Department of Public Health & Human Services

COMMUNICABLE DISEASE CONTROL & PREVENTION

Food & Consumer Safety

Immunization

STD / HIV Treatment & Prevention

Tuberculosis

You need to have the Adobe Acrobat Reader installed on your computer to view the PDF files.

CDC/DTBE - Core Curriculum on Tuberculosis

What the Clinician Should Know

Third Edition, 1994

The Core Curriculum on Tuberculosis is accompanied by a slide series for use in presentations and training programs. To order the Core Curriculum Slide Series, call CDC Voice Information System at (404) 639-1819

CONTENTS

1. Introduction
   • References
2. Transmission and Pathogenesis
   • Transmission
   • Pathogenesis
   • Classification System
3. Epidemiology of TB in the United States
   • Trends
   • Risk Groups
   • Outbreaks and Transmission Sites
4. Screening for TB Disease and Infection
   • Groups That Should Be Screened
   • Tuberculin Skin Testing
     • Administration of the Tuberculin Test
     • Classification of the Tuberculin Reaction
     • Anergy Testing
     • Two-Step Testing
5. Diagnosis of TB
   • Medical History
   • Physical Examination
   • Tuberculin Skin Testing
   • Radiographic Examination
   • Diagnostic Microbiology
     • Specimen Collection
     • Laboratory Examination
6. Preventive Therapy: Treatment of TB Infection
   • Candidates
   • Standard Regimens
   • Alternative Regimens
   • Monitoring
7. Treatment of TB Disease
   • Adherence
   • Pulmonary TB
   • Extrapulmonary TB
   • Pregnant or Lactating Women
   • Children and Adolescents
   • Drug-Resistant TB
   • Persons with Additional Medical Problems
   • Monitoring
     • Adverse Reactions
     • Response to Treatment
8. Infection Control
   • Infectiousness
   • Infection Control
     • Administrative Controls
     • Engineering Controls
     • Personal Respirators
9. Community TB Control
   • Role of the Health Department
     • Surveillance
     • Containment
     • Contact Investigation
     • Overall Planning and Policy
   • Role of the Voluntary Organizations
10. BCG Vaccination
    • Recommendations for the Use of BCG Vaccine
    • Interpretation of Tuberculin Reactions in Persons with a History of BCG Vaccination
11. Tables, Selected Bibliography, and Self-Test
    • Tables
      1. Regimen Options for Treatment
      2. First-Line TB Drugs
      3. TB Drugs in Special Situations
      4. Second-Line TB Drugs
    • Selected Bibliography
    • Self-Test

Updated November 5, 1996

Chapter One: INTRODUCTION

In 1989, the Centers for Disease Control and Prevention announced the goal of eliminating tuberculosis (TB) from the United States by the year 2010. The Strategic Plan for the Elimination of Tuberculosis in the United States was published at that time to identify the actions necessary to achieve elimination. In 1992, a special federal task force was convened to address the problem of increasing case rates and outbreaks of drug-resistant TB. This task force developed the National Action Plan to Combat Multidrug-Resistant Tuberculosis, which enhanced the original Strategic Plan. Both plans stress the need to increase clinical knowledge about TB disease and infection.

An update on TB for clinicians is critical today. After a decades-long decrease in the number of TB cases reported in the United States, TB has reemerged as a serious national problem. From 1985 through 1993, the number of new TB cases increased by 14% -- from 22,201 to 25,313. We can attribute this recent increase to at least four factors:

• the association of TB with the HIV epidemic
• immigration from countries where TB is common
• the transmission of TB in congregate settings (e.g., health care facilities, correctional facilities, and homeless shelters)
• a deterioration of the health care infrastructure

Moreover, the recent occurrence of several outbreaks of multidrug-resistant TB has pointed to the need for new treatment regimens. New methods of diagnosis have been introduced, and guidelines for patient management and public health practice have been revised. In addition, studies have shown that the appropriate diagnosis and management of patients with TB disease and infection continue to present problems for clinicians. Especially disturbing is the fact that approximately 25% of patients who start treatment do not complete a recommended regimen within 12 months.

This curriculum was designed to present basic information about TB that could be useful in developing educational programs for health care professionals. It is intended for use as a reference manual for clinicians caring for persons with or at high risk for TB disease or infection. It is not meant to provide detailed answers to all public health or clinical questions about TB.

In preparing this document, our aim was to meet the following objectives:

• Increase clinicians' awareness of the current TB problem and those at highest risk for TB infection and disease.
• Increase clinicians' index of suspicion for TB in high-risk patients in order to screen appropriately for TB infection and disease.
• Ensure that clinicians prescribe appropriate and effective treatment regimens.
• Increase the use of directly observed therapy (DOT) and other adherence-promoting methods ensure that all patients with TB disease complete therapy.
• Increase the use of preventive therapy among high-risk persons with TB infection.
• Increase clinicians' awareness of appropriate measures to prevent TB transmission in health care settings.
• Increase clinicians' awareness of resources for patients with TB, such as health departments and local lung associations.
• Encourage medical specialty societies to develop educational programs about TB for their members.

This document was originally developed by the National Tuberculosis Training Initiative, cosponsored by the American Thoracic Society and the Centers for Disease Control and Prevention. The current document is the third edition of the Core Curriculum on Tuberculosis. Because the guidelines for treating and controlling TB continue to evolve, it has been necessary to revise this curriculum periodically.

This curriculum is based on documents published by the American Thoracic Society, the Advisory Council for the Elimination of Tuberculosis, and the Centers for Disease Control and Prevention. We recognize that documents prepared by other professional organizations may contain minor differences in recommendations.

Click here to return to Table of Contents

References

Classification System for TB

Click here to return to Table of Contents

Chapter Three: EPIDEMIOLOGY OF TB IN THE UNITED STATES

Summary. After a decades-long decrease from 1953 through 1984 in the number of TB cases reported annually in the United States, TB has reemerged as a serious national problem. From 1985 through 1993, the number of new TB cases increased by 14%--from 22,201 to 25,313. During this period, approximately 64,000 more cases were reported than would have been predicted from the trend of decline from 1980 through 1984. The major factors contributing to this recent increase are (1) the association of TB with the HIV epidemic; (2) immigration from countries where TB is common; (3) the transmission of TB in congregate settings (e.g., health care facilities, correctional facilities, homeless shelters); and (4) a deterioration of the health care infrastructure. Some groups are at higher risk for TB than others. These groups can be divided into two categories: persons more likely to be exposed to or infected with M. tuberculosis and persons more likely to develop TB disease once infected.

