Tuberculosis Screening and Prophylaxis

Benjamin Davis

An estimated 7% of the US population has evidence of tuberculosis (TB) infection; most are asymptomatic, discovered largely by screening. The epidemiology of TB is changing, with active increasingly likely to emerge from recent infection rather than from reactivation of latent tuberculosis infection (LTBI). This is especially true among certain populations, such as the homeless or patients infected with HIV. Recently infected persons are at much greater risk of progression to clinically active disease. On a daily basis, the primary physician faces the questions of whether to test for reactivity and how to respond when testing is positive. Priority is given for identifying, testing, and treating those at highest risk for progression to active disease so that an effective, timely program of prophylactic antibiotic therapy can be implemented and prevent the development of active disease.

EPIDEMIOLOGY AND RISK FACTORS (1, 2, 3, 4, 5, 6, 7, 8 and 9)

Until the mid-1980s, the number of reported TB cases in the United States was declining at an annual rate of about 6%, with most new cases occurring among the institutionalized elderly, who represented a remaining pool of latent endogenous infection. The prevalence of tuberculin skin test (TST) positivity in this population has been estimated at 20% and the prevalence of active disease at 2.4%. In 1985, the incidence of active TB began to grow for the first time in half a century, in part because of the HIV epidemic but also because of cutbacks in funding for the public health clinics responsible for treating and preventing TB. Federal resources were returned to state and local TB control programs in the early 1990s. Since 1992, the rates of TB have fallen annually, and by 2012, a rate of 3.4 cases per 100,000 represented the lowest seen since national reporting began in 1953, down over 40%.

Nonetheless, TB remains a problem for patients infected with HIV, the foreign born (23.4 cases per 100,000—highest among persons from sub-Saharan Africa and Southeast Asia), and the urban poor, especially the homeless. Compared to persons uninfected with HIV (whose risk for development of active TB after infection is 10% per lifetime), HIV-infected persons have a risk for development of active disease of 10% per year. Other population groups with a disproportionately high incidence of TB include alcoholics; IV drug users; patients with diabetes, malnutrition, end-stage renal disease, silicosis, or head and neck cancer; and persons who have undergone gastrectomy or are taking immunosuppressive drugs (including tumor necrosis factor [TNF] inhibitors).

NATURAL HISTORY OF TUBERCULOSIS AND EFFECTIVENESS OF THERAPY (4,10, 11, 12, 13, 14, 15, 16 and 17)

Natural History

Mycobacterium tuberculosis is transmitted by way of fresh droplet nuclei expelled by a person with active pulmonary disease. It cannot be spread by hands, utensils, or other fomites, although organisms can be cultivated from room dust. Although inoculation can occur via the gastrointestinal tract, the vast majority of infections in the United States begin in the lung (see Chapter 49). Until the HIV epidemic, it was rare for primary infection to result in early progressive disease; young children were at greatest risk for this complication. However, among HIV-positive patients, the risk for rapid progression to active disease is substantial, with some studies showing a rate of 30% and a mean incubation period of only 80 days. Based on polymerase chain reaction and molecular epidemiology studies, it is now felt that 40% of all active TB cases in urban centers like New York City represent newly acquired infection rather than reactivation of latent disease.

Approximately 5% to 15% of new tuberculous infections eventually progress to serious disease. Risk is greatest during the years immediately following infection. Late reactivation occurs in only 3% to 5% of patients without clinical disease 5 years after infection.

Effectiveness of Therapy

Two basic strategies are used in the prevention of clinical infection: (1) biologic prophylaxis of uninfected persons with Bacille Calmette-Guérin (BCG) vaccine and (2) chemoprophylaxis of both newly or recently infected persons and selected persons with long-standing latent infection.

Biologic Prophylaxis

Biologic prophylaxis with BCG vaccine is widely practiced in countries where TB is prevalent. The vaccine is used for prevention in uninfected persons; it is of no value in infected persons. BCG vaccine contains a live, attenuated strain of Mycobacterium bovis that has little virulence in humans. It should not be administered to patients who react positively to the purified protein derivative (PPD) tuberculin skin test. BCG itself may cause a positive PPD test result in the first 2 to 3 years following vaccination. After this period, however, a positive PPD test result should not be ascribed to vaccination with BCG, nor should prior BCG vaccination be considered a reason not to perform skin testing, if it is otherwise indicated. The vaccine has been in clinical use since 1922, but its role remains controversial. Early trials demonstrated that BCG could prevent TB in up to 80% of recipients, but subsequent trials on the Indian subcontinent failed to demonstrate efficacy. Even though recent studies in Great Britain and Canada suggest that the vaccine may be up to 60% effective, BCG is not currently recommended for routine use in the United States. The relatively low incidence of new tuberculous infections in the United States still makes case finding and INH prophylaxis a more effective approach (see below).

