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 roughly 2 million people die from TB 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.
Human immunodeficiency virus (HIV) is the most important risk factor for active TB, especially among people 25 to 44 years of age. An HIV-infected individual with TB infection is over 100-fold more likely to develop active disease than a HIV-seronegative patient.
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. 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.
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. In the United States, most cases of TB are believed to result from reactivation. Occasionally, a massive inoculum of organisms may be introduced into the bloodstream, causing widely disseminated disease and granuloma formation known as miliary TB.
The classic presentation of pulmonary TB is nonspecific, indicative only of a slowly evolving infectious process. The onset of TB may be gradual. Physical examination is nonspecific but 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 decline of organ function with low-grade fever and other constitutional symptoms.
Patients with HIV may have atypical presentation. HIV-positive patients are less likely to have positive skin tests, cavitary lesions, or fever. They have a higher incidence of extrapulmonary TB and are more likely to present with progressive primary disease.
TB in the elderly is easily confused with other respiratory diseases. It is far less likely to present with positive skin tests, fevers, night sweats, sputum production, or hemoptysis. TB in children may present as typical bacterial pneumonia and is called progressive primary TB.
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 consists of the intracutaneous injection of PPD containing five tuberculin units. 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 1 week after an initial negative test; this is referred to as a booster effect. Confirmatory diagnosis of a clinical suspicion of TB must be made via chest radiograph and microbiologic examination of sputum or other infected material to rule out active disease.
When active TB is suspected, attempts should be made to isolate M. tuberculosis from the infected site. Daily sputum collection over three consecutive days is recommended. Tests to measure release of interferon-γ in the patient’s blood in response to TB antigens may provide quick and specific results for identifying M. tuberculosis.
The goals are prompt resolution of signs and symptoms of disease, achievement of a noninfectious state, thus ending isolation, adherence to the treatment regimen by the patient, and cure as quickly as possible (generally with at least 6 months of treatment)
Drug treatment is the cornerstone of TB management. A minimum of two drugs, and generally three or four drugs, must be used simultaneously. Directly observed therapy (DOT) by a healthcare worker is a cost effective way to ensure completion of treatment and is considered the standard of care. 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).
Patients with active disease should be isolated to prevent spread of the disease. Public health departments are responsible for preventing the spread of TB, finding where TB has already spread using contact investigation. Debilitated patients may require therapy for other medical conditions, including substance abuse and HIV infection, and some may need nutritional support. Surgery may be needed to remove destroyed lung tissue, space-occupying lesions, and some extrapulmonary lesions.Latent Infection
• Isoniazid, 300 mg daily in adults, is the preferred treatment for latent TB in the United States, generally given for 9 months.
• Rifampin, 600 mg daily for 4 months, can be used when isoniazid resistance is suspected or when the patient cannot tolerate isoniazid. Rifabutin, 300 mg daily, may be substituted for rifampin for patients at high risk of drug interactions.
The CDC recommends the 12-week isoniazid/rifapentine regimen as an equal alternative to 9 months of daily isoniazid for treating latent tuberculosis infection (LTBI) in otherwise healthy patients aged 12 years or older who have a predictive factor for greater likelihood of TB developing, which included recent exposure to contagious TB, conversion from negative to positive on an indirect test for infection (i.e., interferon-gamma release assays [IGRA] or tuberculin skin test), and radiographic findings of healed pulmonary TB.
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
The standard TB treatment regimen is isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifampin for 4 months. Ethambutol can be stopped if susceptibility to isoniazid, rifampin, and pyrazinamide is shown.
Appropriate samples should be sent for culture and susceptibility testing prior to initiating therapy for all patients with active TB. The data should guide the initial drug selection for the new patient. If susceptibility data are not available, 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.
Patients who are slow to respond, those who remain culture positive at 2 months of treatment, those with cavitary lesions on chest radiograph, and HIV-positive patients should be treated for 9 months and for at least 6 months from the time they convert to smear and culture negativity.
Ant-Tuberculosis drug resistance
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 (South Africa, Mexico, Southeast Asia, the Baltic countries, and the former Soviet states)
✓ Patients who are homeless, institutionalized, IV drug abusers, and/or infected with HIV
✓ Patients who still have acid-fast bacilli–positive sputum smears after 2 months of therapy
✓ Patients who still have positive cultures after 2 to 4 months of therapy
✓ Patients who fail therapy or relapse after retreatment
✓ Patients known to be exposed to MDR-TB cases
Tuberculous Meningitis and Extrapulmonary Disease
In general, isoniazid, pyrazinamide, ethionamide, and cycloserine penetrate the cerebrospinal fluid readily. Patients with CNS TB are often treated for longer periods (9–12 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.
TB in children may be treated with regimens similar to those used in adults, although some physicians still prefer to extend treatment to 9 months. Pediatric doses of drugs should be used.
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 is 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 syndrome when used during pregnancy, so it cannot be recommended in pregnancy. Streptomycin has been associated with hearing impairment in the newborn, including complete deafness and must be reserved for critical situations where alternatives do not exist. Cycloserine is not recommended during pregnancy. Fluoroquinolones should be avoided in pregnancy and during nursing.
In nearly all patients, isoniazid and rifampin do not require dose modifications in renal failure. Pyrazinamide and ethambutol typically require a reduction in dosing frequency from daily to three times weekly