Tuberculosis (TB) : Definition, Diagnosis, Treatment, And Pathopysiology
- Tuberculosis (TB) is a communicable infectious disease caused by Mycobacterium tuberculosis. It can produce silent, latent infection as well as progressive, active disease.
- Globally, 2 billion people are infected and 2 to 3 million people die from tuberculosis each year.
- M. tuberculosis is transmitted from person to person by coughing or sneezing. Close contacts of TB patients are most likely to become infected.
- Fifty-one percent of TB patients in the United States are foreign born, most often from Mexico, the Philippines, Vietnam, India, China, Haiti, or South Korea. In the United States, TB disproportionately affects ethnic minorities (blacks and Hispanics).
- HIV is the most important risk factor for active TB, especially among people 25 to 44 years of age. An HIV-infected individual with tuberculous infection is over 100-fold more likely to develop active disease than an HIV-seronegative patient.
PATHOPHYSIOLOGY of TUBERCULOSIS (TB):
- Primary infection is initiated by the alveolar implantation of organisms in droplet nuclei that are small enough (1 to 5 mm) to escape the ciliary epithelial cells of the upper respiratory tract. Once implanted, the organisms multiply and are ingested by pulmonary macrophages, where they continue to multiply, albeit more slowly. Tissue necrosis and calcification of the originally infected site and regional lymph nodes may occur, resulting in the formation of a radiodense area referred to as a Ghon complex.
- Large numbers of activated macrophages surround the solid caseous (cheeselike) tuberculosis foci (the necrotic area) as a part of cell-mediated immunity. Delayed-type hypersensitivity also develops through activation and multiplication of T lymphocytes. Macrophages form granulomas to contain the organisms.
- Successful containment of M. tuberculosis requires activation of a subset of CD4 lymphocytes, referred to as Th-1 cells, which activate macrophages through secretion of interferon Î³.
- Approximately 90% of patients who experience primary disease have no further clinical manifestations other than a positive skin test either alone or in combination with radiographic evidence of stable granulomas.
- Approximately 5% of patients (usually children, the elderly, or the immunocompromised) experience progressive primary disease at the site of the primary infection (usually the lower lobes) and frequently by dissemination, leading to meningitis and often to involvement of the upper lobes of the lung as well.
- Approximately 10% of patients develop reactivation disease, which arises subsequent to the hematogenous spread of the organism.
- Occasionally, a massive inoculum of organisms may be introduced into the bloodstream, causing widely disseminated disease and granuloma formation known as miliary tuberculosis.
- The clinical presentation of pulmonary TB is nonspecific, indicative only of a slowly evolving infectious process.
- Physical examination is nonspecific, suggestive of progressive pulmonary disease.
- Clinical features associated with extrapulmonary TB vary depending on the organ system(s) involved but typically consist of slowly progressive compromise of organ function with low-grade fever and other constitutional symptoms.
- The clinical features of patients with HIV infection who develop TB may be markedly different from those classically observed in immunocompetent individuals. (In AIDS patients, TB is much more likely to present as the progressive primary form, to involve extrapulmonary sites, and to involve multiple lobes of the lung.
- TB in AIDS patients is less likely to involve cavitary disease, be associated with a positive skin test, or be associated with fever.
TUBERCULIN SKIN TEST
- The most widely used screening method for tuberculous infection is the tuberculin skin test, which uses purified protein derivative (PPD). .
- The Mantoux method of PPD administration, which is the most reliable technique, consists of the intradermal injection of PPD containing 5 TU. The test is read 48 to 72 hours after injection by measuring the diameter of the zone of induration.
- Some patients may exhibit a positive test after an initial negative test, and this is referred to as a booster effect.
Confirmatory diagnosis of a clinical suspicion of TB must be made via chest x-ray and microbiologic examination of sputum or other infected material to rule out active disease.
