A review of the pathogenesis, modes of transmission, and diagnostic and treatment modalities of TB with a focus on high-risk populations.

According to the most recent statistics of the World Health Organization,1 new worldwide cases of tuberculosis (TB) in 1997 added almost 8 million to the 16.2 million cases of TB disease already present. Most of these cases are located in Africa and Southeast Asia. Estimates1 for 1997 are that 1.87 million people died of the disease, which had a fatality rate as high as 50% in some countries having high rates of HIV coinfection. In addition, approximately one third of the world’s population is infected with Mycobacterium tuberculosis.1 To make matters worse, the worldwide incidence of drug-resistant TB is increasing.

TB is still a significant problem in the United States, as well. In 1998, there were 18,361 US cases reported, for an incidence rate of 6.8 per 100,000 people.2 The highest numbers of cases were reported from California, Florida, Illinois, New York, and Texas, which collectively accounted for 54% of TB in the United States.2 The TB rate among US residents born elsewhere is approximately four to six times higher than that found among those born in the United States.2 While the number of cases in the United States has recently been decreasing, there has been an increase in the proportion of cases seen in foreign-born US residents from 27% in 1992 to 42% in 1998.2

While the overall number of cases in the United States has decreased, there are several possible reasons for the resurgence of TB that was witnessed a decade ago. HIV disease played a major role in this resurgence and is still very much a factor. Other high-risk populations for TB exposure and infection must, however, be kept in mind: people from high-incidence areas; medically underserved, low-income populations; residents and staff of long-term facilities, such as prisons, nursing homes, and substance-abuse–treatment centers; health care workers; and locally recognized high-prevalence groups, such as migrant farm workers or the homeless.

Pathogenesis and Transmission
TB is usually spread from human to human via an airborne route. M. tuberculosis enters the air when patients with active pulmonary TB speak, talk, sneeze, or sing, although coughing remains the most effective method of aerosolization. Individuals who are in prolonged close contact with patients with active TB, especially in environments with poor ventilation, are most likely to inhale the organism and become infected with TB (particularly in congregate settings such as jails, prisons, shelters, and hospitals); however, only approximately one third of all individuals who have close contact with patients with active TB for a prolonged period of time become infected.3 In countries where TB is endemic, the chances of being exposed to a person with active TB are higher, thus increasing the likelihood of transmission. Congregate settings, with their increased risk of TB transmission, use infection-control procedures to prevent the spread of the organism.4

When a person inhales a droplet nucleus (which may contain 1 to 400 organisms), it is usually trapped in the upper respiratory tract and cleared. The smallest droplets, those less than 5 µm in diameter, can reach the alveolus and are phagocytized by resident alveolar macrophages. At this primary site of infection, bacilli multiply initially; within 2 weeks, they are transported through the lymphatic system to establish secondary sites. An intact immune response, heralded by the development of delayed-type hypersensitivity over the next 4 weeks, leads to granuloma formation, with a subsequent decrease in bacillary numbers. This stage of disease is called TB infection. Patients with TB infection are asymptomatic, but have the potential for progression to active disease at a later time. Active disease develops in those individuals whose immune system can no longer contain the organisms. The presence of symptoms (Table 1) and contagiousness characterizes active disease. Once infected with TB, 3% to 5% of immunocompetent individuals develop active disease within 1 year, and an additional 3% to 5% develop TB during their lifetimes.5 Most individuals who have TB in their bodies are able to mount an effective immune response that encapsulates the organisms (usually for the rest of the host’s life), thus preventing the progression from infection to disease.

• Unexplained cough (lasting more than 3 weeks)
• Unexplained cough with fever (lasting more than 3 days)
• Unexplained pleuritic chest pain, hemoptysis,
and/or dyspnea (appearing promptly)
• Unexplained fever, night sweats, or weight loss
Table 1. Symptoms of TB

It appears that some individuals are more susceptible than others to progressing from TB infection to TB disease. This is particularly apparent among individuals with certain medical conditions (such as HIV infection, diabetes mellitus, certain cancers, chemotherapy use, silicosis, and gastrectomy) that are associated with varying degrees of immunosuppression. Most patients in these groups have conditions that are believed to impair their cellular immunity. In fact, HIV-infected patients, with their severe defect in cellular immunity, are significantly more likely to progress from infection to disease (at an increased relative risk 80 to 170 times that of individuals without HIV).6 It is still important to note, however, that a significant number of individuals with apparently normal immune systems still progress from infection to TB disease.

