortunately, when it comes to AIDS patients, that might mean that by the time you figure out what drugs will work on the TB, the patient is dead.(8)
Closing Remarks
Tuberculosis has been one of the most persistent infectious diseases in our history. From the looks of things, it will continue to do so. Back in my first TB post, I talked about how many Western nations have negligible TB rates while other countries are being overwhelmed. The three nations with the greatest number of tuberculosis cases on the planet are China, Indonesia, and India. These three countries also have some of the largest populations on the planet.(14) Remember, TB spreads in the air and thrives in close, cramped quarters. These are nations with some of the largest, most crowded cities on the planet. Is it a surprise then that there are so many tuberculosis cases?
Large populations are not the only factor in a nation's TB burden. In the cases of China, India, and Indonesia, having such huge populations can obscure the fact that other, smaller nations have higher rates of tuberculosis. So who are some of the countries with the highest rates of tuberculosis infection and death? They are Angola, the Democratic Republic of the Congo, North Korea, Mozambique, South Africa, Lesotho, and other nations.(14) Some of these nations also have high numbers of HIV and AIDS cases, a weakness TB exploits. Many of these nations are some of the world's poorest, lacking the funds, medicine, and public health infrastructure to control a more and more drug-resistant tuberculosis. North Korea starves its people and funnels money into its nuclear program. Is it much of a surprise to see a high TB rate in their people?
When we talk about infectious disease, it is important that we don't merely write something like TB off as another country's problem. As per their name, infectious diseases spread. They will never remain one country's problem. TB is a global issue, and it remains a major concern for the United States and other nations with low (but rising) levels of tuberculosis cases. Remember, one-in-three are infected. TB will remain a problem for a long time.
You won't be seeing a new post for a bit as I do more research. Then, we will continue covering the Big Three and talk about HIV.
Sources
- Bos, KI et al. 2014. Pre-Columbian mycobacterial genomes reveal seals as a source of New World human tuberculosis. Nature 514(7523): 494-7.
- CDC. https://www.cdc.gov/tb/default.htm
- CDC. 1996. The Role of BCG Vaccine in the Prevention and Control of Tuberculosis in the United States. MMWR 45(RR-4)
- Deuteronomy 28:22.
- Forbes, M. et al. 1962. Mode of action of Ethambutol. J Bacteriol 84(5): 1099-1103.
- Frith, John. 2014. History of Tuberculosis. Part 1 - Phthisis, consumption and the White Plague. JMVH vol 22(2). Accessed 23 Aug 2017.
- Frith, John. 2014. History of Tuberculosis. Part 2 - the Sanatoria and the Discoveries of the Tubercle Bacilus. JMVH vol 22(2). Accessed 23 Aug 2017.
- Garrett, Laurie. 1994. The Coming Plague: Newly Emerging Diseases in a World Out of Balance. Harper Collins Canada Ltd.
- Gill, Wendy P et al. “A Replication Clock for Mycobacterium Tuberculosis.” Nature medicine 15.2 (2009): 211–214. PMC. Web. 23 Aug. 2017.
- Knechel, Nancy A. Tuberculosis: Pathophysiology, Clinical Features, and Diagnosis. Crit Care Nurse April 2009vol. 29 no. 2 34-43. Web. 28 Aug 2017.
- PV, Prasad. "General medicine in Atharvaveda with special reference to Yaksma (consumption/tuberculosis)." Bull Indian Inst Hist Med Hyderabad 32(1): 1-14. PMC. Web. 23 Aug. 2017.
- Smith, Issar. “Mycobacterium Tuberculosis Pathogenesis and Molecular Determinants of Virulence.” Clinical Microbiology Reviews 16.3 (2003): 463–496. PMC. Web. 23 Aug. 2017.
- Timmins, GS, Deretic, V. 2006. Mechanisms of action of isoniazid. Mol Microbiol 62(5): 1220-7.
- WHO. 2016. Global Tuberculosis Report.
- Wehril, W. 1983. Rifampin: mechanisms of action and resistance. Rev Infect Dis 5(3): S407-11.
- Wirth, Thierry et al. “Origin, Spread and Demography of the Mycobacterium Tuberculosis Complex.” Ed. Mark Achtman. PLoS Pathogens 4.9 (2008): e1000160. PMC. Web. 23 Aug. 2017.
- Zhang, Y. et al. 2014. Mechanisms of Pyrazinamide Action and Resistance. Microbiol Spectr 2(4): 1-12.
- Zink, Albert R. et al. “Characterization of Mycobacterium Tuberculosis Complex DNAs from Egyptian Mummies by Spoligotyping.” Journal of Clinical Microbiology 41.1 (2003): 359–367. PMC. Web. 23 Aug. 2017.
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