Tuberculosis disease overview¶
IDM is committed to supporting data-driven tuberculosis control and elimination efforts. This page provides information about tuberculosis itself: the biology, symptoms, treatment, and prevention. See Tuberculosis model overview for information about the Epidemiological MODeling software (EMOD) TBHIV simulation type developed by IDM to aid in TB control and elimination.
Tuberculosis infection is caused by Mycobacterium tuberculosis bacteria. M. tuberculosis is a nonmotile, acid-fast, aerobic bacteria that is extremely slow-growing. The average generation time is between 15 and 20 hours, whereas most bacteria reproduce in 20 to 30 minutes. In part due to this slow growth, it can take many months or even years for the bacteria to grow to a point where the infection begins to cause symptoms or is capable of being transmitted to others. However, at that point it is very infectious; just 10 bacteria can cause an infection. In large part, the ease if transmission is due to a unique cell wall that is composed of acidic waxes that protect the bacteria from drying and chemicals.
The unique qualities of tuberculosis growth and transmission cause the infection to be divided into two distinct phases: latent infection and active infection.
Immediately after an individual is infected with M. tuberculosis, they may have mild flu-like symptoms, but generally will be asymptomatic. The bacteria enter the alveoli of the lungs and initiate an immune response that causes a granuloma to form at the primary site of infection. The granuloma is a collection of inflammatory cells that are thought to provide a physical and immunologic barrier that contains the infection and prevents its spread.
In a healthy individual, this immune response to the primary TB infection then transitions to the establishment of a latent tuberculosis infection (LTBI) in which the M. tuberulosis bacteria continue to live within the granuloma in a dormant state. Individuals with latent TB do not experience any symptoms and cannot transmit the disease to others. However, there will be a persistent immune response due to stimulation by antigens on the surface of the bacteria. Individuals can remain in this state for many years.
When the immune system cannot stop the M. tuberculosis bacteria from growing, this is considered active tuberculosis disease. Bacterial growth causes more granulomas to develop, leading to symptoms such as coughing or fatigue. Individuals with active TB can transmit the illness to others. Some individuals may pass through a presymptomatic active TB state in which they are contagious but have such mild symptoms that they do not recognize them as such.
Healthy individuals with latent infections may never develop active TB; the overall lifetime risk of developing active TB disease is only about 10%. When individuals with LTBI go one to develop active TB disease, it is a process called TB reactivation.
However, individuals with compromised immune systems are at much higher risk of developing active TB. The immune system may never contain the primary infection and it can progress to active disease in as little as four weeks. Individuals with HIV who have latent TB have a 10% annual risk of developing active TB.
Generally, M. tuberculosis colonizes the lungs, but it can live in many different areas of the body. Wherever infection occurs, granulomas are a characteristic feature.
The majority of TB infection occurs in the lungs (pulmonary). The symptoms of pulmonary TB include the following:
Bad cough lasting 3 weeks or longer
Coughing up blood or sputum
Excessive sweating, especially at night
Fatigue or weakness
Fever and chills
Weight loss and lack of appetite
Only 10-25% of TB cases occur outside the lungs (extrapulmonary). M. tuberculosis bacteria in the lungs can be carried by blood or lymph to other areas of the body. Commonly affected areas are lymph nodes, pleura, and bones or joints, although any organ in the body can be involved. The symptoms of extrapulmonary TB vary by location but generally include fever, fatigue, and weight loss. In the EMOD model, extrapulmonary individuals are considered non-infectious.
Diagnosis & treatment¶
Unfortunately, there is no direct measuring tool for TB infection in humans. Currently available tests are not ideal and can produce a high number of both false positives and false negatives. Additionally, there are several drug treatments available, and a growing concern about multidrug-resistant tuberculosis (MDR-TB) strains. Prevention and early diagnosis are considered key in controlling the spread of TB.
Because latent infections do not cause symptoms, screening for latent infections is generally recommended based on the risk of infection, likelihood of progressing to active TB if infected, and the benefit of therapy. For example, TB tests are recommended for certain high-risk populations such as health care workers.
To diagnose latent infections, a tuberculin skin test is usually administered. This test measures if someone has developed an immune response to the M. tuberculosis bacteria. If the result is positive, further tests are needed to determine if the person has latent TB or active TB. Additionally, the result will be positive if an individual has received the BCG vaccine for TB prevention, even though they do not have a infection. Interferon-gamma release assays (IGRA) blood tests are also available, but are higher in cost and generally used less often.
