The keys to managing tuberculosis include prevention and prompt, appropriate, and complete treatment of all active cases.

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 worldwide, 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 Organization (WHO) predicts continued increases in TB and an estimated worldwide incidence of nearly 12 million cases each year by 2005.²

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 in health care workers.³ However, the incidence of M. tuberculosis infection has been decreasing in the United States since 1992 and is now at historic lows.³ In contrast, TB rates in some Asian and sub-Saharan Africa nations have increased to more than 300 cases per 100,000 population, and in some of these areas, nearly 50% of the HIV-infected population are coinfected with M. tuberculosis.^2,4

A crucial strategy for 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 mini epidemics.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 more than a half century later—in the late 1940s—that the first effective anti-TB medications (streptomycin and P-aminosalicylic acid) became available.⁶ Then, in 1952, isoniazid (INH) became available.⁶

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

Starting in 1993, the trend began to reverse again, with a yearly decline in TB cases reaching a record low of 18,361 cases 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 strategies to ensure compliance.⁸

Multidrug-Resistant TB
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 occurs when: resistance develops to two or more anti-TB drugs, specifically INH and rifampin (RIF); 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

MDR can be classified as primary (initial) or secondary (acquired). Primary resistance occurs with the detection of drug resistance in a patient with TB who has never been treated with anti-TB medications. This may occur as a result of random spontaneous genetic mutations, as is the case with any large population of bacteria regardless of their exposure to antibiotic agents, or through the acquisition of drug-resistant TB.^6,8

Secondary MDR occurs when drug-resistant organisms develop as a result of the inappropriate use of anti-TB medications or patient noncompliance with the prescribed therapy (this presumes that the patient initially had drug-susceptible organisms).^6,8

Pathophysiology
The development of TB begins with inhalation of the M. tuberculosis organism within airborne droplets expelled from 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 the blood and lymphatic systems.

In the majority of persons 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 to disseminate to the kidneys, bones, meninges, and other sites where there exists a potential for reactivation years later.

Latent TB infection occurs when an individual becomes infected with 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 (TST)—an intracutaneous test using purified protein derivative (PPD). The risk of reactivation of active disease is greatest among persons with HIV disease or other immunosuppressive illnesses or conditions, the elderly, and organ transplant recipients.

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.

Pulmonary Disease
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 TST will be falsely negative in up to 25% of cases. Acid-fast bacilli may be found in respiratory secretions.

Extrapulmonary Tuberculosis
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 (PMNs) in patients with early-stage disease, or a lymphocyte-rich exudate with low concentrations of glucose in those with advanced disease.

TB in Persons with HIV Disease
In the early stages of disease, the clinical manifestations of TB in persons infected with HIV may be indistinguishable from those in persons with competent immune systems. However, as the T-lymphocyte population declines in HIV-infected individuals, 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 effusions.

Diagnosis
The term “tuberculosis infection” refers to a positive TB skin test with no evidence of active disease. The term “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 and confirmed by sputum or tissue smears that show TB bacilli. These methods remain the gold standard for diagnosis, but development of DNA probes, polymerase chain reaction (PCR) assays, and liquid media now allows more sensitive and rapid diagnosis. Unfortunately, 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. In extrapulmonary TB, site-specific tissue or fluid samples or both are submitted for smear, culture, and histologic analysis. Typically, histologic features of a tuberculous lesion include caseating and noncaseating granulomata with giant cells.

Treatment of TB: Current Perspectives
Perhaps the single most important aspect of treatment is the public-health mandate that persons with communicable TB be either treated or quarantined. In the past, patients with communicable TB were often quarantined in asylums or sanitariums. 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: 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 INH and ethambutol (EMB) requires 18 months to cure the typical case of pulmonary TB; adding RIF to INH reduces the duration to 9 months; and when an initial 2-month phase of pyrazinamide (PZA) is added to INH and RIF, the duration may be shortened to 6 months.⁹

Because of the concern regarding MDR TB, the American Thoracic Society recommends a four-drug regimen for most cases of known or suspected TB.¹⁰ INH and RIF are key agents of any regimen because of their superior bactericidal activity and relatively low toxicity. PZA is useful for promoting rapid, early reduction in bacillary burden. EMB 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 regularly administering intramuscular injections (the agent must be given parenterally); however, in patients with extensive TB, streptomycin may accelerate initial bactericidal activity.^9,10

