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.
The prevalence of drug-resistant strains is increasing worldwide; however, in the United States, the rate of drug-resistant isolates has fallen to less than 1.3%. Risk factors for drug resistance include immigration from countries with a high prevalence of drug-resistant tuberculosis, close and prolonged contact with individuals with drug-resistant tuberculosis, unsuccessful previous therapy, and nonadherence to treatment. Drug resistance may be single or multiple.
Drug-resistant tuberculosis is resistant to one first-line antituberculous drug, either isoniazid or rifampin. Multidrug-resistant tuberculosis is resistant to isoniazid and rifampin, and possibly additional agents.
Extensively drug-resistant tuberculosis is resistant to isoniazid, rifampin, fluoroquinolones, and either aminoglycosides or capreomycin or both. Outcomes of drug-resistant tuberculosis treatment are worse than when the isolate is drugsensitive, but outcomes appear to vary with HIV status. In a review of extensively drug-resistant tuberculosis cases in the United States, mortality was 10% and 68% in HIVnegative and HIV-positive patients, respectively.
Infection with M tuberculosis begins when a susceptible person inhales airborne droplet nuclei containing viable organisms. Tubercle bacilli that reach the alveoli are ingested by alveolar macrophages. Infection follows if the inoculum escapes alveolar macrophage microbicidal activity.
Once infection is established, lymphatic and hematogenous dissemination of tuberculosis typically occurs before the development of an effective immune response.
This stage of infection, primary tuberculosis, is usually clinically and radiographically silent. In most persons with intact cellmediated immunity, T-cells and macrophages surround the organisms in granulomas that limit their multiplication and spread. The infection is contained but not eradicated, since viable organisms may lie dormant within granulomas for years to decades.
Individuals with latent tuberculosis infection do not have active disease and cannot transmit the organism to others.
However, reactivation of disease may occur if the host’s immune defenses are impaired. Active tuberculosis will develop in approximately 6% of individuals with latent tuberculosis infection who are not given preventive therapy; half of these cases occur in the 2 years following primary infection.
Diverse conditions such as gastrectomy, silicosis, diabetes mellitus, and an impaired immune response (eg, HIV infection; therapy with corticosteroids, tumor necrosis factor inhibitors or other immunosuppressive drugs) are associated with an increased risk of reactivation.
Signs and symptoms
Symptoms and Signs
The patient with pulmonary tuberculosis typically presents with slowly progressive constitutional symptoms of malaise, anorexia, weight loss, fever, and night sweats.
Chronic cough is the most common pulmonary symptom. It may be dry at first but typically becomes productive of purulent sputum as the disease progresses.
Blood-streaked sputum is common, but significant hemoptysis is rarely a presenting symptom; life-threatening hemoptysis may occur in advanced disease.
Dyspnea is unusual unless there is extensive disease. Rarely, the patient is asymptomatic. On physical examination, the patient appears chronically ill and malnourished.
On chest examination, there are no physical findings specific for tuberculosis infection. The examination may be normal or may reveal classic findings such as posttussive apical rales.
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.
Definitive diagnosis depends on recovery of M tuberculosis from cultures or identification of the organism by DNA or RNA amplification techniques. Three consecutive morning sputum specimens are advised. Fluorochrome staining with rhodamine-auramine of concentrated, digested sputum specimens is performed initially as a screening method, with confirmation by the Kinyoun or ZiehlNeelsen stains.
Demonstration of acid-fast bacilli on sputum smear does not establish a diagnosis of M tuberculosis, since nontuberculous mycobacteria may colonize the airways and are increasingly recognized to cause clinical illness in patients with underlying structural lung disease.
In patients thought to have tuberculosis who cannot produce satisfactory specimens or when the smear of the spontaneously expectorated sputum is negative for acidfast bacilli, sputum induction with 3% hypertonic saline should be performed.
Flexible bronchoscopy with bronchial washings has similar diagnostic yield to induced sputum; transbronchial lung biopsies do not significantly increase the diagnostic yield but may lead to earlier diagnosis by identifying tissue granulomas. Post-bronchoscopy expectorated sputum specimens should be collected.
Positive blood cultures for M tuberculosis are uncommon in patients with normal CD4 cell counts, but the organism may be cultured from blood in up to 50% of HIV-seropositive patients with tuberculosis whose CD4 cell counts are less than 100/mcL (less than 0.1 × 109 /L).
Traditional light-microscopic examination of stained sputum for acid-fast bacilli and culture of sputum specimens remain the mainstay of tuberculosis diagnosis. The slow rate of mycobacterial growth, the urgency to provide early, appropriate treatment to patients to improve their outcomes and limit community spread, and concerns about potential drug toxicities in patients treated empirically who do not have tuberculosis infection have fostered the use of rapid diagnostic techniques.
Molecular diagnostics offer multiple options and many advantages at significantly increased expense. Nucleic acid amplification testing not only detects M tuberculosis (NAAT-TB) but it also identifies resistance markers (NAAT-R). NAAT-TB can identify M tuberculosis within hours of sputum processing, allowing early isolation and treatment, but the negative predictive value is low in smear-negative patients.
NAAT-R allows rapid identification of primary drug resistance and is indicated in the following patients:
- those treated previously for tuberculosis,
- those born (or who lived for more than 1 year) in a country with moderate tuberculosis incidence or a high incidence of multiple drug-resistant isolates,
- contacts of patients with multidrug-resistant tuberculosis, or
- those who are HIV seropositive. Clinical suspicion remains the critical factor in interpreting all these studies. Standard drug susceptibility testing of culture isolates is considered routine for the first isolate of M tuberculosis, when a treatment regimen is failing, and when sputum cultures remain positive after 2 months of therapy.
Needle biopsy of the pleura reveals granulomatous inflammation in approximately 60% of patients with pleural effusions caused by M tuberculosis. Pleural fluid cultures are positive for M tuberculosis in less than 23–58% of cases of pleural tuberculosis.
Culture of three pleural biopsy specimens combined with microscopic examination of a pleural biopsy yields a diagnosis in up to 90% of patients with pleural tuberculosis.
Tests for pleural fluid adenosine deaminase (approximately 90% sensitivity and specificity for pleural tuberculosis at levels greater than 70 units/L) and interferon-gamma (89% sensitivity, 97% specificity in a recent meta-analysis) can be extremely helpful diagnostic aids, particularly in making decisions to pursue invasive testing in complex cases.
Treatment of 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