Course Authors

E. Neil Schachter, M.D.

Dr. Schachter reports no commercial conflict of interest.

This activity is made possible by an unrestricted educational grant from the Novartis Foundation for Gerontology.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 

Learning Objectives

Upon completion of this Cyberounds^®, you should be able to:

• Discuss the pathogenesis of tuberculosis in the pre- and post-AIDS eras

• Describe atypical mycobacterioses

• Apply current approaches to therapy.

 

Tuberculosis is an ancient disease that remains one of the world's most serious infections. In 1990, the World Health Organization (WHO) 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.(1) 2.9 million people die annually from this disease. Currently, it is estimated that 15 million individuals are infected in the United States.(2)

History

The tubercle bacillus, discovered in 1882 by Koch, is the number one cause of death in developing countries.(3) In the United States, tuberculosis was initially recorded as increasing as early as the eighteenth century, accounting for 300 deaths/100,000 in 1786, when statistics were first gathered in Massachusetts, and climbing to 1,600/100,000 in 1800. The disease began in the Northeast and spread to the Midwest, Southwest and West. African-Americans and Native Americans experienced epidemics only later, in the wake of the spread of this disease. 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. At that time, tuberculosis was still the second most common cause of death in the United States.(4)

The incidence of tuberculosis in the United States declined steadily until 1985, when the rate of newly reported cases was 9/100,000. The decline was seen as the beginning of the end for this disease in the United States and, as a result, enthusiasm and resources allocated for the control of the disease dropped dramatically. With this decline in vigilance, the country was ill-prepared for the recrudescence of the disease, as well as the more ominous emergence of drug resistant organisms, which began in the 1980s. 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. It is better adapted for establishing a parasitic relationship with man. Examination of preserved Egyptian mummies show frequent pathologic signs of Pott's disease (tuberculosis of the spine) without pulmonary involvement. This, it is argued, suggests that early tuberculosis was primarily caused by the bovine strain, since the route of infection through the GI tract reduces the likelihood of pulmonary involvement.

Tuberculosis throughout antiquity and the post-classical era adopted its more modern clinical description and pathology, manifesting primarily in its pulmonary form (although virtually every organ in the body can be involved). With a predilection for young victims and a long debilitating course, tuberculosis has had a unique association with literature, the arts and the evolution of medicine.(5)

Microbiology

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 (differentiating these syndromes from tuberculosis, which is reserved for disease caused by M. tuberculosis). The non-tuberculous mycobacteria are ubiquitous. Many of these are pathogenic, primarily for animal hosts, while others exist as environmental contaminants. Their presence in man has been associated with granulomatous disease but often they are saprophytes or contaminants cultured incidentally because of their widespread occurrence.

A common classification used to identify non-tuberculous mycobacteria is the Runyon grouping.(6),(7) Four groups are recognized: I Photochromogens (e.g., M. kansasii); II Scotochromagens (e.g., M. scrofulaceum); III Non-photochromogens (e.g., M. avium) and IV Rapid growers (e.g., M. fortuitum). Because of the difficulty in distinguishing pathogens from saprophytes or contaminants, the American Thoracic Society (ATS) has developed criteria for establishing the diagnosis (see Table 1).(8)

For decades, biochemical tests remained the only means of identifying mycobacterial species. Such testing usually adds two to four weeks to the time that it normally takes to grow the original isolate on culture media. Traditional culture media contains inhibiting agents for bacteria, along with a complex nutritional base such as whole eggs (e.g., Lowenstein-Jensen media). Young cultures are examined twice weekly for the first four weeks, then weekly up to the eighth week. Improved growth rates have been achieved with newer growth media such as the BACTEC system.(9)

Non-subculture methods for identifying M. tuberculosis have been introduced. They include a high pressure liquid chromatography (HPLC) system which extracts and identifies mycobacterial cell wall lipids from organisms grown in the original culture;(10) and nucleic acid probes and nucleic acid amplification (NAA), which can confirm that culture material contains M.tuberculosis within an hour. When combined with BACTEC medium, organisms can be isolated in less than three weeks.(11) Finally, NAA methods may permit direct identification of pathogens from the original collected material. These methods remain investigational, requiring confirmation by standard methods, and do not offer a substitute for susceptibility testing for drug resistance.(12)

The FDA has approved two nucleic acid amplification (NAA) tests: the Mycobacterium Direct Test^® (MTD) and AMPLICOR^®. MTD uses transcription-mediated amplification to amplify the RNA in mycobacteria. This technique is coupled with the standard probe, which allows for the identification of nucleic acid in a direct sputum sample. AMPLICOR^® uses polymerase chain reaction (PCR) to amplify DNA in sputum samples in order to identify M. tuberculosis. These tests are licensed only for use in smear positive respiratory specimens. In this situation, they are 96% sensitive and 100% specific. This allows for immediate distinction between M. tuberculosis and other non-tuberculous mycobacterium. If Acid Fast Bacillus (AFB) smears are positive and the NAA test is negative, this strongly suggests atypical mycobacteria.

