Tuberculosis (TB) is an airborne infectious disease caused by Mycobacterium tuberculosis. A third of the world’s population is infected with the tubercle bacillus, 10 million new cases of TB occur annually, and two to three million people die of the disease each year. Most cases occur in Africa and Asia, 30 percent in India alone, where one person dies of TB every minute. In 1993, the World Health Organization declared TB a "global emergency"; it has killed 30 million people since then. Current mathematical models predict 225 million new cases and 80 million deaths from TB over the next three decades.

TB, the "white plague," was the leading cause of death among young people in the 19th century. During the first half of the 20th century, incidence and mortality steadily declined and TB was on the brink of elimination in many industrialized nations. In the 1980s, TB rates in the United States suddenly doubled, in an explosive collision with HIV. Ineffective infection-control practices, poor adherence to treatment, and resistance to medications were important ingredients in numerous outbreaks. The concentration of TB among minorities, the homeless, and intravenous drug users, however, bespoke additional important socioeconomic factors.

Some 10 to 15 million people in the U.S. are infected with M. tuberculosis. There are 16,000 new cases of TB in the country every year, 1,300 in NYC (compared to a peak of almost 4,000 cases in 1992). In NYC, half the cases occur between the ages of 25 and 54. Two-thirds of the cases are men, 40 percent are African American (though incidence rates are twice as high among Asian Americans), and 60 percent are born abroad; approximately 20 percent are HIV-positive.

TB incidence in the U.S. peaked in 1992 and has since been reduced to a new historical low (6 cases per 100,000 people – although six times that in foreign-born people). The tide was turned by physician education, hospital isolation policies, and directly observed therapy (DOT) efforts spearheaded by the NYC Department of Health. From 1992 to 2000, TB incidence declined by 70 percent (from 52 to 16 per 100,000), particularly among US-born and HIV-infected people, while the numbers of multi-drug-resistant TB (MDR-TB) have decreased by 95 percent (from 441 to just 25 cases.) Despite this success, the complacency of the 1980s and its tragic consequences must be avoided. Indeed, with proportion of TB among foreign-born patients is increasing, and early detection and prophylaxis is a new challenge. Controlling TB abroad, of course, is the ultimate solution to this problem.

Surveillance of high-risk groups (prisons, shelters, hospitals) and continued education and alertness among health care professionals are important strategies to maintain control of TB. Coordinating efforts by Departments of Health are critical as are timely reporting of cases and contact investigation. Chest X-ray screening campaigns were abandoned long ago, and today’s favored strategy is targeted PPD screening and isoniazid (INH) prophylaxis. Since one patient with TB will infect ten other people, the most important preventive strategy remains the prompt detection, isolation and cure of active infectious cases.

The BCG (bacille Calmette-Guerin) vaccine (attenuated strains of M. bovis) is widely used, with 70 percent coverage of the world population, especially in developing countries. BCG is safe, even among persons with asymptomatic HIV infection. The vaccination is not practiced in North America, however, because of the relatively low incidence of TB, possible interference with PPD testing, and limited efficacy. A recent meta-analysis of 14 prospective trials and 12 case-control studies of BCG vaccination, however, found that it decreases TB incidence by 50 percent and mortality by 70 percent, particularly in children. Elucidation of the full sequence of the 4,000 genes of M. tuberculosis in 1998 has boosted hopes for a better vaccine.

Nurses are the health care professionals at highest risk of acquiring TB. Physicians have twice the age-specific incidence rate as the general population. Teaching hospitals care for a large proportion of TB patients in NYC where PPD conversion among junior housestaff reached 10 to 15 percent per year in 1990. Proper isolation practices at Presbyterian Hospital have reduced this rate to virtually zero. Continued vigilance is key.

Although the majority of TB patients in NYC have contact with a health care provider prior to diagnosis, less than one-third have had PPD testing. Reactivity from childhood BCG vaccination (usually less than 15 mm) does not explain PPD results in adults. Unless already known to be positive or treated, PPD testing should be repeated every 6 months to two years while indicated (Table 1). People 35 years or older with no risk factors and a previously normal CXR need not be screened; on the other hand, foreign-born diabetics in our clinics should not be ignored.

A positive PPD is presumptive evidence of mycobacterial infection and does not occur as a result of prior PPD testing or allergy to the diluent. If active TB infection has been excluded, a person with a positive PPD is said to have "latent TB infection" (LTBI). Anergy occurs in pulmonary TB (15 percent), but is more common in pleural or miliary TB (30 to 50 percent), patients with HIV infection (30 percent) or AIDS (70 percent), and those with malnutrition. Technical problems in storage or subcutaneous administration of PPD also lead to false-negative results. False positive reactions may be seen in BCG-vaccinated people (within 10 years of initial vaccination, rarely > 15mm), and in people from areas with nonpathogenic mycobacteria (tropical countries and the SE USA). In our setting, positive PPD reactions in BCG-vaccinated persons usually indicate TB infection.

