Fundamentals of Tuberculosis and Tuberculosis Control
Tuberculosis has affected humans since before recorded history. Some speculate that the first cases may have been attributable to Mycobacterium bovis infections acquired by humans from domesticated animals and that Mycobacterium tuberculosis may have evolved from M. bovis (Daniel, 1994). Whatever the source, modeling of epidemiological data suggests that tuberculosis became endemic in human populations when stable social networks of about 200 to 440 people were established, about 10,000 years ago (McGrath, 1988). Tuberculosis is thought to have occurred in Europe, the Americas, and North Africa from prehistoric times. Mummies and skeletal remains that show evidence of deformities characteristic of spinal tuberculosis, with accompanying indications of fibrotic lesions in the lung, provide evidence of the disease in northern Africa as far back as 3,000 years ago (Morse et al., 1964). Similar evidence from remains in Peru (Salo et al., 1994) and Chile (Arriaza et al., 1995), supported by the presence of restriction fragment length polymorphism analysis (commonly referred to as “DNA fingerprinting”) patterns that are characteristic of M. tuberculosis, indicates that tuberculosis was present in pre-Columbian times. However, tuberculosis does not seem to have been introduced into sub-Saharan Africa, East Asia, or the Pacific Islands until after contact with Europeans during the period of colonization.
Tuberculosis grew to epidemic proportions in Europe beginning in the early 1600s as populations shifted to expanding cities and population densities increased (Dubos and Dubos, 1952). Conditions were ideal for
the spread of this airborne disease and, as environmental conditions worsened, tuberculosis came to be the leading cause of death in Western Europe in the 18th and early 19th centuries (Dubos and Dubos, 1952).
What appeared to be a natural and inevitable decline in tuberculosis in Europe and North America caused many experts to think about the eventual eradication of the disease. Wade Hampton Frost (Frost, 1937) may have been the first to suggest the possibility of elimination of tuberculosis when he observed,
We need not assume that tuberculosis is permanently and ineradicably engrafted upon our civilization. On the contrary, the evidence indicates that in this country the balance is already against the survival of the tubercle bacilli; and we may reasonably expect that the disease will eventually be eradicated. (Frost, 1937)
Although World War II interrupted the decline in tuberculosis mortality rates and discussion of elimination, the idea was raised again as the number of active cases and the rate of mortality showed accelerated declines after the advent of chemotherapy. Palmer (1958) and Perkins (1959) independently issued calls for the eradication of tuberculosis. Recognizing the difficulty of eradication, the Arden House Conference Report of the United States Public Health Service called for “eliminating tuberculosis as a public health problem” in the United States (Communicable Disease Center, 1960; U.S. Public Health Service, 1944). This concept was repeated and defined as a case rate of less than 1 per 1 million population at the 16th International Conference on Tuberculosis (Canetti, 1962). Later, this definition was again used by the Advisory Council for the Elimination of Tuberculosis to define the goal for elimination of tuberculosis in the United States, with a target date set for the year 2010 (Centers for Disease Control, 1989).
Despite these calls and plans for eradication or elimination that would have required intensification of control efforts, the continuing decline in tuberculosis resulted, instead, in complacency and neglect. Rather than increasing resources to fund the efforts that would lead to elimination, tuberculosis program funding was progressively reduced and categorical funding was entirely eliminated from the Center for Disease Control budget in 1972.
The neglect of tuberculosis was also reflected in a laissez-faire attitude toward treatment of the disease. This in turn led to poor adherence to treatment and development of drug resistance.
There was also neglect at the international level that was fostered by a general attitude that all the tools were available and that all that was needed was their assiduous application. The failure to recognize that, internationally, tuberculosis was as much, if not more, of a political chal
lenge as it was a technical challenge led to there being a tuberculosis control program at the World Health Organization that in 1989 had a budget of approximately $2.5 million and a staff of only two professionals. The World Health Organization attitude and neglect fostered a similar neglect in developing countries.
The price of the neglect in the United States and abroad was a resurgence in the number of cases of tuberculosis in this country as well as in many other parts of the world and the development of multidrug-resistant tuberculosis. The resurgence of tuberculosis resulted in turn in a resurgence of interest in the elimination of and resources directed toward the elimination of tuberculosis that resulted in resumption in the decline of tuberculosis in the United States. This process was described as the “U-shaped curve of concern” (Reichman, 1991). The question yet to be answered is whether the renewed opportunity that now presents itself to move toward elimination of tuberculosis will be seized or whether tuberculosis will be subject to another period of neglect until the next resurgence.