It is suggested that, in the face of a negative AFB smear on three occasions and a negative NAA test, the negative predictive value is almost certain, implying that the combination of these methods may be as predictive as a negative culture. However, the finding of negative sputum smears and a positive NAA test is equivocal for predicting M. tuberculosis infection (50% false positive).(13)

Diagnosis

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 by either multiple puncture technique or by the intracutaneous Mantoux test. 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, immunocompromised individuals or persons with close contact with infected individuals. Reactions of 10 mm or greater are considered positive in other high risk groups (I.V. 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.(14)(2)

BCG inoculation is uncommon in the US, but is a major form of prevention in many countries. BCG is a modified form of M. bovis. Infection with this artificially weakened strain can cause a positive reaction to tuberculin, though the positive response wanes with time. Specific recommendations for persons known to have been immunized with BCG are not available, but the age of the inoculation may be helpful in judging whether the BCG is contributing to the skin test.

Negative reactions do not rule out infection or disease with M. tuberculosis. Reasons for false negative responses are listed in Table 2.

Clinical Manifestations

The diagnosis of active pulmonary tuberculosis is frequently difficult and time consuming. One study, from the 1970s, indicated that 50 percent of patients admitted to the hospital were initially misdiagnosed.(15)

The pathogenesis of tuberculosis is now well understood, although changes in the prevalence of this disease and disease susceptibility have dramatically altered classical findings. For the original (primary) infection, inhaled tubercle bacilli settle in distal air spaces, usually in the lower lung fields. These organisms are ingested by naïve alveolar macrophages. These macrophages are unable to contain the infection, which progresses over a period of three to four weeks until activated macrophages and lymphocytes become capable of limiting the bacilli in granulomas.

During the initial few weeks, tubercle bacilli can disseminate through blood and lymph channels, invading virtually every organ in the body. Those areas with high levels of oxygen saturation favor their growth, in particular the upper lobes of the lungs, the brain, the vertebral bodies, the kidneys and the epiphyses of the long bones. The original lower lobe infection is, usually, eradicated but the disseminated sites harbor granulomas with live bacilli, only to remain dormant until favorable conditions reactivate the site. Rarely, delayed hypersensitivity does not kick in and this leads to progressive primary tuberculosis and, occasionally, miliary tuberculosis.

Of those individuals developing the infection as a result of this initial exposure, three to five percent develop clinical tuberculosis within the first year. 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.

Pleural effusion, without accompanying apical disease, occurs within the first year following tuberculin conversion, usually in the first three to four months. As many as 30 percent of tuberculin converters develop pleural effusion (most of them asymptomatic). Progressive pulmonary infiltrates are far less common.

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. When this reactivation occurs in the lung, it overwhelmingly involves apical and posterior segments of the upper lobes. Typical X-rays still commonly occur in non-HIV patients (see Table 3).

Complications of pulmonary tuberculosis, in the post-chemotherapy era, are much less common but may still occur. These include: (1) pneumothorax (<1%); (2) hemoptysis -- less than 20 percent of all patients complaining of hemoptysis have tuberculosis. It may, nonetheless, be associated with cavitary disease, fungus balls and broncholiths; (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.

The diagnosis of pulmonary tuberculosis is based on a compatible clinical history and confirmation using:

1. Tuberculin skin testing
2. Sputum analysis
3. Radiologic evaluation
4. Bronchoscopy

In most situations, a negative tuberculin skin test strongly weighs against active tuberculosis. Nevertheless, as many as 25 percent of patients with active pulmonary tuberculosis may fail to react to tuberculin for a variety of reasons (see Table 2).

The definitive diagnosis of pulmonary tuberculosis rests on the isolation of M. tuberculosis from the patient's respiratory secretions. Three to six fresh morning sputum specimens are usually recommended to optimize the chance of organism recovery. False positive, Acid Fast Bacillus (AFB) smears are uncommon. Smear negative, culture positive tuberculosis, on the other hand, is a common occurrence, particularly in laboratories with less experience in screening for the disease. Patients in this situation may ultimately require bronchoscopy or open lung biopsy to make the diagnosis.

HIV and Mycobacterial Disease

The observation that M. tuberculosis and atypical mycobacteria were opportunistic infections common in individuals with HIV was noted early in the description of Acquired Immunodeficiency Syndrome.(16) Prior to the HIV era, most cases of atypical mycobacterial infection resembled tuberculosis and tended to affect middle aged individuals with an indolent disease. As with many atypical mycobacteria, M. avium-intracellulare is ubiquitous. By contrast, infection with M. avium causes substantial morbidity and mortality in the HIV population.