Click here to return to Table of Contents

Trends

In 1944, the year the U.S. Public Health Service Tuberculosis Program was created, more than 126,000 cases were reported. After the introduction of treatment for TB in the late 1940s, there was hope that TB would soon be eradicated. The number of reported cases declined by an average of 5.6% per year, from more than 84,000 cases in 1953 to 22,255 cases in 1984.

From 1985 through 1993, however, annual TB morbidity in the United States increased by 14%--from 22,201 to 25,313 cases. During this period, approximately 64,000 more cases of TB were reported than would have been predicted from the trend of decline from 1980 through 1984. These excess cases can be attributed to at least four factors: the HIV epidemic, immigration from countries where TB is common, the transmission of TB in congregate settings (e.g., health care facilities, correctional facilities, and homeless shelters), and a deterioration of the health care infrastructure.

An estimated 10 to 15 million persons in this country are infected with M. tuberculosis. TB disease may develop in these persons at some time in the future. In fact, the majority of new cases in the United States arise from this population. However, as the transmission of TB continues, newly infected persons are added to this population and become at risk for TB disease.

Click here to return to Table of Contents

Risk Groups

• close contacts of a person with infectious TB
• foreign-born persons from areas of the world where TB is common (e.g., Asia, Africa, and Latin America)
• medically underserved, low-income populations, including high-risk
• racial and ethnic groups (e.g., Asians and Pacific Islanders, blacks,
• Hispanics, and Native Americans)
• the elderly
• residents of long-term care facilities (e.g., correctional facilities and nursing homes)
• persons who inject drugs
• other groups identified locally as having an increased prevalence of
• TB (e.g., migrant farmworkers or homeless persons)
• persons who may have occupational exposure to TB

Many foreign-born persons from areas where TB is common acquire TB infection in their country of origin. In 1993, 30% of all new TB cases reported in the United States occurred in foreign-born persons, many of whom were probably infected before arrival in the United States. This percentage represents an increase over the percentage in previous years.

More than two thirds of TB cases reported in the United States occur in racial and ethnic minorities. Compared with non-Hispanic whites, Asians are 10 times more likely to have TB; blacks 8 times more likely; and Hispanics, Native Americans, and Alaskan Natives 5 times more likely. TB disease in blacks and Hispanics occurs more frequently in young adults, whereas in non-Hispanic whites, TB occurs most often in the elderly. One reason for the increased rates in racial and ethnic minorities may be that a greater proportion of these persons have other risk factors for TB, such as birth in a country where TB is common, HIV infection, low socioeconomic status, and exposure in a congregate setting.

Persons who are at a particularly high risk of developing TB disease once infected include:

• persons with HIV infection
• persons who were recently infected with M. tuberculosis (within the past 2 years)
• persons with certain medical conditions (see Transmission and Pathogenesis)
• persons who inject drugs
• persons with a history of inadequately treated TB

HIV infection is the strongest known risk factor for the development of TB disease in persons with TB infection; for persons coinfected with M. tuberculosis and HIV, the risk of TB disease may be more than 100 times greater than for persons with TB infection alone.

Recent increases in TB cases reported in geographic areas and demographic populations with large numbers of AIDS cases suggest a strong association between the HIV epidemic and the increased TB morbidity. In 1991, a median of 9.5% (range, 0% - 61%) of patients from selected TB clinics, primarily in large urban centers, were also infected with HIV. In addition, approximately 5% of all AIDS cases reported in the AIDS case registry from 1981 through 1990 were also reported as TB cases in the TB registry.

Click here to return to Table of Contents

Outbreaks and Transmission Sites

Recently, several outbreaks of multidrug-resistant TB have occurred in hospitals and correctional facilities. Most of the cases in these outbreaks were caused by strains of M. tuberculosis resistant to isoniazid and rifampin, the two best TB drugs. Moreover, most of the patients involved in these outbreaks were HIV-infected persons. The morality rates were high, and multidrug-resistant TB was transmitted to health care workers.

Some correctional facilities have a large problem with TB transmission. A CDC study conducted in 1984 and 1985 showed that there were four times as many TB cases in persons living in correctional facilities as there were in persons of the same age living outside correctional facilities. Several factors may contribute to this difference, including (1) a high rate of TB infection in the prison population; (2) an increasing number of inmates infected with HIV and therefore at higher risk of developing TB disease once infected; and (3) overcrowding and inadequate ventilation in many correctional facilities, factors that increase the risk of transmission.

Nursing home residents may also be at relatively high risk for TB. In a 29-state survey conducted in 1984 and 1985, the CDC found that the rate of TB disease was twice as high for elderly persons living in nursing homes as for elderly persons not living in nursing homes.

Transmission continues to occur in the community at large. TB case rates are increasing for children younger than 15 years of age, especially for children younger than 5 years of age. Young children with TB must have been infected relatively recently; thus, TB cases in children indicate the transmission of TB in the home or community. In 1993, 84% of childhood cases of TB occurred in children from high-risk racial and ethnic populations.

Click here to return to Table of Contents

Chapter Four: SCREENING FOR TB DISEASE AND INFECTION

Summary. In most U.S. populations, screening for TB is done to identify infected persons at high risk for TB disease who would benefit from preventive therapy and to identify persons with TB disease who need treatment. Screening should be done in groups for which rates of TB are substantially higher than for the general population. Clinicians should tuberculin test high-risk persons as part of their routine evaluation. Institutional screening is recommended for the staff of health care facilities, as well as for the staff and residents of long-term care institutions where TB cases are found or the case rates of TB are high. The Mantoux tuberculin skin test is the preferred method of screening for TB infection.

Click here to return to Table of Contents

Groups That Should Be Screened

In most U.S. populations, screening is done to identify infected persons at high risk of developing TB disease who would benefit from preventive therapy and to identify persons with TB disease who need treatment. Therefore, all screening activities should be accompanied by a plan for follow-up care for persons with TB infection or disease.

The preferred method of screening for TB infection is the Mantoux tuberculin skin test. Screening for TB infection should be done in well-defined groups for which rates of TB are substantially higher than for the general population. Groups that are not at high risk for TB should not be screened routinely, because they are more likely to have false-positive reactions and they may be inappropriately treated.