TRANSMISSION AND PATHOGENESIS OF TUBERCULOSIS
Tuberculosis is spread from person to person through the air. When an individual with active tuberculosis of the respiratory tract, coughs, sneezes, yells, or sings, droplets that contain M. tuberculosis are expelled into the air. The largest of these particles quickly settle out of the air, but the smaller particles remain suspended, often for several hours. When inhaled, the larger particles are filtered in the upper airways or are deposited on the lining of the airways and are removed. However, droplets of approximately 1 to 5 µm in diameter can reach the alveoli, leading to infection. Macrophages in the lung usually engulf the bacilli in the alveoli, but unless specific immunity is present, the bacilli are often able to resist the attempts of the macrophage to kill them. The bacilli in macrophages begin to multiply and are transported to regional lymph nodes, enter the bloodstream, and can establish sites of infection throughout the body. The most common site where the tubercle bacilli establish an infection is the upper portions of the lungs, but the lymph nodes, kidneys, brain, and bones may also be affected. Within 2 to 10 weeks of the original infection a specific cell-mediated immunity usually develops. This immunity activates the macrophages and other immune cells, preventing further multiplication and spread of the bacilli. Individuals who have a successful immune response usually will have a positive tuberculin skin test but still harbor live tubercle bacilli in the parts of the body seeded by the early dissemination of the organism, so-called latent tuberculosis infection.
In latent tuberculosis infection the organisms are presumably capable
of becoming active at any time, although the factors that govern reactivation are not known. Thus, individuals with a latent infection are at risk of developing active tuberculosis at any time in the future. The risk is greatest during the first 2 years after being infected, during which time about 5 percent of infected persons develop active tuberculosis. Another 5 percent of infected persons will develop active tuberculosis at a later time in their lives. It is generally thought that approximately 90 percent of individuals with latent infection will never develop tuberculosis (Comstock et al., 1974). If active tuberculosis develops in the lungs and becomes sufficiently advanced, tubercle bacilli will be expelled by any maneuver that produces rapid exhalation, such as coughing, sneezing, yelling, or singing. These bacilli can then cause new infections in susceptible individuals and perpetuate the cycle.
It is the airborne route by which tuberculosis infection is spread that causes the disease to be a public health threat. Individuals with untreated tuberculosis can unknowingly spread the infection to others in their environment. Generally, however, tuberculosis is not highly infectious and transmission usually requires close and prolonged exposure. Individuals living in the household of a person with active tuberculosis are usually at the highest risk of infection, but recent epidemiological investigations have shown that tuberculosis infection can be acquired in more casual settings (Curtis et al., 1999; Mangura et al., 1998; Tabet et al., 1994), such as a bar, a church, or a classroom. The degree of infectiousness of a person with tuberculosis can be inferred from the results of microscopic examination of sputum. Patients who are excreting sufficient numbers of bacilli that the bacilli can be seen on microscopic examination (i.e., the patient is smear positive) are more infectious than patients who are smear negative (Grzybowski and Allen, 1964; Shaw and Wynn-Williams, 1954). However, patients who are smear negative and culture positive can transmit the infection, and even those patients who have negative smears and cultures but who have radiographic evidence of tuberculosis can infect others (Behr et al., 1999).
DIAGNOSIS AND TREATMENT
The signs and symptoms of tuberculosis depend on the sites involved. In general, however, systemic symptoms and signs, such as fatigue, anorexia, weight loss, and persistent low-grade fever, occur with any site of involvement. Respiratory tract symptoms, especially cough, predominate when the lungs are involved. Epidemiological circumstances and the presence of signs and symptoms associated with the disease suggest the diag
nosis of tuberculosis. Pulmonary tuberculosis may be suggested by abnormalities on a chest radiograph. The finding of acid-fast organisms on microscopic examination of sputum or other material is more highly suggestive of the diagnosis. However, the “gold standard” for the diagnosis of tuberculosis is isolation of the tubercle bacillus in a culture of a patient's sputum or another biological specimen. In the United States, about 80 percent of reported cases of tuberculosis are confirmed by a positive culture. Other diagnostic tests, based on the amplification of nucleic acids (RNA and DNA) specific for M. tuberculosis, have been developed, but their exact role in diagnosis is still being defined.