In a relatively early study of the clinical course of HIV, among individuals infected with M. avium, the mean survival was only three months.(17) A number of clinical presentations characterize this virulent course:

1. Disseminated infection with severe systemic symptoms; and
2. GI involvement.

Lung involvement is rare. The diagnosis can be made on the basis of isolation of the organism from the bone marrow, lymphoid tissue, skin and spinal fluid, as well as by blood cultures. The major risk factor is a low CD4 count.(18) Patients with HIV, treated with protease inhibitor containing retroviral regimens, may develop a benign syndrome characterized by fever and secondary lymphadenitis secondary to M. avium.(19)

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).(20) 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.(21) 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.(22) 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.

Chemotherapy

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. This principle, developed by Canetti & Grosset,(23) is based on the observation that single drug regimens favor the emergence of resistant strains. In the early days of chemotherapy, a majority of patients relapsed following treatment with a single drug.

By the early 1970s, experience of the East African/British Medical Association Council indicated that short-term chemotherapy for six months with first line drugs, including Isoniazid (INH), rifampin, streptomycin and pyrizinamide (PZA), could be extremely effective in controlling the disease.(24) Regimens shorter than six months were associated with unacceptably high rates of relapse. First and second line drugs in the treatment of tuberculosis are listed in Table 5.

Six-month therapy is considered acceptable for most patients with clinically responsive tuberculosis. Therapy should be extended in patients who convert their sputum cultures at a slow rate, those who are unreliable and those receiving inadequate regimens, particularly over the first two months of therapy.

Extrapulmonary tuberculosis is usually treated with the same regimen as pulmonary tuberculosis. Children also receive similar regimens with two caveats. First, the dosages are usually adjusted according to weight and age. Ethambutol, which can damage the optic nerve, is, usually, not included for young children because of the difficulty administering eye examinations in this age group.

Drug resistance has become a major issue in the treatment of tuberculosis. With the increase of tuberculosis cases in the 1980s, particularly among difficult to manage groups, the prevalence of drug resistant organisms has climbed. A number of factors contributed to these related events (see Table 4).

Treatment of drug resistant organisms is less effective than that of susceptible organisms. Drug resistance has been classified as primary, if it is due to the transmission of an already resistant organism from an infected patient to a second person who has never before received treatment. Alternatively, the infection is classified as secondary, if it is due to the emergence of a drug resistant organism in a patient receiving chemotherapy. This, usually, results from an inadequate drug regimen or a lack of compliance.

Currently, accurate data on the prevalence of multi-drug resistant TB (MDR-TB) organisms are limited for both the U.S. and abroad. In many Third World countries and in certain areas of New York City, the prevalence of multi-drug resistant organisms is greater than 30 percent.(25) In particular, among New York City patients with relapsing disease, many have a very high prevalence of resistant disease.

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.(26) When the organism is resistant to more than one agent, second line drugs are often necessary and longer courses are frequently recommended.(27)

Response to therapy in MDR-TB in non-HIV patients can approach 90 percent but depends on the extent of the disease.(28) MDR-TB in HIV patients was initially characterized by an exceedingly high mortality over a short period of time. With improved outcomes for HIV patients, the prognosis for co-infection with MDR-TB has also improved. Overall response rates have 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.(29) The presence of severe immune-compromise is a predictor of mortality.

A strategy for the treatment of MDR-TB (potentially, any case in an area of high prevalence) is predicated on implementing a regimen with at least two effective drugs. This, of course, must be balanced against the increasing likelihood of drug toxicity in patients taking a multi-drug regimen (see Table 6).

In HIV-infected patients, regimens with as many as six or seven drugs have been advocated while awaiting susceptibility testing.

Public Policy and Legal Issues

The recrudescence of pulmonary tuberculosis, in general, and of the emergence of MDR-TB, in particular, has 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 for the problem of non-compliance (which underlies much of the MDR-TB issue) is Directly Observed Therapy (DOT). While the call for across-the-board, mandatory DOT therapy has been rejected, the use of DOT for patients documented as non-compliant during the noninfectious stage of their illness (post initial therapy) has been implemented in New York City.(30) Confinement for such patients for public safety concerns may be implemented but the decision to take therapy remains with the patient and cannot be imposed against the patient's will. Nevertheless, DOT strategies implemented in New York City have led to a decline in new cases of tuberculosis.(31)

Several factors have contributed to the increase in the number of cases of tuberculosis in the United States. They include:

1. HIV infections;
2. changing social conditions (e.g., homelessness) favoring the transmission of tuberculosis.