In general, high-risk groups that should be screened for infection include:

• persons with HIV infection or risk factors for HIV but unknown HIV status
• close contacts of a person with infectious TB
• persons with certain medical conditions (see Transmission and Pathogenesis)
• persons who inject drugs
• foreign-born persons from areas of the world where TB is common (e.g., Asia, Africa, and Latin America)
• medically underserved, low-income populations, including high-risk racial and ethnic groups (e.g., Asians and Pacific Islanders, blacks, Hispanics, and Native Americans)
• residents of long-term care facilities (e.g., correctional facilities and nursing homes)
• other groups identified locally as having an increased prevalence of TB (e.g., migrant farmworkers or homeless persons)

In some circumstances, screening for TB disease with chest radiographs or sputum smears may be more appropriate than screening for infection with the tuberculin skin test. For example, chest radiography may be the best method in jails or homeless shelters, where the risk of transmission is high but the time required to give skin tests to large numbers of transient persons and to read results makes screening for infection impractical.

Screening for TB infection or disease should always be carried out in consultation with the health department. Facilities such as drug treatment programs or long-term care facilities should screen high-risk groups only when appropriate follow-up measures can be provided either by that facility or by the health department.

Clinicians should identify patients who are in a high-risk category, and they should tuberculin test these persons as part of their routine evaluation. In particular, persons with certain medical conditions known to increase the risk for TB disease (see Transmission and Pathogenesis) should also be tuberculin tested, and their tuberculin skin test status should be clearly noted on their medical record. Persons with a positive reaction should be evaluated for TB disease and, if disease is ruled out, considered for preventive therapy.

Health care workers should be included in a TB screening and prevention program. In addition, screening is recommended for the staff of long-term care facilities who (1) may be exposed to TB patients on the job (e.g., staff of correctional facilities) or (2) would pose a risk to large numbers of susceptible persons if they developed infectious TB (e.g., staff of child care centers or AIDS hospices). Such persons should be tuberculin tested upon employment and thereafter at intervals determined by the risk of transmission in that facility. This screening is done for two reasons:

• to detect TB infection or disease in staff so that they may be given
• to determine whether TB is being transmitted in the facility (indicated by skin test conversions among staff).

Click here to return to Table of Contents

Tuberculin Skin Testing

Administration of the Tuberculin Test

Mantoux tuberculin skin testing is the standard method of identifying persons infected with M. tuberculosis. Multiple puncture tests should not be used to determine whether a person is infected.

The Mantoux test is performed by giving an intradermal injection of 0.1 ml of purified protein derivative (PPD) tuberculin containing 5 tuberculin units (TU) into either the volar or dorsal surface of the forearm. The injection should be made with a disposable tuberculin syringe, just beneath the surface of the skin, with the needle bevel facing upward. This should produce a discrete, pale elevation of the skin (a wheal) 6 mm to 10 mm in diameter.

To prevent needlestick injuries, needles should not be recapped, purposely bent or broken, removed from disposable syringes, or otherwise manipulated by hand. After they are used, disposable needles and syringes should be placed in puncture-resistant containers for disposal. Institutional guidelines regarding universal precautions for infection control (e.g., the use of gloves) should be followed.

The reaction to the Mantoux test should be read by a trained health care worker 48 to 72 hours after the injection. If a patient fails to show up for the scheduled reading, a positive reaction may still be measurable up to 1 week after testing. However, if a patient who fails to return within 72 hours has a negative test, tuberculin testing should be repeated.

The area of induration (palpable swelling) around the site of injection is the reaction to tuberculin. The diameter of the indurated area should be measured across the forearm (perpendicular to the long axis). Erythema (redness) should not be measured. All reactions should be recorded in millimeters of induration, even those classified as negative. If no induration is found, "0 mm" should be recorded.

Classification of the Tuberculin Reaction

• persons known to have or suspected of having HIV infection
• close contacts of a person with infectious TB
• persons who have chest radiograph findings suggestive of previous TB and who have received inadequate or no treatment persons who inject drugs and whose HIV status is unknown.

A tuberculin reaction of 10 mm or greater of induration is classified as positive in persons who do not meet the preceding criteria but who have other risk factors for TB. These include:

• persons with certain medical conditions (see Transmission and Pathogenesis), excluding HIV infection
• persons who inject drugs and who are known to be HIV negative
• foreign-born persons from areas of the world where TB is common (e.g., Asia, Africa, and Latin America)
• medically underserved, low-income populations, including high-risk racial and ethnic groups (e.g., Asians and Pacific Islanders, blacks, Hispanics, and Native Americans)
• residents of long-term care facilities (e.g., correctional facilities and nursing homes)
• children younger than 4 years of age
• other groups identified locally as having an increased prevalence of TB (e.g., migrant farmworkers or homeless persons)

A tuberculin reaction of 15 mm or greater of induration is classified as positive in persons with no known risk factors for TB. Determining whether those persons identified as positive are candidates for preventive therapy is discussed in Preventive Therapy.

In general, these guidelines for interpreting skin test reactions should also be applied to persons who may have occupational exposure to TB (e.g., health care workers and staff of nursing homes, drug treatment centers, or correctional facilities). Thus, the appropriate cutoff for defining a positive reaction depends on the employee's individual risk factors for TB. However, the appropriate cutoff also depends on the prevalence of TB in the facility. In facilities where the risk of exposure is very low, 15 mm or greater may be an appropriate cutoff for employees with no other risk factors. In facilities where TB patients receive care, 10 mm or greater may be an appropriate cutoff for employees with no other risk factors.

The tuberculin skin test is a valuable tool, but it is not perfect. Several factors can affect the skin test reaction: for example, infection with mycobacteria other than M. tuberculosis (nontuberculous mycobacteria) and vaccination with bacille Calmette-Gu,rin (BCG). These factors can lead to false-positive reactions (a positive skin test reaction in a person not infected with M. tuberculosis). See BCG Vaccination for further information on interpreting tuberculin reactions in persons with a history of BCG vaccination. Other factors, such as anergy, can lead to false-negative reactions.

Anergy Testing

The absence of a reaction to the tuberculin test does not rule out the diagnosis of TB disease or infection. In immunosuppressed persons, delayed-type hypersensitivity responses such as tuberculin reactions may decrease or disappear. This condition, known as anergy, may be caused by many factors, such as HIV infection, overwhelming miliary or pulmonary TB, severe or febrile illness, measles or other viral infections, Hodgkin's disease, sarcoidosis, live-virus vaccination, and the administration of corticosteroids or immunosuppressive drugs. On average, 10% to 25% of patients with TB disease have negative reactions when tested with a tuberculin skin test. Approximately one third of patients with HIV infection and more than 60% of patients with AIDS may have skin test reactions of <5 mm even though they are infected with M. tuberculosis.