TB Disease diagnosis
The key element in the diagnosis of TB is a high degree of suspicion, especially when treating members of high-risk groups. Early recognition of the disease is essential in order to stop further transmission. Patients with prolonged symptoms, especially those at high risk for TB (Table 1), should be suspected of having TB and should have chest radiography performed immediately. Those suspected of having pulmonary TB should be placed in an appropriate isolation room immediately, if they are to be admitted to a health care facility or congregate setting. At least three sputum specimens should be sent for acid-fast bacilli (AFB) smear testing, culture, and (in some cases) nucleic acid amplification as soon as possible.

The Role of the TB Lab
The foundation of rapid, accurate microbiological diagnosis of TB is the proper collection of specimens and their rapid transport to the laboratory. A high-quality sputum specimen should have a volume of 5 to 10 mL. Even with the best specimen, the diagnosis of TB has always been hampered by the long time it takes to grow and identify M. tuberculosis in the laboratory, as well as the poor sensitivity of some of the conventional diagnostic tests. For example, while the sputum smear may be rapidly performed and is inexpensive, its sensitivity in detecting tubercle bacilli is only about 50%. Of diagnosed TB cases, 15% to 20% cannot be confirmed microbiologically. Traditional solid-media techniques can require up to 6 to 8 weeks to grow and speciate the organism. Susceptibility testing may take another 3 to 4 weeks, and is often too complex for most small to moderate-sized laboratories to conduct.

One way to deal with the many problems encountered in the turnaround times and reporting of M. tuberculosis is to assign priority to newly diagnosed AFB-smear-positive patients and those for whom there is a clinical suspicion of drug resistance. The Fast Track system, developed by the New York State Department of Health, is such a priority system. It has four primary effects:
• broader accessibility to state-of-the-art laboratory procedures enhances the health care of highly infectious patients by identifying them earlier;
• infection control and public health officials are able to stay focused on highly infectious TB patients to provide directly observed therapy (DOT) and contact investigations, both of which demand substantial resources;
• for patients infected with nontuberculous mycobacteria (NTM), the period of exposure to potentially toxic and unnecessary anti-TB drugs is dramatically shortened, and these patients can also be released from respiratory isolation earlier, conserving health care resources; and
• centralized laboratory services are helpful in a effort to control costs.

In recent experience using Fast Track, it was shown7 that species-identification and susceptibility-testing times can be reduced from 7 to 9 weeks to only 2 to 3 weeks (Table 2).

Methodology Traditional Laboratory Fast Track Laboratory Intervention
Rule in/rule out diagnosis of mycobacterial diseases 1. Clinical suspicion for drug-resistan tuberculosis 2. Newly diagnosed patient with an acid-fast bacilli (AFB) smear-positive respiratory specimen
Microscopy Smear reported within 24 hours of receipt in laboratory Smear reported within 24 hours of receipt in laboratory
Nucleic acid amplification (NAA) No testing available Performed daily on newly diagnosed AFB smear-positive, or other patient; reported within 24 hours 1. Respiratory isolation rooms can be primarily used for AFB-smear–positive and NAA-positive patients 2. In the event of a negative result, contact investigation may be delayed until culture results become available
Growth detection Solid media only; detection in 14 to 21 days Liquid culture and various solid media, detection in 7 to 10 days
Identification Identification of Mycobacterium tuberculosis complex using biochemical techniques may require 2 to 3 weeks Identification of M. tuberculosis complex within 1 day using molecular techniques, such as DNA probes
Susceptibility testing Solid media within 3 weeks Indirect susceptibility testing of first-line drugs within 5 days using radiometric methodology Adjustment of drug regimen in the event of drug resistance.
Turnaround times 7 to 9 weeks 2 to 3 weeks
Net gain Not applicable 5 to 6 weeks
Table 2. Fast Track and conventional laboratory testing times.

Laboratory test results should always be correlated with the patient’s clinical presentation, and the clinician should notify the laboratory when the results are not consistent. Health care providers and laboratory staff need to communicate and cooperate to bridge any gap between them. Only when physicians, laboratories, and public health officials work together can clinical outcomes be optimized.