Chemoprophylaxis

Effective regimens for chemoprophylaxis have been established. Chemoprophylaxis significantly reduces the risk for progression from newly acquired or latent infection to active disease.

Isoniazid.

Daily administration of isoniazid (INH) reduces the risk for reactivation by up to 90% in persons completing a 9-month course and by 80% in those completing a 6-month course. When INH is used for prophylaxis, best results are achieved when there is good compliance with daily use for 9 months. This recommendation applies to persons with or without HIV infection and with or without fibronodular infiltrates on chest radiograph. INH may also be given twice weekly via directly observed therapy (DOT). Enthusiasm for INH prophylaxis must be tempered by the significant side effects of the drug, particularly hepatotoxicity. Liver injury is quite rare in patients younger than 20 years and occurs in no more than 0.2% of those between ages 20 and 34. On the other hand, INH-induced liver disease may develop in more than 2% of patients older than 50 (see Chapter 49).

Alternative Programs.

Reasonably effective alternatives to INH chemoprophylaxis have been established. Daily rifampin for 3 months (typical program is 4 months) has an observed 60% efficacy and is useful for persons who cannot tolerate the hepatic side effects of INH (drug-drug interactions and cytopenias are drawbacks). Compliance is better, and the drug is better tolerated compared to 9 months of INH. The combination INH plus rifampin for 3 months represents a potentially more effective alternative for those unlikely to maintain compliance with a 6- to 9-month INH prophylaxis program. Rifabutin, a new rifamycin agent with fewer drug-drug interactions (an important consideration in patients being treated for HIV infection), is being studied for use in conjunction with INH. Similarly, rifapentine plus INH represents another rifamycinderived shorter-course treatment program.

Response to Treatment.

As noted, response to chemoprophylaxis is good even in persons who are compromised hosts such as those with HIV. In an era of emerging resistant and multidrugresistant strains of TB, concerns have surfaced regarding the continued efficacy of standard INH chemoprophylaxis. New first-line chemoprophylaxis programs have been suggested. In a study of persons with latent TB and HIV infection comparing the standard INH program with newer regimens such as 3-month intermittent rifapentine, rifampin plus isoniazid for 3 months, or continuous INH, all regimens were found equally effective, and concerns about emergence of multidrug-resistant TB strains did not materialize. (Of note, adherence averaged 90% during the study, which might be greater than in everyday practice.) Whether such efficacy will be sustained in the setting of increasing exposure to multidrug-resistant strains of TB remains to be seen. Of note, compliance is a major determinant of response, falling from 75% for 3-month programs to as little as 45% with a 9-month program.

Patient Selection and Maximizing Adherence.

Patient selection needs to take into account the risk of developing active disease, the patient’s overall medical condition, and ability to tolerate and comply with a protracted prophylactic program of chemoprophylaxis. Because the risk for progressive disease is greatest soon after infection, recent converters to tuberculin reactivity are most likely to benefit from such therapy. Guidelines for chemoprophylaxis of LTBI were revised over a decade ago by the American Thoracic Society (ATS), the Centers for Disease Control (CDC), and the Infectious Disease Society of America (IDSA) to sharpen the focus of tuberculin screening and chemoprophylaxis to those populations most likely to progress from latent infection to active pulmonary TB and to deemphasize the routine screening and chemoprophylaxis of persons at low risk of active TB. A person’s candidacy for INH chemoprophylaxis should no longer depend on age, provided that other risk factors for progression to active disease are present. Such risk factors include known or suspected HIV infection;
contacts of patients with known active pulmonary TB, including children and adolescents; chest radiography compatible with old, healed TB (5 mm); solid organ transplantation or treatment with immunosuppressive drugs; recent immigration from countries where TB is endemic; homelessness; documented PPD conversion within the preceding 2 years; injection drug abuse; other medical conditions predisposing to active TB; and occupational exposure.

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