Anergy is detected by administering at least two other delayed-type hypersensitivity antigens, such as tetanus toxoid, mumps, or Candida, by the Mantoux technique. This should be done in conjunction with tuberculin skin testing. Persons who have a reaction of 3 mm or greater to any of the antigens (including PPD) are not anergic. In addition, persons who have a positive reaction to tuberculin should be considered infected with M. tuberculosis, regardless of their reaction to the other antigens. The results of anergy testing should be recorded in millimeters of induration, not simply as positive or negative.

If anergy is demonstrated, the probability of infection should be assessed, and persons whose risk of exposure is judged to the high (known contacts of persons with infectious TB or persons from a group with a high prevalence of TB infection) should be evaluated for preventive therapy.

Although low CD4+ T-lymphocyte counts (200/microliter or less) and anergy seem closely correlated, anergy can occur in patients with a relatively high CD4+ T-lymphocyte count. In addition, reactivity to PPD or control antigens may be present at very low CD4+ T-lymphocyte levels. Currently, CD4+ T-lymphocyte testing is not recommended as a substitute for anergy testing.

Two-Step Testing

In some people who are infected with M. tuberculosis, delayed-type hypersensitivity to tuberculin may wane over the years. When these people are skin tested many years after infection, they may have a negative reaction. However, this skin test may stimulate (boost) their ability to react to tuberculin, causing a positive reaction to subsequent tests. This boosted reaction may be misinterpreted as a new infection.

Two-step testing is used to distinguish boosted reactions and reactions due to new infection. If the reaction to the first test is classified as negative, a second test should be done 1 to 3 weeks later. A positive reaction to the second test probably represents a boosted reaction. On the basis of this second test result, the person should be classified as previously infected and cared for accordingly. This would not be considered a skin test conversion. If the second test result is also negative, the person should be classified as uninfected. In these persons, a positive reaction to any subsequent test is likely to represent new infection with M. tuberculosis (skin test conversion). Two-step testing should be used for the initial skin testing of adults who will be retested periodically, such as health care workers.

Click here to return to Table of Contents

Chapter Five: DIAGNOSIS OF TB

A complete medical evaluation for TB should include a medical history, a physical examination, a Mantoux tuberculin skin test, a chest radiograph, and any appropriate bacteriologic or histologic examinations.

Click here to return to Table of Contents

Medical History

The symptoms of pulmonary TB include a productive, prolonged cough (duration of more than 3 weeks), chest pain, and hemoptysis. Systemic symptoms of TB include fever, chills, night sweats, easy fatigability, loss of appetite, and weight loss. TB should be considered in persons who have these symptoms.

Approximately 15% of TB cases are extrapulmonary. The symptoms of extrapulmonary TB depend on the site affected. TB of the spine may cause pain in the back; TB of the kidney may cause blood in the urine. Extrapulmonary TB should be considered in the differential diagnosis of ill persons who have systemic symptoms and who are at high risk for TB.

It is important to ask persons suspected of having TB about their history of exposure to TB and history of TB disease or infection. Clinicians may also contact the local health department for information about whether a patient has received TB treatment. If a regimen was inadequate or if the patient did not adhere to therapy, TB may recur and may be drug resistant.

It is also important to consider demographic factors (country of origin, age, ethnic or racial group, occupation) that may increase the patient's risk for exposure to TB.

In addition, clinicians should determine whether the patient has medical conditions, especially HIV infection, that increase the risk for TB disease (see Transmission and Pathogenesis). Patients who have risk factors for HIV infection but who do not know their current HIV status should be referred for HIV counseling and testing.

Click here to return to Table of Contents

Physical Examination

A physical examination is an essential part of the evaluation of any patient. It cannot be used to confirm or rule out TB, but it can provide valuable information about the patient's overall condition and other factors that may affect how TB is treated.

Click here to return to Table of Contents

Tuberculin Skin Testing

The tuberculin skin test is useful for:

1. examining a person who is not ill but may be infected with M. tuberculosis, such as a person who has been exposed to someone who has TB. The tuberculin skin test is the only way to diagnose TB infection before the infection has progressed to TB disease
2. determining how many people in a group are infected with M. tuberculosis
3. examining a person who has symptoms of TB

The preferred method of tuberculin testing is the Mantoux tuberculin skin test. The administration of the Mantoux test and interpretation of its results are discussed in Screening for TB Disease and Infection.

Some persons may have a false-negative reaction to the tuberculin skin test if they are tested too soon after being exposed to TB. In general, it takes 2 to 10 weeks after infection for a person to develop an immune response to tuberculin. Persons who have recently been around someone who has TB and who have a negative reaction to the tuberculin skin test should be retested 10 weeks after the last time they were exposed to infectious TB.

Children younger than 6 months of age may have a false-negative reaction to the tuberculin skin test because their immune systems are not yet fully developed.

As noted in Screening for TB Disease and Infection, a negative reaction to the tuberculin test does not exclude the diagnosis of TB, especially for patients with severe illness or HIV infection.

Click here to return to Table of Contents

Radiographic Examination

In pulmonary TB, chest radiograph abnormalities often occur in the apical and posterior segments of the upper lobe or in the superior segments of the lower lobe. However, lesions may appear anywhere in the lungs and may differ in size, shape, density, and cavitation, especially in HIV-infected and other immunosuppressed persons.

In HIV-infected persons with pulmonary TB, the chest radiograph may have an unusual appearance. For example, TB may cause infiltrates without cavities in any lung zone, or it may cause mediastinal or hilar lymphadenopathy. In HIV-infected persons, almost any abnormality on a chest radiograph may indicate TB. In fact, the radiograph of an HIV-infected person with TB disease may even appear entirely normal.

Abnormalities on chest radiographs may be suggestive of, but are never diagnostic of, TB. However, chest radiographs may be used to rule out the possibility of pulmonary TB in a person who has a positive reaction to the tuberculin skin test and no symptoms of disease.

An isolated granuloma on a chest radiograph is not considered a fibrotic lesion compatible with previous TB. Clinicians may wish to consult with a radiologist or clinician expert in the interpretation of such radiographs to become more familiar with this categorization.

Click here to return to Table of Contents

Diagnostic Microbiology

Specimen Collection

Patients should be properly instructed how to produce a good specimen. They should be informed that sputum is the material brought up from the lungs and that mucus from the nose and throat and saliva are not good specimens. They should be instructed to follow these steps for producing a sputum specimen.

• Clean and thoroughly rinse the mouth with water.
• Breathe deeply three times (you should have a tickling feeling at the end of a very deep breath).
• After the third breath, cough hard and try to bring up sputum from deep in the lungs.
• Expectorate the sputum into a sterile container, collecting at least one teaspoonful.
• Remain in the collection booth or isolation room until coughing stops.

