Update on Tuberculosis

For patients with TB, chemical quarantine via pharmacotherapy is the modern alternative to isolation in asylums or sanitaria.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, a small, rod-shaped, aerobic bacillus that does not form spores. Globally, TB remains a leading infectious cause of morbidity and mortality. The incidence of TB increased worldwide in 2003 (the most recent year for which comprehensive data are available), but the incidence of TB and TB-related mortality remained stable or decreased in several regions, including Latin America and Central Europe.¹ Incidence remains high in Eastern Europe and eastern and southern Africa, where rates of HIV infection are also high.¹ 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 the HIV-infected population is co-infected with M. tuberculosis.^2,3 In the United States, 28 states have TB rates of more than 3.5 cases per 100,000 (the cutoff point below which the Advisory Council for the Elimination of Tuberculosis⁴ considers incidence to be low). Costs for TB-related hospitalizations exceed $385 million annually in the United States.⁵

Prompt, appropriate, complete treatment of all active cases is crucial to the successful elimination of TB. 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.⁶

Multidrug-Resistant TB
During the past 3 decades, the prevalence of multidrug-resistant TB among individuals with pulmonary TB in the United States has steadily increased from 2% to 9%.⁷ Multidrug-resistant TB occurs 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.^7,8

Multidrug-resistant TB 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 initial infection by drug-resistant TB.^6,9 Secondary multidrug-resistant TB 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 definition presumes that the patient was initially infected by drug-susceptible organisms.^6,9

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 through the blood and lymphatic systems.

In the majority of 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 to disseminate to the kidneys, bones, meninges, and other sites where there is a possibility of 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 intracutaneous test using purified protein derivative (PPD). The risk of reactivation of active disease is greatest among those with HIV disease or other immunosuppressive illnesses or conditions, the elderly, and organ transplant recipients. TB may, in fact, be one of the most common HIV-related opportunistic infections.^10,11

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.

Classic TB 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. 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 granulomata 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 people infected with HIV may be indistinguishable from those in people 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 effusions.

Diagnosis
The term tuberculosis infection refers to a positive PPD tuberculin skin test with no evidence of active disease. The term tuberculosis disease refers to cases that have positive acid-fast smears or cultures for M. tuberculosis or radiographic and clinical presentations 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 the development of DNA probes, polymerase chain reaction assays, and liquid media now allows 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. In extrapulmonary TB, site-specific tissue or fluid samples, or both, are submitted for smear, culture, and histologic analysis. Typically, the histologic features of a tuberculous lesion include caseating and noncaseating granulomata with giant cells.

The tuberculin skin test is the most reliable means of identifying infection by M. tuberculosis in people who do not have TB disease.¹² The reaction to subcutaneously injected tuberculin is a delayed-type (cellular) hypersensitivity (DTH) reaction, and infection by M. tuberculosis usually results in a DTH response to PPD tuberculin that is detectable 2 to 12 weeks after infection.¹³ The DTH reaction to PPD tuberculin usually begins about 56 hours after injection, peaks at about 48 to 72 hours, and subsides over a period of a few days, although positive reactions may persist for up to a week.¹⁴

In its latest guidelines for the diagnosis and treatment of latent TB infection,¹² the American Thoracic Society (ATS) has identified three cutoff levels for the amount of induration that indicates tuberculin positivity: 5 mm, 10 mm, and 15 mm. The cutoff levels are based on the sensitivity and specificity of the tuberculin skin test and the prevalence of TB in groups at different risk levels. High-risk groups (those with the greatest risk of developing TB disease if they become infected with M. tuberculosis) include HIV-positive people, those who have been in contact with known TB cases, those with fibrotic changes on chest radiography consistent with prior TB, and those who are immunosuppressed (for example, people with organ transplants) or otherwise immunocompromised. For such high-risk patients, the recommended cutoff level of skin induration indicating a positive test is 5 mm. People with intermediate risk include those who have immigrated from high-prevalence countries within the previous 5 years; injection drug users; residents and employees of high-risk settings (such as nursing homes, jails, and homeless shelters); mycobacteriology laboratory personnel; people with clinical conditions that place them at risk for TB (chronic renal failure, diabetes, leukemia, lymphoma, silicosis, gastrectomy, and jejunoileal bypass); children less than 4 years of age; and infants, children, or adolescents exposed to high-risk adults. For intermediate-risk patients, the recommended cutoff level of skin induration indicating tuberculin positivity is 10 mm. Low-risk people are those with no risk factors for TB; in this group, the recommended cutoff level of skin induration that indicates tuberculin positivity is 15 mm. A tuberculin skin test conversion is now defined as an increase of 10 mm or more of induration within a 2-year period, regardless of age.¹²

Current Perspectives
Perhaps the single most important aspect of treatment is the public-health mandate that people with communicable TB be either treated or quarantined. Long ago, patients with communicable TB were often quarantined in asylums or sanitaria. 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 may shorten the required duration of treatment.

In 2000, the ATS revised its guidelines for the treatment of latent TB infection.¹² One of the major changes from previous guidelines is the recognition that long-term isoniazid treatment may be associated with adverse events and poor adherence; hence, there has been a shift toward shorter, rifampin-based regimens. Additional changes from the previous guidelines are summarized in the table.

