What is Tuberculosis?
Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include productive cough, fever, weight loss, and malaise. Diagnosis is most often by sputum smear and culture and, when available, by nucleic acid amplification tests. Treatment is with multiple antimicrobial drugs given for at least 4 months.
Mycobacteria are small, slow-growing, aerobic bacilli. They are distinguished by a complex, lipid-rich cell envelope that makes them acid-fast (ie, resistant to decolorization by acid after staining with carbolfuchsin) and relatively resistant to Gram stain. The most common mycobacterial infection is tuberculosis; others include leprosy and various environmental nontuberculous mycobacterial infections, such as those caused by Mycobacterium avium complex.
Tuberculosis (TB) is a leading infectious cause of death in adults worldwide, killing about 1.5 million people in 2020, most of them in low- and middle-income countries (1). HIV/AIDS is the most important factor predisposing to TB infection and mortality in parts of the world where both infections are prevalent.
Only the illness brought on by Mycobacterium tuberculosis is correctly referred to as tuberculosis (for which humans are the main reservoir). The closely related mycobacteria M. bovis, M. africanum, and M. microti can infrequently cause similar symptoms. The Mycobacterium TB complex includes these three microorganisms as well as M. tuberculosis and other uncommon mycobacteria.
Almost exclusively, inhaling airborne droplet nuclei carrying M. tuberculosis causes TB. People with active pulmonary or laryngeal TB, whose sputum contains a significant number of organisms (approximately 10,000 organisms/mL, the limit of detection by fluorescence microscopy), predominantly distribute them through coughing, singing, and other forceful respiratory techniques. Because pulmonary cavitary lesions contain so many bacteria, those who have them are particularly contagious.
For several hours, droplet nuclei (particles smaller than 5 micrometers in diameter) harboring tubercle bacilli may be suspended in the air currents of the room, increasing the likelihood of transmission. It is challenging to resuspend the organisms as respirable particles once these droplets land on a surface (for example, by cleaning the floor or shaking out bed sheets). Despite the fact that such operations can resuspend dust particles containing tubercle bacilli, these particles are too big to reach the alveolar surfaces required to start an infection. Contact with fomites does not seem to promote dissemination (e.g., contaminated surfaces, food, or personal respirators).
As a result, different estimations of contagiousness exist. The World Health Organization (WHO) predicts that each untreated patient may infect 10 to 15 persons each year, contrary to certain studies that claim only 1 in 3 patients with untreated pulmonary TB transmit any close contacts. However, the majority of infected people do not experience symptoms of a disease.
Once appropriate treatment is started, contagiousness quickly declines. Cough also lessens, and even if an organism persists in sputum, it is not contagious. Although more accurate human-to-animal studies imply that transmission terminates a few days after commencing therapy, epidemiologic studies of household contacts suggest that transmission ends two weeks after patients begin effective treatment.
TB of the tonsils, lymph nodes, abdominal organs, bones, and joints was once commonly caused by ingestion of milk or milk products (eg, cheese) contaminated with M. bovis, but this transmission route has been largely eradicated in countries where milk is pasteurized and cows that have a positive tuberculin skin test result are slaughtered. Tuberculosis due to M. bovis still occurs in countries where bovine tuberculosis is endemic (eg, some Latin American countries) and in immigrants from those countries. The increasing popularity of cheese made from unpasteurized milk raises new concerns if the cheeses come from countries with a bovine TB problem (eg, Mexico, the United Kingdom). Bovine and human TB can be transmitted to other species such as badgers, deer, primates, and zoo animals. Slaughterhouses have been associated with zoonotic TB transmission.
Tuberculosis may occur in 3 stages:
- Primary infection
- Latent infection
- Active infection
M. tuberculosis bacilli initially cause a primary infection, a small percentage of which eventually progress to clinical disease of variable severity. However, most (about 95%) primary infections are asymptomatic. An unknown percentage of primary infections resolve spontaneously, but the majority are followed by a latent (dormant) phase. A variable percentage (5 to 10%) of latent infections subsequently reactivate with symptoms and signs of disease.
Infection is usually not transmissible in the primary stage and is never contagious in the latent stage.
Primary TB infection
A particle must be inhaled that is small enough to get past the upper respiratory defenses and land deep inside the lungs, typically in the subpleural airspaces of the middle or lower lobes, to cause an infection. Larger droplets normally do not cause infection since they tend to become stuck in the closer airways. A single droplet nucleus, which typically contains few organisms, is where infection usually starts. People who are vulnerable to infection might only need one organism to do so, whilst less susceptible individuals might need multiple exposures before becoming infected.