Coaching patients individually on how to expectorate can facilitate sputum collection. Unsupervised patients are seldom successful in providing an adequate specimen, especially the first time. The amount of coaching required on later visits will depend on individual patient needs.

For patients unable to cough up sputum, aerosol induction can be used to stimulate the production of sputum. Patients should be instructed to take several normal breaths of aerosol mist, inhale deeply, cough hard, and then expectorate into the specimen container. They should be given time--15 minutes is usually sufficient--to produce sputum, which is usually brought up by a deep cough. Because induced sputum is very watery and resembles saliva, it should be labeled "induced" to ensure that the laboratory staff do not discard it.

Bronchoscopy can be done if the patient cannot cough up sputum and there is reasonable suspicion of TB. Bronchial washings, brushings, and biopsy specimens may be obtained, depending on the diagnostic possibilities and findings. Sputum collected after bronchoscopy may also be useful for a diagnosis.

Gastric aspiration can also be used to obtain swallowed sputum specimens, but it is uncomfortable and invasive. It is, however, the best way to obtain specimens from infants and some young children who cannot produce sputum even with aerosol inhalation.

During specimen collection, patients produce an aerosol that may be hazardous to health care workers or other patients in close proximity. For this reason, precautionary measures for infection control must be followed during sputum induction, bronchoscopy, and other common diagnostic procedures (see Infection Control).

Because TB can occur in almost any anatomical site, a variety of clinical specimens other than sputum (e.g., urine, cerebrospinal fluid, pleural fluid, pus, or biopsy specimens) may be submitted for examination when nonpulmonary mycobacterial disease is suspected. Tissue specimens for the culture of M. tuberculosis should be placed in a saline solution, not in formalin, and should be delivered to the laboratory promptly.

Laboratory Examination

Detection of acid-fast bacilli (AFB) in stained smears examined microscopically may provide the first bacteriologic clue of TB. Fluorescent staining with Auramine O is the preferred staining method because it is faster and more sensitive than the traditional methods in which Ziehl-Neelsen or Kinyoun stains are used. Smear examination is an easy and quick procedure; results should be available within 24 hours of specimen collection. However, smear examination permits only the presumptive diagnosis of TB because the AFB on a smear may be mycobacteria other than M. tuberculosis. Furthermore, many TB patients have negative AFB smears.

A positive culture for M. tuberculosis confirms a diagnosis of TB; however, TB may also be diagnosed on the basis of clinical signs and symptoms in the absence of a positive culture. Culture examinations should be done on all specimens, regardless of AFB smear results. When a liquid medium is inoculated for growth (using the BACTEC radiometric system) and rapid methods are used for species identification, culture results should be available within 10 to 14 days of specimen collection. If a solid medium and conventional biochemical tests are used, the isolation of the organism can take 6 to 12 weeks.

Nucleic acid probes specific for the genus Mycobacterium, the M. tuberculosis complex, M. avium, and M. intracellulare provide a rapid method of species identification. Once the mycobacteria have been grown in culture, nucleic acid probes can identify the species in 2 to 8 hours. High-performance liquid chromatography (HPLC), which detects differences in the spectrum of mycolic acids in the cell wall, is equally rapid. A test inhibition by NAP can identify M. tuberculosis in 3 to 5 days.

Polymerase chain reaction (PCR) techniques are being developed that could be performed directly on sputum or other clinical specimens to diagnose TB disease more quickly. However, until the evaluation of this method is completed, PCR should be considered an experimental technique; it is not available for the routine diagnosis of TB. In the future, this technique may become widely available to clinicians.

Follow-up bacteriologic examinations are important for assessing the patient's infectiousness and response to therapy. At a minimum, specimens should be obtained at monthly intervals until culture conversion to negative.

Laboratories should report positive smears and positive cultures within 24 hours by telephone or fax to the primary health care provider. Follow-up results may be reported by mail. It is the responsibility of the primary health care provider to report promptly all suspected or confirmed cases of TB to the health department so that a contact investigation can be initiated as quickly as possible (see Community TB Control).

For all patients, the initial M. tuberculosis isolate should be tested for drug susceptibility. It is crucial to identify drug resistance as early as possible in order to ensure appropriate treatment. Drug susceptibility patterns should be repeated for patients who do not respond adequately or who have positive culture results after 2 months of therapy. Susceptibility results from laboratories should be promptly forwarded to the health department.

The radiometric BACTEC method, which uses liquid media cultures, is faster than conventional methods for determining susceptibility to first-line TB medications. When BACTEC is used, results can be obtained within 5 days of inoculation; conventional methods, which use solid media for growth, can take as long as 21 days after inoculation.

Patients at an increased risk for drug resistance include:

• persons who have a history of treatment with TB drugs
• contacts of persons known to have drug-resistant TB
• foreign-born persons from areas where the prevalence of drug-resistant TB is high (e.g., Asia, Africa, and Latin America)
• residents of geographic areas in the United States where the prevalence of isoniazid-resistant TB is documented to be 4% or greater
• persons whose smears or cultures remain positive after 2 months of therapy with TB drugs

Restriction fragment length polymorphism (RFLP), a method of DNA fingerprinting, can be used to identify specific strains of M. tuberculosis and thus to track TB transmission during outbreaks. The restriction enzymes used in this technique cut DNA at certain sites to produce fragments. These fragments are separated by size to produce a pattern, or "fingerprint," that is specific for each strain. Related isolates show the same pattern.

Further details about the collection and processing of specimens, smear examination and culture, and drug susceptibility testing can be found in the article "Diagnostic Standards and Classification of Tuberculosis" (American Thoracic Society and Centers for Disease Control, Am Rev Respir Dis 1990;142:725-735).

Click here to return to Table of Contents

Chapter Six:
PREVENTIVE THERAPY TREATMENT OF TB INFECTION

Summary. Preventive therapy substantially reduces the risk that TB infection will progress to disease. Certain groups are at very high risk of developing TB disease once infected. Persons in these groups should be considered candidates for preventive therapy, regardless of their age. In addition, infected persons younger than 35 years of age in high-prevalence groups should be given priority for preventive therapy. The current preventive therapy regimen is 6 to 12 months of daily isoniazid. Patients must be monitored monthly (or more frequently, if necessary) for symptoms of adverse reactions, as well as for their adherence to the prescribed regimen. In instances of known exposure to drug-resistant organisms, alternative preventive therapy regimens may be recommended. New, short-course preventive regimens are currently being evaluated.