Drug Therapy
Since the advent and use of effective chemotherapy against TB, 95% of all individuals with pansusceptible TB who completed therapy have been cured. Among those with multidrug-resistant strains, however, more than 40% may fail to respond to traditional chemotherapy.8

The initiation of anti-TB therapy should not await mycobacteriologic results if TB is strongly suspected. When clinicians determine what medications should be used, the consideration of the incidence of TB drug resistance in that area of the country needs to be taken into account. It is recommended that four-drug therapy with isoniazid (INH), rifampin, pyrazinamide (PZA), and either ethambutol or streptomycin be used initially for patients from areas of the United States or other countries where INH resistance exceeds 4% until susceptibility test results are available. Once these results reveal susceptibility to INH, rifampin, and PZA, the ethambutol or streptomycin should be discontinued. After 2 months of therapy, PZA should be stopped and INH and rifampin are continued for an additional 4 months, for a total of 6 months of treatment. This regimen may also be used for those individuals infected with HIV.9

The need to treat patients using multiple drugs for prolonged periods leads to the major obstacle facing the control of TB: adherence to therapy. If patients do not take their medications as prescribed for the entire time, treatment failure, as well as the development of resistance, has been shown to develop.10 Once medication use has begun, adherence needs to be ensured. The recent decline of TB in the United States has been attributed, in part, to the implementation and utilization of DOT. This program has been shown to improve completion rates of TB therapy significantly and to reduce the development of resistant strains.11 Through DOT, representatives of health care facilities (usually from the public health system) go into the community to observe patients and ensure that they take their medications. Numerous studies12 have demonstrated that no reliable way exists to predict which patients will not adhere to therapy, so all patients with active TB disease should be considered for DOT.

Therapeutic Monitoring
Drug interactions, adverse effects, and treatment response must be monitored during TB therapy. Rifampin and INH, due to their significant effect on hepatic P-450 function, interact with numerous other medications. Either toxic or subtherapeutic levels of drugs may occur with the concomitant use of drugs such as phenytoin, warfarin, theophylline, hormone-based contraceptives, methadone, or the protease inhibitors together with INH or rifampin. Rifabutin, a newer member of the rifamycin family with equivalent efficacy against TB but approximately one third of the potential to affect the liver, may be a viable alternative in many cases.13

Adverse reactions are not uncommon in the treatment of TB. INH, best known for its hepatotoxicity, also causes peripheral neuropathy. Vitamin B6 (pyridoxine) is prescribed as prophylaxis for this condition. Rifampin may cause hepatotoxicity in addition to muscle and joint stiffness and pain. The most striking effect of rifampin is a red-orange discoloration of all bodily fluids.

Patients need to be monitored to determine the effectiveness of treatment. Soon after starting therapy, patients should experience improvement in symptoms such as cough, fevers, night sweats, and weight loss. Those patients who do not experience an improvement in symptoms, or those who fail to convert their cultures to negative status within 2 months of starting treatment, should be evaluated for treatment failure.

Potential reasons for treatment failure include: an inadequate dosage of medication; the use of an inadequate combination of drugs, resulting in increased drug resistance; inadequate serum levels of medication caused by malabsorption, food or drug interactions, or concurrent medical conditions; and nonadherence with prescribed treatment regimens. Of these, nonadherence is by far the most common cause of treatment failure. In patients whose treatment fails and for whom nonadherence is not a concern, it may be advisable to perform serum-drug-level analysis to ensure adequate treatment. It is important to seek the advice of a TB expert when patients have resistant disease, complicating concurrent medical conditions, or are not responding to therapy as expected.

Role of the Public Health System
Public health departments are committed to curing every case of TB in the community. TB is a reportable disease, and the applicable health department must be notified of patients with active disease in all states; in some, even a suspected case of TB has to be reported.14 Health departments possess resources (such as DOT and incentives) to enhance treatment completion. These resources must be used by the health care community to ensure a cure in every case of TB.

Issues in TB Infection
The tuberculin skin test (TST) is used to diagnose TB infection. Although TST is often called a screening test, there is no confirmatory test for TB infection. The TST is not highly specific, though the positive predictive value of the TST increases as the prevalence of infection increases in the population. A positive TST in a low-risk individual frequently represents a false-positive reaction, usually due to cross-reaction with an NTM infection. For this reason, different levels of induration are considered positive for different groups (Table 3). Previous bacillus Calmette-Guérin (BCG) vaccination may cause a false-positive TST. The positive reaction caused by BCG wanes after 7 to 10 years, however. Thus, the TST result in those who received BCG more than 10 years ago should be interpreted using the standard criteria.15 As the TST has a low positive predictive value in a community with a low prevalence of TB, universal screening (as seen in mandatory school-admission TST requirements) may lead to confusion and divert limited public health resources and personnel away from essential TB-control activities.