In patients with acquired immunodeficiency syndrome (AIDS) and TB, an important concern is to ensure adequate absorption of the anti-TB medications.¹¹ Such patients may not achieve adequate serum concentrations of drug 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- to 12-month INH programs, alternative short-course TB preventive regimens have been evaluated. Recently, the Centers for Disease Control and Prevention Study Group reported results of an international, randomized, 7-year trial that compared the effectiveness of two regimens in preventing TB in persons with HIV infection.¹² The two regimens were a 2-month regimen of daily RIF plus PZA, and a 12-month regimen of daily INH.

There were 1,583 HIV-positive persons aged 13 years or older enrolled in the study. All subjects had a positive tuberculin skin test. Subjects were randomized to one of two study arms: INH 300 mg/day (with pyridoxine hydrochloride) for 12 months (n=792); or RIF 600 mg/day plus PZA 20 mg/kg per day for 2 months (n=791).

Of patients assigned to RIF plus PZA, 80% completed the regimen, compared with 69% assigned to INH (P<0.001). After a mean follow-up of 37 months, 19 patients (2.4%) assigned to RIF plus PZA and 26 (3.3%) assigned to INH 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=0.83), HIV progression and/or death (P=0.09), or overall adverse events (P=0.27), although drug discontinuation was slightly more prevalent in the group receiving RIF plus PZA (P=0.01). Neither regimen appeared to lead to the development of drug-resistant TB. The investigators concluded that a 2-month regimen of RIF plus PZA and a 12-month regimen of INH were similar in safety and efficacy, and suggested that the shorter regimen might offer practical advantages to both patients and TB control programs.

Conclusion
TB is a serious, highly communicable disease that poses special health concerns to persons with an immunocompromised status. 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. 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 Magazine and Phyllis C. Braun, PhD, is Professor, Department of Biology, Fairfield University, Conn.

References
1. Raviglione MC, Snider DE Jr, Kochi A. Global epidemiology of tuberculosis: morbidity and mortality of a worldwide epidemic. JAMA. 1995;273:220-226.
2. Global tuberculosis programme. In: Global Tuberculosis Control. WHO report 1998. Geneva: World Health Organization; 1998:237.
3. Centers for Disease Control and Prevention. Reported Tuberculosis in the United States, 1998. Atlanta: Centers for Disease Control and Prevention; 1999.
4. Bates JH, Stead WW. The history of tuberculosis as a global epidemic. Med Clin North Am. 1993;77:1205-1217.
5. Chaulk CP. Tuberculosis elimination and the challenge of the long-term completer. Int J Tuberc Lung Dis. 1999;3:269.
6. McCray E, Weinbaum CM, Braden CR. The epidemiology of tuberculosis in the United States. Clin Chest Med. 1997;18:99-113.
7. Drobniewski FA, Yates MD. Multiple drug resistant tuberculosis. J Clin Pathol. 1997;50:89-90.
8. Centers for Disease Control and Prevention. Tuberculosis elimination revisited: obstacles, opportunities, and a renewed commitment. MMWR Morb Mortal Wkly Rep. 1999;48(RR-9):2.
9. Iseman MD. Tuberculosis. In: Goldman L, Bennett JC, eds. Cecil Textbook of Medicine. 21st ed. Philadelphia: WB Saunders Co; 2000:1723-1731.
10. American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med. 1994;149:1359-1364.
11. Advisory Committee for the Elimination of Tuberculosis. Screening for tuberculosis and tuberculosis infection in high-risk populations and the use of preventive therapy for tuberculosis infection in the United States. Recommendation of the Advisory Committee for the Elimination of Tuberculosis. MMWR Morb Mortal Wkly Rep. 1990;39:7-15.
12. Gordin F, Chaisson RE, Matts JP, et al. Rifampin and pyrazinamide vs isoniazid for prevention of tuberculosis in HIV-infected persons. An international randomized trial. JAMA. 2000;283:1445-1450.