Click here to return to Table of Contents

Candidates

Persons in the following high-risk groups should be given high priority for preventive therapy if they have positive skin test results, regardless of their age (the criterion for a positive reaction, in millimeters of induration, is given in parentheses):

1. persons known to have or suspected of having HIV infection, including persons who inject drugs and whose HIV status is unknown (5 mm or greater)
2. close contacts of a person with infectious TB (5 mm or greater)
3. persons who have chest radiograph findings suggestive of previous TB and who have received inadequate or no treatment (5 mm or greater)
4. persons who inject drugs and who are known to be HIV negative (10 mm or greater)
5. persons with certain medical conditions (see Transmission and Pathogenesis) (10 mm or greater)
6. persons whose tuberculin skin test reaction converted from negative to positive within the past 2 years (10 mm or greater increase if younger than 35 years of age; 15 mm or greater increase if 35 years of age or older)

In addition, in the absence of any of the preceding risk factors, persons younger than 35 years of age in the following high-prevalence groups should be evaluated for preventive therapy if their reaction to the tuberculin skin test is 10 mm or greater:

1. foreign-born persons from areas of the world where TB is common (e.g., Asia, Africa, and Latin America)
2. medically underserved, low-income populations, including high-risk racial and ethnic groups (e.g., Asians and Pacific Islanders, blacks, Hispanics, and Native Americans)
3. residents of long-term care facilities (e.g., correctional facilities and nursing homes)
4. children younger than 4 years of age
5. other groups identified locally as having an increased prevalence of TB (e.g., migrant farmworkers or homeless persons)

Persons younger than 35 years of age with no known risk factors for TB should be evaluated for preventive therapy if their reaction to the tuberculin test is 15 mm or greater. This group should be given a lower priority for prevention efforts than the groups already listed.

Persons who may have occupational exposure to TB (e.g., health care workers and staff of nursing homes, drug treatment centers, or correctional facilities) should be considered for preventive therapy if they have a positive tuberculin reaction. The appropriate cutoff for defining a positive reaction depends on the employee's individual risk factors for TB and on the prevalence of TB in the facility (see Screening for TB Disease and Infection).

Isoniazid preventive therapy is not recommended for infected persons who are 35 years of age or older unless these persons are at high risk of developing TB disease. This is because the risk of isoniazid-related hepatitis outweighs the benefits of preventive therapy in this age group.

Close contacts with an initial tuberculin reaction of <5 mm should receive a chest radiograph and should be considered for preventive therapy in any of the following situations:

• circumstances suggest a high probability of infection
• evaluation of other contacts with a similar degree of exposure demonstrates a high prevalence of infection
• the contact is a child or an adolescent, or the contact is immunosuppressed (e.g., HIV infected)

Close contacts who have a negative reaction to an initial skin test should be retested 10 weeks after they were last exposed to TB. Preventive therapy may be discontinued if the skin test result is again negative and if the person is no longer being exposed to TB. However, persons known to have or suspected of having HIV infection should be given preventive therapy regardless of their skin test reaction if anergy is demonstrated and their risk of infection is judged to be high.

Infants who are exposed to a person with TB disease should be evaluated with a tuberculin skin test and a chest radiograph. If the skin test result is negative and the chest radiograph is normal, the infant should be skin tested again at 3 to 4 months and at 6 months. The infant should receive preventive therapy even if the tuberculin skin test result and chest radiograph do not suggest TB, because infected infants may be anergic as late as 6 months of age. Isoniazid can be discontinued if the skin test result is negative at 6 months, provided that at least 10 weeks have passed since the infant was last exposed to infectious TB.

Generally, pregnant women who are found to be tuberculin positive upon routine screening should not be given preventive therapy until after delivery. However, pregnant women who are likely to have been recently infected or who have high-risk medical conditions, especially HIV infection, should be given isoniazid preventive therapy as soon as TB infection is documented and TB disease has been ruled out. Tuberculin skin testing is both safe and reliable throughout the course of pregnancy.

Preventive therapy may not be an option for all persons who have positive skin test results. Persons for whom preventive therapy might not be indicated include

• persons at high risk for adverse reactions to isoniazid (e.g., persons 35 years of age or older who are not in high-risk groups and persons for whom isoniazid is contraindicated)
• persons who cannot tolerate isoniazid
• persons likely to be infected with drug-resistant M. tuberculosis
• persons who are highly unlikely to complete a course of preventive therapy (e.g., some homeless persons or migrant farmworkers)

Clinicians should educate these persons about TB infection and disease and advise them to seek medical evaluation immediately if any symptoms of TB disease develop.

Click here to return to Table of Contents

Standard Regimens

Clinical trials have shown that daily isoniazid preventive therapy for 12 months reduces the risk for TB disease by more than 90% in infected patients who complete a full course of therapy. There is evidence that 6 months of preventive therapy with isoniazid also confers a high degree of protection (approximately 69% in patients who complete the regimen) against the progression of TB infection to TB disease. Every effort should be made to ensure that patient adhere to preventive therapy for at least 6 months. Children should receive at least 9 months of preventive therapy. HIV-infected persons should receive 12 months of isoniazid preventive therapy.

Isoniazid is normally used alone for preventive therapy in a single daily dose of 300 mg in adults and 10 to 15 mg/kg body weight in children, not to exceed 300 mg per dose.

For persons who are at especially high risk for TB and whose adherence is questionable, directly observed preventive therapy should be considered. This method of treatment is especially appropriate in institutions and facilities where preventive therapy can be observed by a staff member. Isoniazid can be given two times a week at a dosage of 15 mg/kg as directly observed preventive therapy. Data on the effectiveness of intermittent isoniazid preventive therapy are limited. However, the results of studies of twice-weekly therapy with isoniazid suggest that it is an effective form of preventive therapy in adults and children.

Click here to return to Table of Contents

Alternative Regimens

For patients who have a positive tuberculin skin test result and either silicosis or a chest radiograph demonstrating old fibrotic lesions and who have no evidence of current disease, acceptable regimens include either 4 months of isoniazid plus rifampin or 12 months of isoniazid, provided that infection with drug-resistant organisms is judged to be unlikely.

For close contacts of infectious patients who have isoniazid-resistant TB, preventive therapy with rifampin should be considered. Therapy should last at least 6 months for adults and 9 months for children, and the usual therapeutic dose should be given. In addition, a rifampin-based preventive therapy regimen should be considered for isoniazid-intolerant patients. However, if a patient is unlikely to be infected with an isoniazid-resistant strain of M. tuberculosis and can tolerate isoniazid, preventive therapy with isoniazid should be used.

