Barriers to optimal control include poor compliance, drug resistance, and the HIV pandemic.

 Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, a small, rod-shaped, aerobic, non–spore-forming bacillus. Globally, TB is the leading infectious cause of death (with about 8 million new infections and nearly 3 million deaths occurring annually),1 as well as a major cause of morbidity. The World Health Organization2 predicts continued increases in TB and an estimated worldwide incidence of nearly 12 million cases per year by 2005.

In the United States, an increase in TB rates in the late 1980s was largely attributable to the increasing populations of immigrants, homeless persons, injection drug users, HIV-infected patients, and prison inmates. TB rates also increased among residents of nursing homes and mental-health institutions, as well as among health care workers.3 The incidence of M. tuberculosis infection has been decreasing in the United States since 1992, however, and is now at historic lows.3 In contrast, TB rates in some Asian and sub-Saharan African nations have increased to more than 300 cases per 100,000 people. In some of these areas, nearly 50% of HIV-infected individuals are coinfected by M. tuberculosis.2,4

The successful elimination of TB involves prompt, appropriate, and complete treatment of all active cases. Delays or interruptions in therapy may compromise care, cause drug resistance, and sustain infection in the community. A single unchecked case can foster a miniepidemic.5

Historical Perspective
TB has been causing disease and death in humans for centuries, but it was not until 1882 that the tubercle bacillus was identified.6 It was not until the late 1940s that the first effective anti-TB medications (streptomycin and p-aminosalicylic acid) became available, followed in 1952 by isoniazid.

Initially, TB was treated using single agents, but the emergence of drug-resistant M. tuberculosis strains in the 1950s necessitated combination therapy. In addition, public health measures such as the creation of the National Surveillance System were enacted to combat TB transmission.6,7 Combination therapy and modification of public health policies led to a significant reduction in TB rates in the United States until 1985. Between 1985 and 1992, however, there was a significant increase in TB cases.

Starting in 1993, the trend began to reverse again, with a yearly decline in TB cases; a record low of 18,361 cases was reached in 1998.6,8 This positive trend has been attributed to improvements in TB-control programs, with prompt identification of TB patients, prompt initiation of appropriate therapy, and the use of strategies to ensure compliance.8

During the past 3 decades, the prevalence of multidrug-resistant (MDR) TB among individuals with pulmonary TB in the United States has steadily increased from 2% to 9%.8 MDR is said to occur when resistance develops to two or more anti-TB drugs, specifically isoniazid and rifampin; when resistance develops to two or more of the five first-line anti-TB agents; or when more than 1% of TB organisms in a particular isolate are resistant to a critical concentration of a particular anti-TB agent.6,8

Pathophysiology
The development of TB begins with inhalation of the M. tuberculosis organism within airborne droplets expelled by an infected individual during coughing, sneezing, or talking. If the organism bypasses the nasal turbinates and bronchial mucociliary defenses and reaches the alveoli, it can replicate locally and spread throughout the body via blood and lymphatic systems.

In most people with healthy immune systems, alveolar macrophages engulf the tubercle bacillus and release a substance that attracts T lymphocytes. Prior to this point, the bacillus has the potential for dissemination to the kidneys, bones, meninges, and other sites where reactivation may occur years later.

Latent TB infection occurs when an individual becomes infected by the TB bacillus, but does not become acutely ill. For any number of reasons, the individual may not be able to eliminate the infection without taking anti-TB medications. A person with latent TB is asymptomatic and cannot spread the infection to others, but will demonstrate a positive Mantoux tuberculin skin test. The risk of reactivation of active disease is greatest in people with HIV disease or other immunosuppressive conditions, the elderly, and organ-transplant recipients. TB may, in fact, be one of the most common HIV-related opportunistic infections.9,10