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 regularly administering intramuscular injections (the agent must be given parenterally); however, in patients with extensive TB, streptomycin may accelerate initial bactericidal activity.¹⁵

In patients with AIDS and TB, an important concern is to ensure adequate absorption of the anti-TB medications.¹⁶ 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.

Treatments in Development
Several anti-TB drugs in development are variations of existing drugs. Nitroimidazole (PA-824)^17,18 and an ethambutol analog (SQ-109)¹⁹ are currently being evaluated in preclinical trials. Some quinolone antibiotics, including moxifloxacin^20,21 and gatifloxacin,^22,23 are also being tested in clinical trials for efficacy in patients with TB. A quinolone derivative, diarylquinoline R207910, is being evaluated in early clinical trials for efficacy against TB. This agent appears to inhibit both drug-sensitive and drug-resistant M. tuberculosis, possibly because of a unique mechanism of action that targets the proton pump of ATP synthase.²⁴ In preclinical trials, R207910 accelerated bactericidal activity, leading to complete culture conversion after 2 months of treatment with various combinations of rifampin, isoniazid, and pyrazinamide.²⁴

Conclusion
TB is a serious, highly communicable disease that poses special health concerns to immunocompromised people. Although prevalence rates for TB have been in decline in most parts of the developed world, 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 adherence 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.

References
1. Dye C, Watt CJ, Bleed DM, Hosseini SM, Raviglione MC. Evolution of tuberculosis control and prospects for reducing tuberculosis incidence, prevalence, and deaths globally. JAMA. 2005;293:2767-2775.
2. Global tuberculosis programme. In: Global Tuberculosis Control. WHO Report 1998. Geneva: World Health Organization; 1998:237.
3. Bates JH, Stead WW. The history of tuberculosis as a global epidemic. Med Clin North Am. 1993;77:1205-1217.
4. Jereb JA. Progressing toward tuberculosis elimination in low-incidence areas of the United States. Recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR Recomm Rep. 2002;51:1-14.
5. Hansel NN, Merriman B, Haponik EF, Diette GB. Hospitalizations for tuberculosis in the United States in 2000: predictors of in-hospital mortality. Chest. 2004;126:1079-1086.
6. Chaulk CP. Tuberculosis elimination and the challenge of the long-term completer. Int J Tuberc Lung Dis. 1999;3:269.
7. Advisory Council for the Elimination of Tuberculosis (ACET). Tuberculosis elimination revisited: obstacles, opportunities, and a renewed commitment. MMWR Recomm Rep. 1999;48:1-13.
8. Drobniewski FA, Yates MD. Multiple drug resistant tuberculosis. J Clin Pathol. 1997;50:89-90.
9. McCray E, Weinbaum CM, Braden CR. The epidemiology of tuberculosis in the United States. Clin Chest Med. 1997;18:99-113.
10. Franco-Paredes C. HIV infection as a risk factor for activation of latent tuberculosis. Infections in Medicine. 2002;19:475-479.
11. Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med. 2003;163:1009-1021.
12. American Thoracic Society/Centers for Disease Control and Prevention Statement Committee on Latent Tuberculosis Infection. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Recomm Rep. 2000;49:1-51.
13. Huebner RE, Schein W, Bass JB Jr. The tuberculin skin test. Clin Infect Dis. 1993;17:968-975.
14. Cauthen GW, Valway SE. Tuberculin reactions read at 2 and 7 days. Am J Respir Crit Care Med. 1994;149:A101.
15. American Thoracic Society/Centers for Disease Control and Prevention. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med. 1994;149:1359-1364.
16. 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.
17. Lenaerts AJ, Gruppo V, Marietta KS, et al. Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models. Antimicrob Agents Chemother. 2005;49:2294-2301.
18. Tyagi S, Nuermberger E, Yoshimatsu T, et al. Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. Antimicrob Agents Chemother. 2005;49:2289-2293.
19. Jia L, Tomaszewski JE, Hanrahan C, et al. Pharmacodynamics and pharmacokinetics of SQ109, a new diamine-based antitubercular drug. Br J Pharmacol. 2005;144:80-87.
20. Ginsburg AS, Lee J, Woolwine SC, Grosset JH, Hamzeh FM, Bishai WR. Modeling in vivo pharmacokinetics and pharmacodynamics of moxifloxacin therapy for Mycobacterium tuberculosis infection by using a novel cartridge system. Antimicrob Agents Chemother. 2005;49:853-856.
21. Tortoli E, Dionisio D, Fabbri C. Evaluation of moxifloxacin activity in vitro against Mycobacterium tuberculosis, including resistant and multidrug-resistant strains. J Chemother. 2004;16:334-336.
22. Paramasivan CN, Sulochana S, Kubendiran G, Venkatesan P, Mitchison DA. Bactericidal action of gatifloxacin, rifampin, and isoniazid on logarithmic- and stationary-phase cultures of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2005;49:627-633.
23. Cynamon MH, Sklaney M. Gatifloxacin and ethionamide as the foundation for therapy of tuberculosis. Antimicrob Agents Chemother. 2003;47:2442-2444.
24. Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science. 2005;307:223-227.