The standard treatment for tuberculosis caused by drug-sensitive organisms is a 6-month regimen consisting of four drugs given for 2 months, followed by two drugs given for 4 months. The two most important drugs, given throughout the 6-month course of therapy, are isoniazid and rifampin. Although the regimen is relatively simple, its administration is quite complicated. Daily ingestion of the eight or nine pills often required during the first phase of therapy can be a daunting and confusing prospect. Even severely ill patients are often symptom-free within a few weeks, and nearly all appear to be cured within a few months. If the treatment is not continued to completion, however, the patient may experience a relapse, and the relapse rate for patients who do not continue treatment to completion is high. A variety of forms of patient-centered care are used to promote adherence with therapy. The most effective way of ensuring that patients are taking their medication is to use directly observed therapy, which involves having a member of the health care team observe the patient take each dose of each drug. Directly observed therapy can be provided in the clinic, the patient's residence, or any mutually agreed upon site. Nearly all patients who have tuberculosis caused by drug-sensitive organisms and who complete therapy will be cured, and the risk of relapse is very low.
Drug-resistant organisms result from random mutations in the tubercle bacilli, and drug-resistant disease results when an ineffective regimen is used or when an effective regimen is taken irregularly. The threat of drug resistance, and the threat of multiple-drug resistance in particular, is another aspect of tuberculosis that is causing it to be an increasing public health threat. Tuberculosis caused by isoniazid-resistant organisms is still readily treatable and may not require the addition of any new drugs to the regimen or an extension of therapy. Tuberculosis caused by rifampin-resistant organisms can also usually be cured, but the duration of therapy must be extended to twelve months or more. Tuberculosis caused by organisms resistant to both isoniazid and rifampin requires treatment with much more expensive and toxic drugs for periods of 24 months or more, and the disease may be incurable in some patients.
Latent Tuberculosis Infection
As noted earlier, latent tuberculosis infection occurs when, because of an effective immune response, the host halts the multiplication of tubercle bacilli but the organisms are not killed. Latent infection causes no symptoms and can be diagnosed only by a positive tuberculin skin test together with an evaluation that does not indicate the presence of active tuberculosis. The tuberculin skin test, however, has several inherent weaknesses. Although the test has a fairly high sensitivity (the proportion of truly infected persons who react to the test), some truly infected people will not have a positive reaction. This happens when the infection is very recent (a positive skin test develops 2 to 10 weeks after infection) or when the immune system is compromised (e.g., in individuals with human immunodeficiency virus [HIV] infection, certain malignancies and other disease states, or individuals who are taking immune-suppressive drugs). Of greater importance is the relatively poor specificity (the proportion of uninfected individuals who test negative) of the skin test. Persons infected with non-M. tuberculosis mycobacteria and those recently vaccinated with BCG (a vaccine against tuberculosis used in many countries outside the United States) will often have a positive reaction.
When the specificity of a test is less than 100 percent, false-positive results will occur; the lower the true prevalence of infection, the larger the proportion of positive results that are false positive becomes. In the United States the prevalence of true tuberculosis infection is believed to be less than 10 percent. Even with a 10 percent prevalence of infection, a tuberculin skin test with a 100 percent sensitivity and a 95 percent specificity would result in about one-third of all positive test results being falsely positive. This is why screening of the general population by a broadbased tuberculin skin test is impractical. However, in a population with a 35 percent prevalence of infection, a tuberculin skin test with 100 percent sensitivity and 95 percent specificity would produce false-positive results for less than 10 percent of samples tested; thus, tuberculin skin testing should be targeted to groups in which there is a high incidence of tuberculosis because it provides a more accurate result.
Treatment of persons with latent tuberculosis infection can greatly reduce the incidence of tuberculosis. A series of clinical trials has shown the effectiveness of isoniazid ranging from 92 percent in preventing active tuberculosis in patients when adherence is high, to 26 percent when adherence is low (Ferebee, 1970). A study of 3-, 6-, and 12-month regimens showed that a 12-month regimen was optimal but additional analysis indicates that a regimen of at least 9 months of treatment gives nearly as much protection as a regimen of 12 months (International Union Against Tuberculosis Committee on Prophylaxis, 1982).
Concerns about liver toxicity have limited the use of isoniazid for the treatment of latent infection. Thus, there has been controversy over the use of isoniazid in persons at relatively low risk of tuberculosis. In contrast, the use of isoniazid has never been challenged for individuals at a high risk of tuberculosis, including recent tuberculin skin test converters, contacts of individuals with infectious cases of tuberculosis, immigrants from countries with high rates of tuberculosis, and individuals with certain medical conditions, especially HIV infection. A recent report of a 7-year study of patients receiving isoniazid for treatment of latent infection showed a rate of clinical hepatitis of only 0.1 percent (11 cases in 11,141 patients), with no deaths and only one hospitalization (Nolan et al., 1999).