For persons likely to have been infected with M. tuberculosis resistant to both isoniazid and rifampin, observation without preventive therapy is usually recommended because only isoniazid and rifampin have been evaluated for preventive therapy. However, for persons at an especially high risk for TB disease once infected (e.g., persons with HIV infection), preventive therapy with an alternative regimen should be strongly considered.

Alternative regimens should include at least two drugs to which the infecting organism has demonstrated susceptibility. Potential alternative regimens include either 6 months of daily ethambutol and pyrazinamide or 6 months of pyrazinamide and one of the quinolones (ofloxacin or ciprofloxacin), in the usual therapeutic doses. Careful assessment to rule out the possibility of TB disease is necessary before preventive therapy is started. Patients treated with an alternative regimen should be followed for 2 years.

New, short-course preventive therapy regimens (e.g., rifampin and pyrazinamide for 2 months and rifampin alone for 4 months) are currently being evaluated.

Click here to return to Table of Contents

Monitoring

• rule out the possibility of TB disease (with a medical history and chest radiograph)
• question for a history of treatment for TB infection or disease
• check for contraindications, including previous isoniazid-associated hepatic injury; history of severe adverse reactions to isoniazid, such as a drug fever, rash, or arthritis; and acute or unstable liver disease of any cause
• determine whether the patient is at high risk for adverse reactions

When isoniazid is used alone to treat persons with TB disease, resistance to isoniazid is likely to develop. For this reason, persons suspected of having TB disease should receive multidrug treatment until the diagnosis is confirmed or ruled out. If previous (not current) TB is diagnosed, multidrug treatment should continue for 4 months for adults and for 6 months for children.

• adherence to the prescribed regimen
• symptoms of hepatitis, such as nausea, loss of appetite, vomiting, persistently dark urine, yellowish skin, malaise, unexplained elevated temperature for more than 3 days, or abdominal tenderness (especially right upper quadrant)
• signs of hepatitis detected during the physical examination
• symptoms of neurotoxicity, such as paresthesias of hands or feet

At follow-up visits, patients should routinely be asked about adherence. Pill counts should be taken routinely, and urine test may periodically be used to check for the presence of isoniazid metabolites. However, urine tests indicate only whether isoniazid was taken in the preceding 24 hours.

Peripheral neuropathy is associated with the use of isoniazid but is uncommon at doses of 5 mg/kg. Persons with conditions in which neuropathy is common (e.g., diabetes, uremia, alcoholism, malnutrition), as well as pregnant women and persons with a seizure disorder, may be given pyridoxine (10-50 mg/day) with isoniazid. As little as 6 mg/day of pyridoxine has been shown to prevent isoniazid-associated neuropathy.

Persons who are considered at high risk for hepatotoxicity should have a measurement of serum glutamic-oxaloacetic transaminase (SGOT or AST) before starting therapy and monthly during the course of therapy. Measurements of hepatic enzymes are not recommended for persons younger than 35 years of age unless the patient is at risk for adverse reactions due to isoniazid preventive therapy.

• are 35 years of age or older
• are currently using another medication that may cause drug interactions
• may abuse alcohol (associated with a higher incidence of isoniazid-associated hepatitis)
• have a history of discontinuing isoniazid because of adverse effects (e.g., headaches, dizziness, nausea)
• have chronic liver disease
• have peripheral neuropathy or a condition that may predispose to the development of neuropathy (e.g., diabetes mellitus or alcoholism)
• are pregnant
• inject drugs

Some evidence suggests that women, particularly black and Hispanic women, are at increased risk for fatal hepatitis associated with isoniazid. This risk may also be increased during the postpartum period. These persons should be closely monitored for adverse reactions throughout the course of treatment.

About 10% to 20% of persons taking isoniazid will have some mild, asymptomatic elevation of liver enzymes. These abnormalities tend to resolve even if isoniazid is continued. If any of the measurements exceeds three to five times the upper limit of normal or if the patient reports symptoms of adverse reactions, the discontinuation of isoniazid should be strongly considered.

Patients should be educated about the symptoms of hepatitis and other adverse reactions to isoniazid, and they should be advised to report immediately to the clinician if any of these symptoms occur during preventive therapy. In addition, clinicians should advise all patients who start preventive therapy to report immediately any symptoms of TB disease.

Dispense no more than a 1-month supply of medicine at a time.

Click here to return to Table of Contents

Chapter Seven: TREATMENT OF TB DISEASE

Summary. For most patients, the initial regimen for treating TB diseaseshould include four drugs: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. The regimen can be adjusted when drug susceptibility results become available. In areas where the rate of isoniazid resistance is documented to be less than 4%, three drugs (isoniazid, rifampin, and pyrazinamide) may be adequate for the initial regimen. A four-drug, 6-month regimen is effective even when the infecting organism is resistant to isoniazid. Alternatively, a 9-month regimen of isoniazid and rifampin is acceptable for persons who cannot or should not take pyrazinamide. Ethambutol or streptomycin should also be included in this regimen until the results of drug susceptibility studies are available, unless there is little possibility of drug resistance. The recommendations for duration of TB treatment in HIV-infected persons are the same as for persons not infected with HIV. The major determinant of the outcome of treatment is patient adherence to the drug regimen. Thus, careful attention should be paid to measures designed to foster adherence, and consideration should be given to treating all patients with DOT. Nearly all the treatment regimens may be given intermittently if they are directly observed. Multidrug-resistant TB (e.g., TB resistant to at least isoniazid and rifampin) presents difficult treatment problems, often requiring expert consultation.

TB must be treated for a long time (6-24 months) compared with many other infectious diseases. If treatment is not continued for a sufficient length of time, some tubercle bacilli may survive, and the patient may become ill and infectious again.

Regimens for the treatment of TB must contain multiple drugs to which the organisms are susceptible. The administration of a single drug can lead to the development of a bacterial population resistant to that drug. Likewise, the addition of a single drug to a failing regimen can lead to resistance to that drug. When two or more drugs are used simultaneously, each helps prevent the emergence of tubercle bacilli resistant to the others.

The initial phase of treatment is crucial for preventing the emergence of drug resistance and for determining the ultimate outcome of the regimen. Four drugs--isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin--should be included in the initial treatment regimen until the results of drug susceptibility tests are available. If there is little possibility of drug resistance (i.e., less than 4% primary resistance to isoniazid in the community and the patient has had no previous treatment with TB drugs, is not from a country with a high prevalence of drug resistance, and has no known exposure to a patient with drug-resistant disease), three drugs (isoniazid, rifampin, and pyrazinamide) may be adequate for the initial regimen.

There are several options for daily and intermittent therapy, but the aim of treatment should be to provide the safest and most effective therapy in the shortest period of time. Given adequate treatment, almost all patients will become bacteriologically negative, recover, and remain well.