Table 1: Indications for PPD screening ^,

Boosting refers to an apparent PPD "conversion" in TB-infected people whose immunologic memory has faded and is then stimulated after repeat tuberculin testing. PPD testing by itself does not sensitize a noninfected person. Boosting may last one to two years after a PPD, and it may lead to otherwise unnecessary prophylaxis and source-case investigations in congregate settings. In order to avoid such confusion, older people with indications for periodic PPD testing should have a confirmatory PPD test within a month of their first negative result (Table 3).

Table 2: Initial PPD strategy in older people (e.g. upon entering a nursing home)

The report "Ending Neglect," issued by the Institute of Medicine and sponsored by the U.S. Centers for Disease Control and Prevention, recommends mandatory screening for latent TB infection in immigrants from high prevalence countries. Some experts have viewed the new guidelines as ineffective at best and as coercive and discriminatory at worst. While a basic principle in clinical epidemiology specifies that the positive predictive value of a test is inversely proportional to the risk (or prevalence) of a disease, there is a flaw in the screening argument that rarely gets exposed. While the incidence of active disease and the prevalence of latent infection are higher in many immigrants, so are the causes of false positive PPD results (BCG vaccination and infection with mycobacteria other than TB.) A healthy immigrant living in the U.S. for five or more years and without explicit risk factors stands to gain little from screening and chemoprophylaxis. We recommend that you remember the guidelines for your Boards, but use clinical judgment with your patients.

Chemoprophylaxis (e.g. treatment of latent TB infection) may prevent infection in PPD-negative contacts of contagious persons (primary prevention), abort disease in those already infected (secondary prevention), and prevent recurrences in those with lung scars from remote disease (tertiary prevention). There is no evidence that prophylactic chemotherapy fosters drug resistance. Current recommendations are based on risk/benefit yields, which vary over time and in different populations (Table 3).

Without prophylaxis, TB undergoes clinical reactivation in five to 15 percent of PPD-positive subjects (three percent of nursing home residents). Since 50 percent of TB reactivates within the first two years of infection, recent converters and PPD-negative contacts of active TB cases are good targets for prophylaxis. Among HIV-infected patients with a positive PPD, the risk of reactivation increases nearly a hundred-fold. Subjects with inactive TB changes in CXR (calcified nodes, pleural thickening and lung scars), a positive PPD, and no prior treatment are also at high risk for reactivation.

INH is the most effective drug for TB prevention. In most situations, 10 mg/kg (max 300 mg/day) is used; pyridoxine (25 mg/day) may be given at the same time to avoid risk of neuropathy. The recommended duration of treatment is six months (70 percent effective); nine-month regimens are preferred in children. Twelve-month regimens are reserved for patients with HIV and those with abnormal CXR. Two-month regimens with RIF and PZA have evolved recently, but liver toxicity is a concern.

Contraindications to chemoprophylaxis include active TB, liver disease, and INH hypersensitivity (rash or fever.) Special precautions (i.e., precise dosing and initial and monthly LFT monitoring) should be taken in patients over 35, those with a history of alcohol abuse, chronic liver disease, peripheral neuropathy and pregnancy. In pregnant women with a positive PPD, prophylaxis should generally be deferred until 3-months postpartum except in HIV-infected patients and recent PPD-converters. INH should not be given in the first trimester of pregnancy; breast-feeding is not contraindicated nor is it a substitute for the infant’s chemophrophylaxis if warranted.

Table 3: Indications for INH chemoprophylaxis* ^,

This is a problem with, as yet, no answer. Despite INH-resistance rates of up to 20 percent in NYC, INH is still given to most patients. For PPD-positive contacts of TB patients with known INH-resistance, the two-month regimen with RIF/PZA is appropriate. A specialist should be consulted in MDRTB cases.

There are two keys to the diagnosis of active TB. First, think TB in any patient with unexplained cough, fever or CXR abnormalities, especially if HIV-infected. Patients with HIV may present with primary rather than reactivation TB, and CXR patterns may not be reliable. In addition, delays in TB treatment in HIV-infected patients may double mortality. Secondly, obtain adequate specimens before treatment is started. Remember that the PPD is positive in 90 percent of patients with active TB, but that PPD-specific anergy does occur (e.g. the test may be negative even when a patient displays a positive reaction to control antigens). Also keep in mind that only 90 percent of reactivated TB occurs in the lungs. Extrapulmonary disease is the main clinical presentation in 15 percent of cases, and may include pleurisy, lymphadenitis, GU tract, bone, miliary, and intracraneal forms. All newly-diagnosed TB must be reported to the NYC Department of Health within two days.

Chest xrays may be suggestive but are never diagnostic for TB. Radiologic presentation may range from ARDS-like (four percent) to totally normal in appearance (five to ten percent.) Lateral and lordotic views and CT scans may be necessary in some cases. The classic presentation of reactivation TB in an immunocompetent patient is posterior apical infiltrates with or without cavitation (50 percent), but hilar adenopathy is most common in immunocompromised hosts (40 percent). Pleural effusion (25 percent) and miliary disease (five to ten percent) may be seen in both clinical settings.