Regimen

Total Duration

Comments
Pyrazinamide plus streptomycin or ethambutol daily for 2 months. 6 months Add streptomycin or ethambutol in areas/patients at risk for initial drug resistance. Stop pyrazinamide, ethambutol, or streptomycin after 2 months if strain is susceptible; continue or modify regimen if resistance is present.
Isoniazid, rifampin, pyrazinamide, and streptomycin daily for 2 weeks; then twice weekly for 6 weeks. Follow with isoniazid and rifampin twice weekly for 18 weeks. 6 months Stop pyrazinamide and streptomycin at 8 weeks if strain is susceptible; continue through 6 months if there is initial isoniazid resistance. May substitute ethambutol for streptomycin; 24 weeks of twice-weekly therapy facilitates directly observed therapy.
Isoniazid, rifampin, pyrazinamide, and streptomycin or ethambutol thrice weekly for 6 months (may stop pyrazinamide, streptomycin, or ethambutol after 2 months). 6 months If strain is susceptible, pyrazinamide and streptomycin or ethambutol may be stopped after 2 months. If there is isoniazid resistance, stop isoniazid and add the fourth drug (ethambutol or streptomycin).
Isoniazid and rifampin daily for 1 month; then isoniazid and rifampin twice weekly for 8 months. 9 months This regimen should be employed only in populations with a very low prevalence of drug resistance. Initial therapy probably should include a third drug until drug susceptibility is reported.
Table. Drug regimens for the treatment of tuberculosis.8,11,12 The Advisory Council for the Elimination of Tuberculosis of the Centers for Disease Control and Prevention advocates four-drug therapy for initial use in communities with a background prevalence of initial drug resistance of 4% or more. If susceptibility has been demonstrated or if resistance is very unlikely, three-drug regimens may be used initially.

Clinical Manifestations
TB may be manifested clinically as pulmonary disease and/or extrathoracic disease because the primary pulmonary infection may result in bacillemic dissemination. As a general rule, hosts with more competent immune systems tend to have disease limited to their lungs or other single sites, whereas those with less competent defenses may experience multifocal disease.6,10

Classic symptoms include cough, hemoptysis, fever, sweating, malaise, weight loss, and dyspnea. Patients with advanced disease may exhibit wasting (consumption). Signs may be limited until the disease reaches the advanced stages. The chest radiograph is an important component of the diagnostic work-up. Chest radiographs often reveal fibronodular shadowing in one or both lung apices. As the lesions advance, they enlarge, cavitate, and produce an intense local inflammatory reaction that may result in tissue necrosis and sloughing. Even when clinical TB is present, the tuberculin skin test will be falsely negative in up to 25% of cases.8 Acid-fast bacilli may be found in respiratory secretions.

Extrapulmonary TB may affect the lymphatic, genitourinary, skeletal, and gastrointestinal systems, as well as the pleura, pericardium, peritoneum, and central nervous system. Diagnosis may be difficult due to the relative paucity of bacilli. Histopathology of involved tissues typically shows giant-cell granulomas with caseating necrosis. Analysis of tuberculous effusions of the pleura, pericardium, and peritoneum may reveal a predominance of polymorphonuclear leukocytes in patients with early-stage disease, or a lymphocyte-rich exudate with low concentrations of glucose in those with advanced disease.

In the early stages of disease, the clinical manifestations of TB in patients with HIV may be indistinguishable from those in patients with competent immune systems. As the T-lymphocyte population declines in HIV-infected individuals, however, TB follows a predictable and devastating course. Extrapulmonary involvement occurs in the majority of HIV-infected individuals, and it may take on an exotic form such as diffuse lymphadenitis or cutaneous disease. Chest radiographs may reveal changing patterns of disease, evolving from classic upper-zone, fibronodular, cavitary changes to lower-zone, nondescript, pneumonic patterns; infrequent cavity formation; prominent hilar adenopathy; and substantial pleural effusion.

Diagnosis
Tuberculosis infection refers to a positive TB skin test with no evidence of active disease. Tuberculosis disease refers to cases that have positive acid-fast smear or culture for M. tuberculosis or radiographic and clinical presentation of TB.

Traditionally, the diagnosis of TB has been made on the basis of clinical findings and chest radiographs, confirmed by sputum or tissue smears that show TB bacilli. These methods remain the gold standard for diagnosis, but DNA probes, polymerase–chain-reaction assays, and liquid media now allow more sensitive and rapid diagnosis. Unfortunately, the increased sensitivity of rapid techniques is not always associated with increased specificity.

Skin testing should be used in conjunction with other clinical findings and is neither a sensitive nor a specific test for establishing the diagnosis.11 In extrapulmonary TB, site-specific tissue or fluid samples are submitted for smear, culture, and histologic analysis. Typically, the histologic features of a tuberculous lesion include caseating and noncaseating granulomas with giant cells.