Alveolar macrophages must consume M. tuberculosis bacilli in order to start an infection. The host macrophage is ultimately destroyed by the bacilli that the macrophages are unable to destroy (with the aid of CD8 lymphocytes); inflammatory cells are drawn to the location, resulting in a focal pneumonitis that coalesces into the distinctive tubercles seen histologically.
Some infected macrophages go to local lymph nodes (such as the hilar or mediastinal) in the early stages of infection, where they gain access to the circulation. Then, organisms may spread hematogenously to any area of the body, but are especially likely to do so to the meninges, kidneys, vertebral bodies, kidney epiphyses, and apical-posterior portions of the lungs. Patients who have partial protection from vaccinations, previous spontaneous infections with M. tuberculosis, or environmental mycobacteria are less prone to experience hematogenous spread.
Latent TB infection
most initial infections arise later. After around 3 weeks of unhindered growth, the immune system suppresses bacillary replication in approximately 95% of cases, typically before symptoms or signs appear. In the lung or other locations, bacilli foci transform into epithelioid cell granulomas, some of which may have caseous and necrotic centers. The balance between the host’s resistance and the microbial virulence determines whether the infection ultimately resolves without therapy, remains dormant, or becomes active. Tubercle bacilli can persist in this substance for years. Simon foci, which are typically caused by hematogenous seeding from another site of infection, can leave fibronodular scars in the apices of one or both lungs, or they can cause tiny areas of consolidation (Ghon foci)
Acute sickness with pneumonia (occasionally cavitary), pleural effusion, and clearly enlarged mediastinal or hilar lymph nodes is less frequently caused by the primary focus progressing quickly (which, in children, may compress bronchi). Small pleural effusions usually contain few organisms, are primarily lymphocytic, and resolve in a few weeks. Young children and people who have recently been infected or have already been infected again may experience this pattern more frequently.
Sometimes extrapulmonary TB can present anywhere without showing lung involvement. Though meningitis is the most dreaded because of its high fatality rate in the very young and the very old, TB lymphadenopathy is the most frequent extrapulmonary presentation.
Active TB disease
The lifetime probability of acquiring active tuberculosis in healthy individuals infected with the disease ranges from 5 to 10%, although the number fluctuates greatly depending on age and other risk factors.
TB reactivates during the first two years in 50 to 80% of people who get active disease, but it can also reactivate decades later.
Any organ that was initially seeded may turn into a site of reactivation, but lung apices are where it happens the most frequently, perhaps due to the favorable local conditions like high oxygen tension. Sites of reactivation are substantially less likely to occur in ghon foci and impacted hilar lymph nodes.
Conditions that impair cellular immunity (which is essential for defense against TB) significantly facilitate reactivation. Thus, patients coinfected with HIV and not receiving appropriate antiretroviral therapy (ART) have about a 10% annual risk of developing active disease.
Other risk factors that facilitate reactivation, but to a lesser extent than HIV infection, include
- Head and neck cancer
- Jejunoileal bypass surgery
- Dialysis-dependent chronic kidney disease
- Significant weight loss
- Use of drugs that suppress the immune system
Patients who require immunosuppression after solid organ transplantation are at the highest risk, but other immunosuppressants such as corticosteroids and tumor necrosis factor (TNF) inhibitors also commonly cause reactivation. Tobacco use also is a risk factor.
Signs and Symptoms
Latent TB doesn’t have symptoms. A skin or blood test can tell if you have it.
Signs of active TB disease include:
- A cough that lasts more than 3 weeks
- Chest pain
- Coughing up blood
- Feeling tired all the time
- Night sweats
- Loss of appetite
- Weight loss
If you have any of these symptoms, see your doctor to get tested. Get medical help right away if you have chest pain.
A person with TB exhales microscopic droplets that are contaminated with the disease when they cough, sneeze, talk, laugh, or sing. You can contract it if you breathe in these microorganisms.
TB is difficult to catch. A person with a lot of the germs in their lungs usually requires a lot of time in close proximity to you. It’s most likely to spread to you through coworkers, friends, and family.
On surfaces, tuberculosis germs do not flourish. You cannot contract it by exchanging food or drinks with a person who has it or by shaking their hand.
There are two common tests for tuberculosis:
- Skin test. This is also known as the Mantoux tuberculin skin test. A technician injects a small amount of fluid into the skin of your lower arm. After 2 or 3 days, they’ll check for swelling in your arm. If your results are positive, you probably have TB bacteria. But you could also get a false positive. If you’ve gotten a tuberculosis vaccine called bacillus Calmette-Guerin (BCG), the test could say that you have TB when you really don’t. The results can also be false negative, saying that you don’t have TB when you really do, if you have a very new infection. You might get this test more than once.