AFB smear of sputum: Three adequate sputum samples will yield AFB in over 60 percent of cases with pulmonary TB; this figure is as high as 95 percent in those with cavitary disease, but as low as 30 percent in AIDS patients or those with primary or miliary TB. Bronchoalveolar lavage does not improve this yield, although it does improve the yield of cultures. If AFB smears are negative in the first three specimens, three additional specimens should be collected in suspected cases. Remember that TB cultures take weeks to grow and that smear-negative culture-positive TB is not a rarity; negative AFB smears do not exclude the possibility of TB infection!

M.Tb. cultures: standard culture techniques require three to six weeks, and cultures may be negative in up to 20 percent of sputum samples (over 50 percent in pleurisy, ascitis or CSF). Rapid and sensitive radiometric methods expedite AFB identification, and DNA-based tests may become standard in the future.

The classic study of the natural history of TB was conducted in India during the 1960’s and showed that 30 percent of patients with active TB die in 18 months and 50 percent die in five years. Nearly one-third of the cases improved with little or no treatment; of those with spontaneous "cure," 28 percent reactivate 15 to 25 years later. Mortality rates in NYC are also high – 25 percent in 1991 – particularly in those patients infected with HIV, those with multi-drug resistant TB, and the elderly.

Effective medical treatment was introduced more than 30 years ago; the efficacy of the so-called "second line" agents has not been appropriately evaluated, although the quinolones are very useful. In the 1980’s, the classically long treatments (one to two years) were progressively replaced by multi-drug, short-course regimens that include RIF and PZA. Tablets with fixed dose combinations of first-line drugs are available and recommended.

One of the most feared complications of anti-TB therapy and chemoprophylaxis is hepatitis, with a case-fatality rate of seven percent if the offending drug is not stopped. This complication is rare in young people (0.5 percent in those under 35), but increases with age; the toxicities of INH and RIF are synergistic. Most cases are noted within the first three months of treatment. Transaminase levels up to three times baseline are common (15 percent) and, if asymptomatic, should only lead to continued monitoring. Five-fold elevation of transaminases call for action - consult a specialist before withdrawing any drug!

As clinicians began to appreciate the scope of nonadherence to TB medication, short-course regimens emerged. Six-month regimens that include three to four drugs in the first two months have proved as effective as prolonged treatment (> 95 percent cure), with minimal increase in toxicity and improved completion rates. Drug-therapy should not be stopped, however, before three months of documented culture conversion.

The therapeutic response among HIV-positive patients is as good as in HIV-negative cases. Late relapse and reinfection do occur, but drug interactions and toxicities are frequent problems; thus treatment should last 6 to 9 months. Adult patients with TB and unknown HIV status should consider counseling and testing. The combination of anti-TB drugs, AZT and lamuvidine is well-tolerated. However, in patients taking protease inhibitors (or some NNRTIs), RIF is contraindicated as suboptimal antiviral levels and RIF toxicity (particularly with Ritonavir) may occur; in such situations low dose rifabutin is recommended.

Baseline LFTs should be obtained in every patient; follow-up LFTs are warranted in older patients, those with abnormal baseline levels, and those with history of alcoholism; periodic monitoring is controversial in asymptomatic young patients, but checking LFTs one or two months after starting treatment seems reasonable. Patients who are alcoholic, diabetic, malnourished or elderly should be given pyridoxine (vitamin B6, 25 mg/day) to prevent INH peripheral neuropathy. Patients on EMB should have their color vision and visual acuity monitored monthly.

Symptoms usually improve after one to two weeks of treatment; AFB cultures become negative after four to 10 weeks of effective treatment (90 percent). Contagiousness drops after two weeks, and isolation may be stopped at that point in the presence of clinical and microbiological response. CXR findings usually resolve in three to four months. The treating physician should follow patients on a monthly basis to ensure adherence, evaluate for drug toxicity, make dose adjustments and detect recurrence of symptoms. Relapse after cure is extremely rare in HIV-negative patients with pansensitive TB (less than three percent) and continued follow-up after the first year is unnecessary.

Adherence is a major problem with all regimens: patient default occurs in 20 to 50 percent of cases and often goes unsuspected. Monitoring missed appointments, pill counting and testing urine for medication metabolites or serum for hyperuricemia (caused by PZA) may be useful. Although patient education and incentives are useful, closely supervised treatment is the preferred strategy to ensure adherence. Directly observed therapy is mandatory in patients with MDRTB and "delinquent" cases. Involuntary detention is rarely required.

Random mutation yields drug resistance in 1 of 10^5-8 mycobacteria. In 1950, INH/SM resistance was found in one to two percent of TB cases. In 1991, resistance to at least one anti-TB drug was found in 33 percent of patients in NYC; 19 percent had resistance to both INH and RIF (seven percent if previously untreated), making them MDR cases. After much work and 1 billion dollars, the prevalence of MDR in new patients is now less than two percent (the global average.) Culturing every patient at the outset and starting a four-drug regimen are critical initial steps. Expert consultation is mandatory in the management of drug-resistant TB and treatment failures; prolonged treatment (one to two years) and complex regimens are necessary in patients with MDR-TB.