Treatment Perspectives
Some experts believe the single most important aspect of treatment is the treatment or quarantine of individuals with communicable TB.12 In the past, patients with communicable TB were often quarantined in asylums or sanatoria. Today, pharmacotherapy has become a chemical quarantine. Hence, noncompliance with drug therapy may be considered a breach of quarantine. Because the consequences of inadequate or incomplete treatment can be devastating, directly observed therapy (DOT) to prevent noncompliance is becoming increasingly common.

Because it usually takes several weeks to culture and identify M. tuberculosis, treatment is often initiated before a definitive diagnosis is established. Generally, treatment involves a combination of drugs. The rationale for combination therapy is twofold: it is intended to prevent the emergence of drug-resistant strains and to accelerate clearance of the microorganism. In addition to combating drug resistance, multiple-drug regimens can shorten the required duration of treatment. For example, a regimen of isoniazid and ethambutol requires 18 months to cure the typical case of pulmonary TB; adding rifampin to isoniazid reduces the duration to 9 months. When an initial 2-month phase of pyrazinamide is added to isoniazid and rifampin, the duration may be shortened to 6 months.11

Because of concern regarding MDR TB, the American Thoracic Society12 recommends a four-drug regimen for most cases of known or suspected TB (Table, page 37). Isoniazid and rifampin are key agents in any regimen because of their superior bactericidal activity and relatively low toxicity. Pyrazinamide is useful for promoting rapid, early reduction in bacillary burden. Ethambutol is useful primarily to protect against the emergence of drug resistance in cases with unknown initial susceptibility patterns. The role of streptomycin is diminishing in modern therapy due to problems with the regular administration of intramuscular injections (the agent must be given parenterally); in patients with extensive TB, however, streptomycin may accelerate initial bactericidal activity.11,12

In patients with AIDS and TB, an important concern is adequate absorption of the anti-TB medications.13 These patients may not achieve adequate serum drug concentrations due to AIDS-associated enteropathy. Attainment of adequate drug levels may be confirmed by direct measurement of serum drug concentrations. If this is not feasible, then very close monitoring of responses to treatment and use of high-range drug dosing may be appropriate.

Because of problems with compliance, hepatotoxicity, and increasing resistance associated with 6-month to 12-month isoniazid programs, alternative short-course regimens have been evaluated. The Centers for Disease Control and Prevention14 reported the results of an international, randomized, 7-year trial that compared the effectiveness of two regimens in preventing TB in people with HIV infection. The two regimens were a 2-month regimen of daily rifampin plus pyrazinamide and a 12-month regimen of daily isoniazid.

The study enrolled 1,583 HIV-positive subjects aged 13 years or more. All subjects had positive tuberculin skin tests. Subjects were randomized to one of two study arms: isoniazid, 300 mg per day (with pyridoxine hydrochloride), for 12 months (n=792) or rifampin, 600 mg per day, plus pyrazinamide, 20 mg/kg per day, for 2 months (n=791).

Of patients assigned to rifampin plus pyrazinamide, 80% completed the regimen, compared with 69% assigned to isoniazid (P<.001). After a mean follow-up period of 37 months, 19 patients (2.4%) assigned to rifampin plus pyrazinamide and 26 (3.3%) assigned to isoniazid developed confirmed TB at rates of 0.8 and 1.1 per 100 person-years, respectively. In multivariate analysis, there were no significant differences in rates for confirmed or probable TB (P=.83), HIV progression and/or death (P=.09), or overall adverse events (P=.27), although drug discontinuation was slightly more prevalent in the group receiving rifampin plus pyrazinamide (P=.01). Neither regimen appeared to lead to the development of drug-resistant TB. The investigators concluded that a 2-month regimen of rifampin plus pyrazinamide and a 12-month regimen of isoniazid were similar in safety and efficacy, and suggested that the shortened regimen might offer practical advantages to both patients and TB control programs.

Conclusion
TB is a serious, highly communicable disease that creates special health concerns for the immunocompromised. Although prevalence rates for TB have been in decline since 1992, there is still concern regarding the potential for serious pulmonary and extrathoracic disease. Multidrug treatment regimens have been developed with the intention of achieving bacillary eradication and preventing drug resistance. The HIV pandemic presents a massive challenge to global TB control. Recent evidence suggests that, in immunocompromised patients, shorter-term regimens are as effective as longer-term regimens, and may offer practical advantages. DOT is becoming more common in order to ensure compliance with therapy.

John D. Zoidis, MD, is a contributing writer for RT. Phyllis C. Braun, PhD, is professor, Department of Biology, Fairfield University, Fairfield, Conn.

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