Patients with conditions that increase the risk that tuberculosis infection will progress to disease:
Preventive treatment is of highest priority and indicated in the following groups, regardless of age. For patients in groups A through C, 5 mm of skin induration constitutes a positive tuberculin skin test (TST) reaction. For patients in groups D through F, 10 mm of skin induration constitutes a positive TST reaction.
a) Persons known to have or suspected of having HIV infection
b) Close contacts of a person with active pulmonary tuberculosis
c) Persons who have a chest radiograph suggestive of previous tuberculosis and who have received inadequate or no treatment
d) Persons who inject drugs and are HIV negative
e) Persons with medical conditions (other than HIV) that impair immunity (uremia; diabetes mellitus; lymphomas; leukemias; cancers of the head, neck, and upper gastrointestinal tract, and other conditions associated with malnutrition; silicosis; and prolonged corticosteroid or other immunosuppressive therapy)
f) Children younger than 4 years of age (who are exposed to persons in high-risk groups for tuberculosis)
g) Persons whose tuberculin skin reaction converted from negative to positive within the past 2 years (10 mm or more increase if aged <35 years; 15 mm or more increase if aged >35 years)
Patients within populations known to have a high risk of tuberculosis exposure and infection:
For the following groups without other risk factors, preventive therapy is indicated in those patients <35 years of age
• Foreign-born persons from areas where tuberculosis is common
• Medically underserved, low-income populations, including high-risk racial and ethnic groups such as Asian, black, and Hispanic populations
• Residents and staff of certain long-term care facilities (prisons, drug treatment centers, and nursing homes)
• Health care workers
• Locally identified high-prevalence groups such as migrant farm workers or homeless people
Table 3. High-risk groups for tuberculosis.

Those at high risk of developing TB disease may benefit from preventive chemotherapy (Table 3). Once the diagnosis of TB infection has been made using TST, clinical assessment (including chest radiography) to exclude active TB disease should be performed in order to avoid the administration of a single drug to an individual with active TB disease. The standard preventive therapy is the use of INH for at least 6 months. INH preventive therapy is not routinely recommended for individuals over the age of 35 years who are not at increased risk for developing TB disease. INH preventive therapy should be given, however, to high-risk individuals, regardless of age. For individuals over the age of 35, it may be prudent to track levels of liver-related enzymes and to add pyridoxine to the regimen.

Completion rates for individuals who started preventive therapy are poor (<50%) in certain populations. It is imperative to ensure that those infected individuals at high risk of developing active disease complete preventive therapy.

In HIV-infected individuals, recent studies16 have revealed that 2 months of combination daily therapy consisting of rifampin and PZA is as effective as INH given for 12 months. Furthermore, twice-weekly administration of rifampin and PZA appeared to be comparable to INH preventive therapy, and if this is proven effective, DOT for prevention will be ideal and practical in high-risk groups and settings.17

Prospects for TB Eradication
The only two methods that have been proven successful in eradicating infectious diseases in the past have been public health interventions (as in the case of yellow fever) or the development of effective vaccines (as for smallpox). BCG is a vaccine that was developed with the hope that it would be effective in preventing TB. Unfortunately, the use of the BCG vaccine has been limited by its approximately 50% efficacy (range, 0% to 80%) for a limited length of time, as compared with a course of INH preventive therapy, which has an efficacy of up to 90% when completed.18 While recent advances in understanding of the pathogenesis and immune responses to TB have fostered new hope, the availability of a highly effective vaccine for TB is still not at hand.

David Ashkin, MD, is medical executive director at A.G. Holley State Tuberculosis Hospital, Lantana, Fla; Yvonne M. Hale, MS, is section head of mycobacteriology, Bureau of Laboratories, Florida Department of Health, Jacksonville, Fla; Elena S. Hollender, MD, is director of clinical services at A.G. Holley State Tuberculosis Hospital, Lantana, Fla; Masahiro Narita,MD, is regional TB consultant, Bureau of Tuberculosis and Refugee Health, Miami, Fla; Max Salfinger, MD, is director of clinical mycobacteriology laboratory, Wadsworth Center, New York State Department of Health, Albany, NY; and Jerry J. Stambaugh, PharmD, is pharmacy director at A.G. Holley State Tuberculosis Hospital, Lantana, Fla.

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References for Tables 1 and 3: Pitchenik AE, Brooks R. The Most Common Clinical Mistakes in Prevention, Diagnosis and Therapy of Tuberculosis. In: Tuberculosis in Florida: The Clinician’s Desktop Reference. 1999 Florida TB Control Coalition.