Tuberculosis is a serious infectious disease that effects one in three people around the world. It's most commonly caused by a strain of bacteria called Mycobacterium tuberculosis. And even though tuberculosis can infect many parts of the body, most frequently it affects the lungs. Once a person becomes infected with Mycobacterium tuberculosis, the bacteria can stay dormant in the lungs for years before it reactivates and starts causing disease. As it did in the case of a 68-year-old grandmother, living in the township of Khayelitsha, outside of Capetown, South Africa. You were doing an elective rotation at a rural hospital near Khayelitsha when this grandmother brought her six-month-old grandson in after the child had suffered a seizure. The grandmother, Numbulelo, had been looking after this child since his mother died only a few months after he was born. At the hospital, you noticed that Numbulelo looked very sick herself. She tells one of the nurses that she's been suffering from prolonged coughing spells and that she's been coughing up blood. She also says that she's been sweating at night, feeling tired during the day and has had almost no appetite for food. To you, she looks very thin ,and when you take her temperature, she has a low-grade fever. So you tell the physician who's examining the baby that you suspect this grandmother has active pulmonary tuberculosis. Knowing this makes the physician suspect that this baby contracted TB meningitis from his grandmother. Who is now experiencing a reactivation of the TB infection in her lungs. When Numbulelo was a young woman, she lived in a shack with six other family members, one of whom later died of tuberculosis. Now during that time, she inhaled an infectious droplet coughed out by the sick relative. And because her immune system was strong, the macrophages in Numbulelo's lungs immediately began containing the infection. There are resident alveolar macrophages in the lungs and their job is to remove foreign particles that reach the alveoli. The first macrophage on the scene engulfed the Mycobacterium into a phagosome, which functions as a temporary holding cell within a macrophage. In most cases, what happens next is that the phagosome fuses with lysosomes that contains acids, powerful chemicals, and enzymes to kill invading microbes. In the case of Mycobacterium tuberculosis, the bacteria have developed a survival mechanism. Whereby they can modify that phagosome so that it can't fuse with the lysosomes. And in this way, the bacteria can survive and even grow and replicate inside the alveolar macrophages. After this replication has gone on for a while, the macrophage may die, and that would release bacteria that can go on to infect other macrophages. And also release the contents of the lysosomes, which causes damage to the surrounding tissue and recruits even more inflammatory cells to the area. Infected macrophages also have innate immune sensors that not only allow them to recognize invading bacterial, but also trigger the release of cytokines and chemokines. And these summon even more immune system defenders, like neutrophils, dendritic cells and lymphocytes, to the site of infection. In this way, infection with mycobacteria elicits an orchestrated immune response that surrounds the damaged tissue and tries to wall off the infection. The end results of this is called a tuberculous granuloma, a local collection of bacteria walled off by immune cells. Granulomas are pretty dynamic, with immune cells entering and exiting. And some of the macrophages or dendritic cells will even travel to nearby lymph nodes in order to make the adaptive immune system aware of the presence of the infection. If the immune system is able to control the infection, the resulting granulomas can persist. And often they can even be too small to be detected on a chest X-ray. Because the infection is contained, it doesn't cause any symptoms or any organ damage in the host. This is called the latent or primary tuberculosis infection. Sometimes it is called LTBI for short and this is why Numbulelo was symptom free as a young woman. She was never tested for tuberculosis back then, but if she had been, a tuberculine skin test would of come back positive. Indicating that her adapted system responded to the presence of mycobacteria. Many years later, when Numbulelo got older and her immune system lost some of its strength, the bacteria trapped inside the granuloma inside her lungs began to grow again. Causing an inflammatory response, and damage to the surrounding tissue. This is when her symptoms of fever, weight loss, and night sweats first began to appear. As cells on the inside of the granuloma begin to die, this focus of infection forms a caseating granuloma. And that can erode into the airways causing in this case, Numbulelo's coughing, hemoptysis, and releasing many bacteria into the surrounding air. This is how her grandson became infected with the Mycobacterium tuberculosis as well. At the hospital in Khayelitsha, Numbulelo's sputum samples were found to contain acid fast bacilli. And her chest X-ray showed a cavity legion consistent with active pulmonary tuberculosis disease. Numbulelo was treated with four anti-tuberculosis medications including isoniazid, Rifampin, pyrazinamide, and ethambutol. And luckily, she began to recover. Shortly after Numbulelo brought her grandson into the hospital, he suffered a second seizure. He also had a fever and was lethargic upon admission. In a more developed part of the world, the doctors would likely have ordered an MRI. And it may have shown inflammation of the meninges at the base of the brain, which is a common finding in tuberculous meningitis. Sometimes also accompanied by hydrocephalus or swelling of the ventricles because of a blockage of the flow of cerebrospinal fluid due to the infection. At the hospital near Khayelitsha there was no MRI machine, but the baby did receive a chest X-ray. Which was very different from his grandmother's X-ray because it showed a miliary pattern. Suggesting that many small granulomas were forming all over the lungs. When Numbulelo was young, her immune system was able to contain the tuberculosis for many years inside a few larger granulomas in her lungs. But babies or other immune-compromised hosts have less effected immune responses, and so the infection often spreads to other parts of the body. The miliary pattern on this child's chest X-ray also suggests that the mycobacteria had spread, not only inside the lungs but also to other organs, including the brain. Which is a common sight of TB infection in babies. It might surprise you to know that this baby's tuberculin skin test came back negative. But cultures from his cerebrospinal fluid that you obtain by doing a lumbar puncture, eventually grew Mycobacterium tuberculosis as well. And this confirmed that he had tuberculous meningitis. Despite being treated with the same four medications that his grandmother had received. And despite the best efforts of the doctors at the hospital in the Khayelitsha, this baby died from his Mycobacterium infection. When a physician suspects an a infection with Mycobacterium tuberculosis, it helps to understand how the interaction between the host immune system and the microbe can result in the different clinical presentations of tuberculosis infection. We know, for example, that granulomas are one of the hallmarks of an infection with Mycobacterium tuberculosis. And granulomas are the result of the immune system's efforts to protect the hosts by engulfing the microbe and deploying other immune cells to try and contain the disease. We also know that mycobacteria have evolved in ways that allow them to colonize, persist, and replicate inside the host. Despite the immune system's efforts to eliminate them. And the capacity of the immune system to remember and recognize this microbe upon re-exposure gives us a powerful diagnostic tool The Tuberculin Skin Test. By understanding that the immune system of a baby is unlikely to be able to contain an infection with Mycobacterium tuberculosis in the same way. Physicians can interpret the physical presentation of the disease in hosts with compromised or naive immune function. And choose a therapeutic approach that's most likely to be successful. Finally, understanding how mycobacteria are spread, how they enter and exit the host, can help with efforts to prevent the local spread of disease. And know the epidemiology of this infection, that one-third of the world's population is infected with Mycobacterium, even though they may be symptom free. This can help with larger scale prevention efforts. As targeted screening protocols can be put into place for individuals at increased risk of being infected with Mycobacterium tuberculosis.
