Tuberculosis is an ancient disease that remains one of the world's most serious infections. In 1990, the World Health Organization estimated that approximately 1.7 billion people were infected (tuberculin positive) with the tubercle bacillus among whom eight million had active disease. The vast majority of active cases were in developing countries. 2.9 million people die annually from this disease.

Discovered in 1882 by Koch, the tubercle bacillus is the number one cause of death in developing countries. In the United States, tuberculosis was initially recorded as increasing as early as the eighteenth century, accounting for 300 deaths/100,000 in 1786 and 1,600/100,000 in 1800. By the end of the 19th century, the prevalence of the disease had peaked and mortality fell to 113/100,000 by the year 1920, steadily declining until 1985 (new case rate of 9/100,000).

The downward trend left the U.S. ill prepared for the recrudescence of TB, as well as the more ominous emergence of drug resistant organisms, which began in the 1980s. Several factors contributed to the increase in the number of cases of tuberculosis in the United States: (1.) HIV infections; (2.) changing social conditions (e.g., homelessness) favoring the transmission of tuberculosis; and (3.) the increase in immigration from high prevalence areas. Nearly a decade passed before the downward trend in new cases began once again.

Two closely related mycobacteria, M.bovis and M. tuberculosis, consistently cause disease in man. Archeological evidence suggests that the disease began in cattle and was transmitted to man at the time of the domestication of these animals, approximately ten thousand years ago. M. tuberculosis, which has a high degree of genetic homology with M. bovis, is felt to be a variant of the original M. bovis strain and is better adapted for establishing a parasitic relationship with man.

There are more than 54 different species of mycobacteria. The cell wall of the mycobacterium is characterized by the presence of mycolic acid, an alpha branched, beta-hydroxyl fatty acid. In addition to M. bovis and M. tuberculosis, there is a wide variety of non-tuberculous mycobacteria. Diseases due to these microorganisms are designated as mycobacteriosis.

A common classification used to identify non-tuberculous mycobacteria is the Runyon grouping: I photochromogens (e.g., M. kansasii); II scotochromagens; III Non-photochromogens (e.g, M. avium) and IV rapid growers (e.g., M. fortuitum).

For decades, biochemical tests remained the only means of identifying mycobacterial species. Such testing usually added two to four weeks to the time that it normally takes to grow the original isolate on culture media. Improved growth rates have been achieved with newer growth media such as the BACTEC system. Non-subculture methods for identifying M.tuberculosis have been introduced: a high pressure liquid chromatography (HPLC) system and nucleic acid probes and nucleic acid amplification (NAA), which can confirm within an hour that culture material contains M.tuberculosis. The FDA has approved two nucleic acid amplification (NAA) tests.

In the United States, tuberculin skin testing is the major method for identifying and diagnosing tuberculous infection. Reactivity to tuberculin antigen separates infected persons (with negative chest X-ray and bacteriology) from persons without infection (tuberculosis exposure with negative skin test). Currently, 0.1ml of 5 TU (tuberculin units) of PPD is administered -- a reaction of 5 mm or greater after 48 hours is considered positive for patients known or suspected with HIV infection, chest X-rays consistent with old "nonactive" tuberculosis or persons with close contact with infected individuals. Reactions of 10 mm or greater are considered positive in other high risk groups (IV drug abusers, ethnic and racial minorities with high prevalence of disease, children under the age of four, institutionalized patients and patients with immuno-compromising diseases, such as diabetes mellitus or malignancy. For all other persons, a reaction of 15 mm or greater is considered positive.

Inoculation with BCG, a modified form of M. bovis, is a major form of prevention in many countries, though less so in the US. Negative reactions do not rule out infection or disease with M. tuberculosis.

In healthy individuals, the majority of infections result from reactivation of an original infection (as opposed to a second infection). By contrast, in patients with HIV infections, two-thirds of those with clinical disease were infected for the first time within a period of months from their initial encounter.

Reactivation tuberculosis results from seeding of distant sites following primary tuberculosis, thus representing reactivation of previously dormant organisms. This is the pattern in 90 percent of adult, non-HIV tuberculosis.

Complications of pulmonary tuberculosis, in the post-chemotherapy era, are much less common but may still occur: (1) pneumothorax (<1%); (2) hemoptysis; (3) bronchiectasis; (4) right middle lobe syndrome (collapse of the right middle lobe usually secondary to swollen lymph hilar nodes (5) respiratory insufficiency, secondary to widespread scarring and destruction of lung tissue.

A resurgence of disease due to M.tuberculosis was associated with the AIDS epidemic in many areas of the United States. Between 1980 and 1987, the number of cases of tuberculosis among non-Hispanic blacks in New York City nearly doubled (699 to 1250). In the prison system, there was a more than six-fold rise among inmates infected with tuberculosis, the vast majority of whom were also HIV infected. It is estimated that 10 percent of the 88 million incident cases of tuberculosis seen worldwide between 1990 and 1999 and 14 percent of the deaths are attributable to co-infection with HIV. Immuno-suppression, even in the face of a positive tuberculin test, leads to a high breakthrough of infection - 14 percent of PPD positive patients develop clinical disease within two years of conversion (HIV positive patients).

The clinical presentation of M.tuberculosis in HIV patients tends to be classic (upper lobe pulmonary TB) in patients with early HIV disease, but disseminated and lethal in patients with long established (particularly untreated) HIV disease.