Rapid identification of new cases of TB
- Isolation of the patient with active disease to prevent spread
- Collection of appropriate samples for smears and cultures
- Prompt resolution of signs and symptoms of disease after initiation of treat- ment
- Achievement of a noninfectious state, thus ending isolation
- Adherence to the treatment regimen
- Cure as quickly as possible (generally with at least 6 months of treatment)
TREATMENT of TUBERCULOSIS (TB)
- Drug treatment is the cornerstone of TB management. A minimum of two drugs, and generally three or four drugs, must be used simultaneously.
- Drug treatment is continued for at least 6 months and up to 2 to 3 years for some cases of multidrug-resistant TB (MDR-TB).
- Measures to assure adherence, such as directly observed therapy (DOT), are important.
- Chemoprophylaxis should be initiated in patients to reduce the risk of progression to active disease.
- Isoniazid (INH), 300 mg daily in adults, is the primary treatment for latent TB in the United States, generally given for 9 months.
- Individuals likely to be noncompliant may be treated with a regimen of 15 mg/kg (to a maximum of 900 mg) twice weekly with observation.
- If the individual has been exposed to a patient with INH-resistant M. tuberculosis or a patient who has failed chemotherapy, chemoprophylaxis with rifampin (RIF) (for 4 months) should be initiated.
- Pregnant women, alcoholics, and patients with poor diets who are treated with isoniazid should receive pyridoxine, 10 to 50 mg daily, to reduce the incidence of central nervous system (CNS) effects or peripheral neuropathies.
Treating Active Disease
- Appropriate samples should be sent for culture and susceptibility testing prior to initiating therapy. Drug susceptibility testing should be done on the initial isolate for all patients with active TB, and this data should guide the initial drug selection for the new patient. If the source case cannot be identified, the drug resistance pattern in the area where the patient likely acquired TB should be used.
- If the patient is being evaluated for the retreatment of TB, it is imperative to know what drugs were used previously and for how long.
- Patients must complete 6 months or more of treatment. HIV-positive patients should be treated for an additional 3 months and at least 6 months from the time that they convert to smear and culture negativity. When isoniazid and rifampin cannot be used, treatment duration becomes 2 years or more, regardless of immune status.
- If the organism is drug resistant, the aim is to introduce two or more active agents that the patient has not received previously. With MDR-TB, no standard regimen can be proposed. It is critical to avoid monotherapy or adding only a single drug to a failing regimen.
- Drug resistance should be suspected in the following situations:
- Patients who have received prior therapy for TB
- Patients from geographic areas with a high prevalence of resistance (New York City, Mexico, Southeast Asia, and the former Soviet states)
- Patients who are homeless, institutionalized, intravenous drug abusers, and/or infected with HIV
- Patients who still have acid-fast bacilli (AFB)-positive sputum smears after 2 months of therapy
- Patients who still have positive cultures after 3 to 4 months of therapy
- Patients who require retreatment
TUBERCULOUS MENINGITIS AND EXTRAPULMONARY DISEASE
In general, isoniazid, pyrazinamide, ethionamide, and cycloserine penetrate the cerebrospinal fluid (CSF) readily. Patients with CNS tuberculosis are often treated for longer periods (9 to 12 months). Extrapulmonary TB of the soft tissues can be treated with conventional regimens. TB of the bone is typically treated for 9 months, occasionally with surgical debridement.
Tuberculosis in children may be treated with regimens similar to those used in adults, although some physicians still prefer to extend treatment to 9 months.
The usual treatment of pregnant women is isoniazid, rifampin, and ethambutol for 9 months.
Women with TB should be cautioned against becoming pregnant, as the disease poses a risk to the fetus as well as to the mother. Isoniazid or ethambutol are relatively safe when used during pregnancy. Supplementation with B vitamins is particularly important during pregnancy. Rifampin has been rarely associated with birth defects, but those seen are occasionally severe, including limb reduction and CNS lesions. Pyrazinamide has not been studied in a large number of pregnant women, but anecdotal information suggests that it may be safe. Ethionamide may be associated with premature delivery, congenital deformities, and Down’s syndrome when used during pregnancy. Streptomycin has been associated with hearing impairment in the newborn, including complete deafness.