- Blood test. These tests, also called interferon-gamma release assays (IGRAs), measure the response when TB proteins are mixed with a small amount of your blood.
Those tests don’t tell you if your infection is latent or active. If you get a positive skin or blood test, your doctor will learn which type you have with:
- A chest X-ray or CT scan to look for changes in your lungs
- Acid-fast bacillus (AFB) tests for TB bacteria in your sputum, the mucus that comes up when you cough
Your treatment will depend on your infection.
- If you have latent TB, your doctor will give you medication to kill the bacteria so the infection doesn’t become active. You might get isoniazid, rifapentine, or rifampin, either alone or combined. You’ll have to take the drugs for up to 9 months. If you see any signs of active TB, call your doctor right away.
- A combination of medicines also treats active TB. The most common are ethambutol, isoniazid, pyrazinamide, and rifampin. You’ll take them for 6 to 12 months.
- If you have drug-resistant TB, your doctor might give you one or more different medicines. You may have to take them for much longer, up to 30 months, and they can cause more side effects.
Whatever kind of infection you have, it’s important to finish taking all of your medications, even when you feel better. If you quit too soon, the bacteria can become resistant to the drugs.
Dosing of Oral First-Line Anti-TB Drugs*
|Drug||Adults or Children||Daily†||Once/Week||2 Times/Week||3 Times/Week|
|Isoniazid||Adults (maximum)||5 mg/kg (300 mg)||15 mg/kg (900 mg)||15 mg/kg (900 mg)||15 mg/kg (900 mg)|
|Children (maximum)||10–20 mg/kg (300 mg)||N/A||20–40 mg/kg (900 mg)||N/A|
|Rifampin||Adults (maximum)||10 mg/kg (600 mg)||N/A||10 mg/kg (600 mg)||10 mg/kg (600 mg)|
|Children (maximum)||10–20 mg/kg (600 mg)||N/A||10–20 mg/kg (600 mg)||N/A|
|Rifabutin||Adults (maximum)||5 mg/kg (300 mg)||N/A||5 mg/kg (300 mg)||5 mg/kg (300 mg)|
|Children||10–20 mg/kg (300 mg)||N/A||10–20 mg/kg (300 mg)||10–20 mg/kg (600 mg)|
|Rifapentine‡||Adults||N/A||10 mg/kg (600 mg)||N/A||N/A|
|Pyrazinamide||Adults (whole tablets):|
|40–55 kg||1 g||N/A||2 g||1.5 g|
|56–75 kg||1.5 g||N/A||3 g||2.5 g|
|≥ 76 kg§||2 g||N/A||4 g||3 g|
|Children (maximum)||15–30 mg/kg (2 g)||N/A||50 mg/kg (2 g)||N/A|
|Ethambutol||Adults (whole tablets):|
|40–55 kg||800 mg||N/A||2000 mg||1200 mg|
|56–75 kg||1200 mg||N/A||2800 mg||2000 mg|
|≥ 76 kg§||1600 mg||N/A||4000 mg||2400 mg|
|Children (maximum)||15–20 mg/kg (1 g)||N/A||50 mg/kg (2.5 g)||N/A|
|Moxifloxacin||≥ 12 years of age||400 mg||N/A||N/A||N/A|
Medication Side Effects
Like any medication, TB drugs can have side effects. Common isoniazid side effects include:
- Numbness and tingling in your hands and feet
- Upset stomach, nausea, and vomiting
- Loss of appetite
- Ethambutol side effects may include:
- Painful or swollen joints
- Belly pain, nausea, and vomiting
- Loss of appetite
Some pyrazinamide side effects include:
- Lack of energy
- Nausea and vomiting
- Loss of appetite
- Muscle or joint pain
- Common rifampin side effects include:
- Skin rash
- Upset stomach, nausea, and vomiting
- Loss of appetite
- Inflamed pancreas
To help stop the spread of TB:
- If you have a latent infection, take all of your medication so it doesn’t become active and contagious.
- If you have active TB, limit your contact with other people. Cover your mouth when you laugh, sneeze, or cough. Wear a surgical mask when you’re around other people during the first weeks of treatment.
- If you’re traveling to a place where TB is common, avoid spending a lot of time in crowded places with sick people.
Children in countries where TB is common often get the BCG vaccine. It isn’t widely used in the United States, and it doesn’t always protect against infection. Doctors recommend it only for children living with someone who has an active TB infection with a very drug-resistant strain or who can’t take antibiotics.
Other vaccines are being developed and tested.