Drug therapy, introduced in the 1940s, has become the mainstay for the prevention and treatment of tuberculosis. Chemotherapy for active disease consists of at least two drugs (to which the organism is sensitive) given concurrently, since single drug regimens favor the emergence of resistant strains.

Short-term chemotherapy for six months with first line drugs, including Isoniazid (INH), rifampin, streptomycin and pyrizinamide (PZA), is extremely effective in controlling the disease. Regimens shorter than six months were associated with unacceptably high rates of relapse. Extrapulmonary tuberculosis is usually treated with the same regimen as pulmonary tuberculosis. Children also receive similar regimens, though the dosages are usually adjusted according to weight and age and ethambutol, which can damage the optic nerve, is, usually, not included for young children.

Drug resistance has become a major issue in the treatment of tuberculosis. In many Third World countries and in certain areas of New York City, the prevalence of multi-drug resistant organisms (MDR-TB) is greater than 30 percent. Treatment of organisms resistant to only one agent is accomplished with other first line agents. Cure in such circumstances is high (>90%), even with short course chemotherapy. When the organism is resistant to more than one agent, second line drugs are often necessary and longer courses are frequently recommended.

With improved outcomes for HIV patients, the prognosis for co-infection with MDR-TB has also improved to 50 percent or better, with the most important predictor of success being the receipt of two drugs with subsequently demonstrated in vitro activity from the outset of treatment. The presence of severe immune-compromise is a predictor of mortality.

Combination drug regimens must be balanced against the increasing likelihood of drug toxicity. In HIV infected patients, regimens with as many as six or seven drugs have been advocated while awaiting susceptibility testing.

We have also seen the re-emergence of an old debate on how intrusive public health measures must be in order to control the new epidemic. One new strategy, Directly Observed Therapy (DOT), especially for patients documented as non-compliant during the noninfectious stage of their illness (post initial therapy), has been implemented in New York City and has led to a decline in new cases of tuberculosis.

While the management of tuberculosis has been complicated by the emergence of drug resistant strains and the susceptibility of HIV patients to atypical mycobacteria, improvement in the diagnosis and management of these diseases, the success in treating HIV infections and a renewed interest in public health strategies have, once again, placed us on the road leading to the control and, conceivably, the elimination of this disease in the United States. By contrast, prospects for tuberculosis control on a worldwide basis have been considerably hampered by the HIV epidemic, which continues unabated.

Table 1. Diagnostic Criteria for Pulmonary Disease Caused By Non-Tuberculous Mycobacteria (NTM)
I. Patients with cavitary disease.
A.Two or more sputums/bronchial washings that are AFB smear positive and/or result in moderate to heavy growth of NTM.
B.Other reasonable causes for the disease excluded (e.g., M. tuberculosis, fungi etc)
II Patients with non-cavitary disease.
A.Two or more sputums/bronchial washings AFB smear positive and/or moderate to heavy growth of NTM on culture.
B.If M. kansasii or M. avium complex is isolated, failure of sputum cultures to clear with bronchial toilette of two weeks of specific mycobacterial drug therapy.
III. Patients without cavitary or typical non-cavitary disease whose sputum is non-diagnostic or another disease cannot be excluded.
A.Trans-bronchial (TBB) or open lung biopsy (OLB) grows organisms and shows mycobacterial histopathology.
B.TBB or OLB which shows typical mycobacterial histopathology plus (1) Two or more positive sputum/bronchial cultures. (2) Other reasonable causes excluded.

Table 2. Reasons for False Negative Tuberculin
Denaturation of antigen
Poor administration technique
Cutaneous anergy secondary to:

• HIV infection
• Viral infection
• Immunosuppressive drugs
• Sarcoidosis
• Hodgkin's Disease
• Malnutrition
• Chronic renal failure
• Overwhelming illness

Table 3. Drugs Used in the Treatment of Tuberculosis

FIRST LINE AGENTS	DOSE	SECOND LINE AGENTS	DOSE
ISONIAZID (INH)	300 mg PO QD	CAPREOMYCIN	15 mg/kg (IM, IV)
RIFAMPIN	600 mg PO QD	QUINOLONES	750 mg PO BID (e.g., ciprofloxacin)
PYRIZINAMIDE	25 mg/kg PO QD	ETHIONAMIDE	250 mg PO (BID-QID)
ETHAMBUTOL	25 then 15 mg/kgPO QD	CYCLOSERINE	250 mg PO (BID-QID)
		PARA-AMINO-SALICYLIC ACID (PAS)	4 g PO (BID-TID)

Table 4. Toxicity of Anti-Tuberculous Medication

ISONIAZID	ABNORMAL LFTs HEPATITIS NEUROPATHY DRUG INTERACTION
RIFAMPIN	ORANGE URINE HEPATITIS DRUG INTERACITONS THROMBOCUTOPENIA
PYRAZINAMIDE	ABNORMAL LFTs RASH GOUT
ETHAMBUTOL	OPTIC NERVE DAMAGE URIC ACID ELEVATION
STREPTOMYCIN	VIII NERVE DAMAGE RENAL TOXICITY
QUINOLONES	GI TOXICITYCNS REACTIONSPHOTOTOXICITY

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