Testing for active TB usually occurs when individuals seek out care because they are experiencing symptoms of TB disease, also known as passive case finding (PCF). To increase early diagnosis, active case finding (ACF) may be used to systematically screen individuals in target groups that have a high risk of active TB. Risk factors for developing active TB are HIV, smoking, alcoholism, diabetes, and living or working in close proximity to people with infectious TB. Usually several tests are included to reach a diagnosis.
One tool in diagnosis is a chest X-ray, which can identify lesions in the lungs caused by bacterial grown and inflammatory immune reactions. However, finding abnormalities in the lungs is not a definitive diagnosis for TB.
Another test is an acid-fast bacilli (AFB) smear, in which the patient coughs up sputum from deep in the lungs. The sputum is spread onto a glass slide, treated with a stain that identifies bacteria in the Mycobacterium genus, and then examined under a microscope. However, there are other, less common, Mycobacterium that can infect humans, so a positive smear does not specifically identify M. tuberculosis infection. Additionally, less severe active TB disease can result in a negative smear result. Smear-negative patients are less infectious, but still contribute to the transmission of the disease.
The most definitive diagnosis of active TB is a sputum culture, which can identify the specific species of Mycobacterium and whether it is resistant to any TB treatment drugs. However, the slow growth of TB bacteria means cultures can take 2-6 weeks to return results.
Prevention & treatment¶
In high-burden countries, prevention is a key component of TB control and eradication. Currently, the :term: bacille Calmette-Guerin (BCG) vaccine` is the only TB vaccine available. It is relatively inexpensive and safe, though effective only for children under five.
Those with latent TB infections often do not require treatment. In high-burden countries, the primary groups that the WHO recommends receive treatment for latent TB are those living with HIV and children under five living with people who have pulmonary TB. Latent TB is generally treated with extended courses of the antibiotics rifampicin or isoniazid, either singly or in combination. Treatment reduces the risk of developing active TB by 60-90%.
Without treatment, the mortality rate of active TB is around 50%. There are several different drug regimens, all with an intensive phase of two months followed by a continuation phase of either four or seven months. The intensive phase uses a combination of the antibiotics isoniazid, rifampicin, ethambutol, and pyrazinamide. The continuation phase uses a combination of rifampicin and isoniazid. Even after cure, the affected areas are replaced by scar tissue. Early diagnosis and treatment is important to reduce transmission and improve health outcomes. Because culture results take so long, if doctors suspect TB due to the results of other tests, they will usually start patients on treatment before the culture results are ready; this is known as empiric treatment.
Unfortunately, resistance to one or more of the antibiotics used to treat TB is a significant obstacle to TB treatment and control. If the drug regimens above are unsuccessful or the culture reveals a resistant strain, the second-line treatment is used. Second-line agents are considered less effective and more toxic.
Because diagnosis and treatment may involve multiple tests and drugs over a long period of time, the cascade of care framework is useful for addressing gaps in TB care. For example, some individuals may never return for test results or not complete the full course of treatment. The WHO recommends the directly observed treatment, short-course (DOTS) strategy, which specifies that the intensive phase of treatment be directly observed by a health care worker.
Global tuberculosis burden¶
An estimated 30% of the world’s population has tuberculosis, though most have a latent infection. The overwhelming majority of cases are in developing countries; for example, incidence in South Africa is 80%. In 2016, 10.4 million people became sick with active TB and there were 1.7 TB-related deaths worldwide.
Because coinfection with HIV increases the risk of active TB so significantly, the emergence of HIV/AIDS has been a significant driver of tuberculosis transmission. TB is the number one cause of death among HIV-positive people; 40% of HIV deaths were due to TB in 2016.
In 2016, 490,000 people developed multidrug-resistant tuberculosis (MDR-TB) and another 110,000 developed rifampicin-resistant TB.
Benefits of mathematical models in TB control and eradication¶
Control and eventual eradication of tuberculosis will require multifaceted intervention efforts. The long lag between infection and the onset of disease, heterogeneity in transmission, and resistance to current treatments creates a need for a combination of interventions specific to the needs of particular areas and individuals. Agent-based models like EMOD are especially helpful in simulating this heterogeneity.
Effective detection and treatment of TB require a strong health system infrastructure and continuity of care, as infected individuals may go undetected for long periods of time and current treatment regimens require a minimum of six months’ adherence.
To better understand how shortening the diagnostic delay and improving treatment adherence can help reduce overall TB burden, we explicitly model the patient treatment-seeking pathway and health care system within each country. Modeling these factors enables researchers to accurately represent baseline transmission, which provides a platform on which to test various interventions and combinations of interventions.