In addition to isoniazid, rifampin-based regimens have recently been recommended as treatment for latent tuberculosis infection. The current recommended regimens for treatment of latent infection include isoniazid for 9 months (with an option for isoniazid for 6 months), rifampin and pyrazinamide for 2 months, and rifampin alone for 4 months (American Thoracic Society and Centers for Disease Control and Prevention, 2000). Although the rifampin-pyrazinamide regimen has the obvious advantages of being much shorter, the experience with this regimen is relatively limited, a high rate of hepatotoxicity was observed in an early pilot study, and programs that use this regimen have been encouraged to maintain surveillance for adverse reactions to this regimen.
PRINCIPLES OF TUBERCULOSIS CONTROL
In the United States, public health departments are charged with the following responsibilities for tuberculosis control (Centers for Disease Control and Prevention, 1995; Etkind, 1993; Simone and Fujiwara, 1999). Ensuring that persons who are suspected of having active tuberculosis disease are identified as soon as possible, evaluated appropriately, placed on the recommended course of treatment, and complete therapy as prescribed is the prime responsibility of the health department. Mechanisms to accomplish this goal are numerous and varied given the diverse population groups affected by tuberculosis today. Ideally, they include patient-centered programs that assess each patient's needs and that identify a treatment plan to ensure the completion of therapy (Chaulk, 1999). The treatment plan may include the use of any or all of the following:
Enablers (defined as “anything that helps the patient to more readily complete therapy” [American Lung Association of South Carolina and the Division of Tuberculosis Control, South Carolina Department of Health and Environmental Control, 1989]). These may include transpor
tation vouchers, assistance with child care, or the use of extended clinic hours.
Incentives (defined as “something which will motivate the patient to take his medicine, keep clinic appointments or do anything else that is necessary to successfully carry out program goals” [Frieden et al., 1995]). These may include food stamps, coupons for fast-food restaurants, assistance with finding housing, etc. Incentives are tailored to meet the needs of the individual and, therefore, must be valued by that individual. This may vary considerably among patients as well as among communities.
Alternate treatment delivery sites, such as workplaces, park benches, street corners, ferry and subway stations.
Directly-observed therapy (where providers observe the patient ingesting the medication).
Outreach workers whose responsibilities may include adherence monitoring, sputum collection, education, contact investigation assistance, social service assistance, translation, and so forth.
Use of strategies that are specifically designed to overcome the social or cultural obstacles to treatment completion.
Treatment plans are developed in conjunction with the patient, the physician or nurse, a social worker (as necessary), and other team members, as appropriate. The plan is reviewed periodically and revised as needed through meetings between the patient and the assigned provider and often more formally through case and cohort reviews. The reviews must include the entire team providing care to the patient, including physicians, nurses, social workers, outreach workers, and so forth. A continuum of increasingly restrictive measures is used beginning with the use of the least restrictive measure (such as monthly monitoring in the outpatient setting) to the most restrictive measure (legally required hospitalization). These measures are invoked in a stepwise fashion to ensure that the needs and the rights of the patient are taken into account and the public's health is protected as well.
The second tuberculosis control priority is contact investigation and follow-up. Every individual with an infectious case or a suspected case of tuberculosis (index case) should prompt a thorough epidemiological investigation to identify other individuals who have potentially been exposed and who are therefore at high risk of having been infected by the index patient. These individuals should be evaluated for latent tuberculosis infection, and if they are found to have latent tuberculosis infection they should be placed on treatment and monitored until completion of therapy. Chapter 4 highlights the subject of contact investigations, their current use, and suggestions for improvement.
The final priority for health departments is the identification of per
sons who, because of epidemiological circumstances, are at high risk of having latent tuberculosis infection. This is done by:
Analysis of local epidemiological data and targeting of high-incidence groups for specific screening projects.
Ensuring that patients, once identified via screening programs, have access to appropriate and adequate tuberculosis services. This again is dependent on the high-risk group being targeted and may require services being provided outside of the “traditional tuberculosis clinic” system.
Ensuring that patients are evaluated and placed on treatment for latent tuberculosis infection (as appropriate).
Ensuring their completion of therapy. Screening without followup does not serve the needs of the patients or public health.
Health departments attain these goals by structuring their tuberculosis services within the framework of essential functions as described in the Institute of Medicine report, The Future of Public Health (Institute of Medicine 1988). This framework includes assessment (epidemiology and surveillance), policy development, and assurance (patient and contact management and education and training). The methods by which these goals are addressed vary according to morbidity rates, public health infrastructure capacity, and resources.
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