Clinical Overview of Tuberculosis

Persons with latent TB infection have TB bacteria in their bodies, but do not have symptoms of TB disease and cannot spread the infection to other people.

The process of latent TB infection begins when extracellular bacilli that are in the alveoli are ingested by macrophages and presented to other white blood cells. This triggers the immune response in which white blood cells kill or encapsulate most of the bacilli, leading to the formation of a granuloma. Once this happens, latent TB infection has been established. People with latent TB infection can be treated to prevent the development of TB disease.

Without treatment, approximately 5% of persons who have been infected with TB bacteria will develop TB disease in the first two years after infection, and another 5% will develop TB disease sometime later in life.

In some people, the TB bacteria overcome the immune system and multiply, resulting in progression from latent TB infection to TB disease. Persons who have TB disease are usually infectious and may spread the bacteria to other people.

The progression from latent TB infection to TB disease may occur at any time, but it is most common within the first two years of infection or in the context of certain medications or health conditions (such as diabetes, cancer, or HIV).

TB disease can occur in different places in the body and in more than one organ or organ system at the same time.

• Pulmonary TB disease occurs in the lungs. Most cases of TB disease are pulmonary.
• Extrapulmonary TB disease occurs in places other than the lungs, such as the larynx, lymph nodes, pleura, brain (TB meningitis), kidneys, or bones.
• Disseminated TB disease (or miliary TB disease) occurs when TB bacteria enter the bloodstream and are carried to all parts of the body where they grow and cause disease in multiple sites.

Drug-resistant TB disease

Drug-resistant TB disease is caused by TB bacteria that are resistant to the drugs normally used to treat the disease.

Drug-resistant TB is transmitted in the same way as drug-susceptible TB, and it is no more infectious than drug-susceptible TB. However, delay in the recognition of drug resistance or prolonged periods of infectiousness may facilitate increased transmission and further development of drug resistance.

• Contacts of people known or presumed to have infectious TB disease
• People who were born in or who frequently travel to countries where TB disease is common
• People who currently live or used to live in large group settings where TB is more common, such as homeless shelters, correctional facilities, or nursing homes
• Employees of high-risk congregate settings
• Health care workers who serve patients with TB disease
• Populations defined locally as having an increased incidence of latent TB infection or TB disease, possibly including medically underserved populations, low-income populations, or persons with alcohol use or substance use disorders
• Infants, children, and adolescents exposed to adults who are at increased risk for latent TB infection or TB disease

• People with HIV
• Children younger than 5 years of age
• People recently infected with TB bacteria (within the last 2 years)
• People with a history of untreated or inadequately treated TB disease
• People who are receiving immunosuppressive therapy such as tumor necrosis factor-alpha (TNF) antagonists, systemic corticosteroids equivalent to/greater than 15 mg of prednisone per day, or immunosuppressive drug therapy following organ transplantation
• People with silicosis; chronic renal failure; leukemia; or cancer of the head, neck, or lung
• People with diabetes mellitus
• People who have had a gastrectomy or jejunoileal bypass
• People with low body weight (<90% of ideal body weight)
• People who use substances (such as injection drug use)
• Populations defined locally as having an increased incidence of TB disease, including medically underserved and low-income populations

Persons with latent TB infection do not have symptoms of TB disease, and they cannot spread TB bacteria to others.

Not everyone with TB disease has signs and symptoms. However, most individuals with TB disease have one or more symptoms that lead them to seek medical care. Symptoms of TB disease may vary depending on the part of the body affected.

When the onset of TB disease is gradual, a person who has TB disease might not notice the symptoms because they seem mild and do not interfere with daily activities.

Symptoms of pulmonary TB disease

• Cough (especially lasting for 3 weeks or longer)
• Coughing up sputum or blood (hemoptysis)
• Chest pain
• Loss of appetite
• Unexplained weight loss
• Night Sweats
• Fever
• Fatigue

Symptoms of extrapulmonary TB disease

Extrapulmonary TB disease, which affects organs in addition to or instead of the lungs, may cause symptoms related to the part of the body that is affected. For example, TB disease of the spine may cause back pain, TB disease of the kidney may cause blood in the urine, and TB meningitis may cause headache or confusion.

The CDC and the U.S. Preventive Services Task Force (USPSTF) recommend testing people who are at higher risk for TB infection. Testing for TB infection should be a routine and integral part of health care for patients with increased risk for TB. Frequency of testing depends on a person's risk factors. This could range from one-time only testing among persons at low risk for future TB exposure to annual testing among those at continued risk of exposure.

There are two first-line diagnostic tests that are used to determine if a person has been infected with TB bacteria: the TB blood test (Interferon Gamma Release Assays [IGRAs]) and the TB skin test (Mantoux tuberculin skin test).

Test results should be interpreted in the context of the likelihood of infection (pretest probability) and medical conditions such as an illness that is suggestive of TB disease.

A positive reaction to a TB blood test (IGRA) or TB skin test usually means TB infection. More tests are needed to rule out TB disease.

Diagnosing latent TB infection

A diagnosis of latent TB infection is made if a person has a positive TB blood test or TB skin test result, and a medical evaluation does not indicate TB disease.

Diagnosing TB disease

People with a positive TB blood test or TB skin test result for TB infection should be evaluated for TB disease. An evaluation for TB disease includes

• A review of systems (medical history) to determine if the patient:
  • Has been exposed to TB bacteria,
  • Has been treated for latent TB infection or TB disease in the past, or
  • Has medical conditions that should be considered during the evaluation and subsequent treatment.
• Chest radiography; and,
• Laboratory tests (sputum smear microscopy, nucleic acid amplification testing, culture, and drug susceptibility testing)

Culture is the gold standard microbiologic test for the diagnosis of TB disease.

There are several regimens for the treatment of latent TB infection. Regimens use one or more of the following drugs:

• Isoniazid (H)
• Rifapentine (P)
• Rifampin (R)

These drugs are selected when the infection is assumed to be drug susceptible. If drug resistance is being considered because of the exposure history, consult with a TB expert.

CDC and the National Tuberculosis Coalition of America preferentially recommend short-course, rifamycin-based, 3- or 4-month latent TB infection treatment regimens over 6- or 9-month isoniazid monotherapy. Short-course regimens are effective, safe, and have higher completion rates than longer regimens.

Short course regimens include:

• Three months of once-weekly isoniazid plus rifapentine (3HP)
• Four months of daily rifampin (4R)
• Three months of daily isoniazid plus rifampin (3HR)

Multiple options for therapy are available. Treatment for drug-susceptible TB disease can take 4, 6, or 9 months depending on the regimen. Regimens include:

• Four months of rifapentine-moxifloxacin
• Six or nine months of rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE)

The goal of treatment for TB disease should be to provide the safest and most effective therapy for the shortest period. Health care providers, with input from local or state TB programs, should choose the TB treatment regimen based on drug-susceptibility results, coexisting medical conditions, and potential for drug-drug interactions.

Given adequate treatment, almost all patients will recover and be cured.

To help patients complete treatment for TB disease, use in-person directly observed therapy (DOT) or video directly observed therapy (vDOT). Contact your local health department for assistance with arranging DOT or vDOT. Many health departments have programs to help monitor treatment for TB disease.

Treating drug-resistant TB disease is complicated. Inappropriate management can have life-threatening results. Drug-resistant TB disease should be managed by or in close consultation with an expert in the disease.