For each new case of TB, a specific treatment and monitoring plan should be developed in collaboration with the local health department within 1 week of the presumptive diagnosis. This plan should include a description of the treatment regimen, the methods of assessing and ensuring adherence, and the methods of monitoring for adverse reactions.

Click here to return to Table of Contents

Adherence

Nonadherence is a major problem in TB control. On average, 25% of persons receiving treatment for TB disease do not complete a recommended regimen within 12 months. Inadequate treatment can lead to relapse, continued transmission, and the development of drug resistance.

Most health departments have public health nurses or community outreach workers who can work with patients and clinicians to help patients adhere to a prescribed regimen. Whenever possible, a worker who has the same cultural and linguistic background as the patient should be assigned to help develop an individualized treatment adherence plan.

One way to ensure that patients adhere to therapy is to use directly observed therapy (DOT). DOT means that a health care worker or another designated person watches the patient swallow each dose of TB medication. DOT should be considered for all patients because clinicians are often inaccurate in predicting which patients will adhere to medication on their own.

In many areas, patients are routinely given DOT. DOT has been shown to be cost-effective when intermittent regimens are used. Nearly all the treatment regimens for TB can be given intermittently if they are directly observed; using intermittent regimens reduces the total number of doses a patient must take, as well as the total number of encounters with the health care provider or outreach worker. Furthermore, DOT can significantly reduce the frequency of acquired drug resistance and relapse.

It is important that DOT be carried out at times and in locations that are as convenient as possible for the individual patient. Therapy may be directly observed in the office or clinic setting but also can be observed by an outreach worker in the field (i.e., the patient's home, place of employment, school, or other mutually agreed-upon place). In some situations, staff of correctional facilities, drug treatment programs, home health care workers, maternal and child health staff, or a responsible community or family member may provide DOT.

All patients should be educated about TB, the dosing of medications, the possible adverse reactions of the medications, and the importance of taking their medication. Health care workers must take the time to explain clearly to patients when the medication should be taken, how much, and how often, especially if the patient is not receiving DOT. Written instructions should also be provided.

Patients who are not receiving DOT should be asked routinely about adherence at follow-up visits. Pill counts should be taken routinely, and urine tests can be used periodically to check for the presence of drug metabolites. In addition, the patient's response to treatment (bacteriologic conversion to negative) should be monitored closely. If the patient's sputum remains positive after 2 months of treatment, DOT should be considered for the remainder of treatment.

Health care professionals, including private practitioners, who note that a particular TB patient has demonstrated an inability or an unwillingness to adhere to a prescribed treatment regimen should consult the health department. The TB control program in the health department should assist in evaluating the patient for causes of nonadherence and should provide additional services, such as the services of outreach workers, to enable the patient to complete the recommended therapy. If these efforts are unsuccessful, the health department should take appropriate action, such as seeking court-ordered DOT or the detention of a patient who is unwilling or unable to complete treatment and who is infectious, at risk of becoming infectious, or at risk for drug-resistant TB.

When therapy is self-administered, the use of fixed-dose combination capsules or tablets may enhance patient adherence and reduce the risk of inappropriate monotherapy; it may also prevent the development of acquired drug resistance. For this reason, the use of such fixed-dose combinations is strongly encouraged for adults prescribed a self-administered regimen. In the United States, the Food and Drug Administration has licensed fixed-dose combinations of isoniazid and rifampin (Rifamate) and of isoniazid, rifampin, and pyrazinamide (Rifater). Clinicians should become familiar with these fixed-dose combination drugs.

Click here to return to Table of Contents

Pulmonary TB

The duration of therapy depends on the drugs used, the drug susceptibility test results, and the patient's response to therapy. Most patients with previously untreated pulmonary TB can be treated with either a 6-month or a 9-month regimen, although the 6-month regimen is preferred. Both the 6-month and 9-month regimens are referred to as short-course regimens. All regimens of 9 months or less must contain isoniazid and rifampin; all 6-month regimens must contain isoniazid, rifampin, and, initially, pyrazinamide.

For adults with smear- or culture-positive pulmonary TB, the initial phase of a 6-month regimen should consist of a 2-month period of isoniazid, rifampin, and pyrazinamide. Ethambutol or streptomycin should be included in the initial regimen until the results of drug susceptibility studies are available, unless there is little possibility of drug resistance (i.e., less than 4% primary drug resistance to isoniazid in the community, and the patient has had no previous treatment with TB drugs, is not from a country with a high prevalence of drug resistance, and has no known exposure to a person with drug resistant TB).

The initial use of a four-drug regimen is recommended to prevent the development of multidrug-resistant TB in areas where primary isoniazid resistance is increased. If susceptibility to isoniazid and rifampin is demonstrated, the second phase of treatment should consist of isoniazid and rifampin for 4 months.

1. Four-drug therapy, administered daily for 8 weeks, may be followed by therapy with isoniazid and rifampin given two or three times a week for 16 weeks (if susceptibility to isoniazid and rifampin is demonstrated).
2. Four-drug therapy, administered daily for 2 weeks and then two times a week for 6 weeks, may be followed by therapy with isoniazid and rifampin given two times a week for 16 weeks (if susceptibility to isoniazid and rifampin is demonstrated).
3. Four-drug therapy may be administered three times a week throughout the 6-month treatment period. All four drugs should be continued throughout the course of treatment in this regimen.

Because intermittent therapy is easier to supervise than daily therapy, intermittent therapy provides an effective tool with which to ensure adherence in the treatment of outpatients.

When isoniazid, pyrazinamide, and ethambutol or streptomycin are given two or three times a week instead of every day, the dose must be increased. However, the dose of rifampin is the same whether the drug is given daily or intermittently.

Alternatively, a 9-month regimen of isoniazid and rifampin is acceptable for persons who cannot or should not take pyrazinamide. Again, ethambutol or streptomycin should be included initially unless there is little possibility of drug resistance (patient has no individual risk factors for drug resistance and resides in an area where the prevalence of isoniazid-resistant TB <4%). If susceptibility to isoniazid and rifampin is demonstrated, isoniazid and rifampin may be given twice weekly after an initial 1 or 2 months of daily treatment.

For adults with smear- and culture-negative pulmonary TB, a 4-month regimen of isoniazid and rifampin, combined with pyrazinamide for the first 2 months, may be used when drug resistance is unlikely. However, for adults with smear- and culture-negative pulmonary TB who have individual risk factors for drug resistance or who live in an area where the prevalence of isoniazid-resistant TB is 4% or greater, four drugs (isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin) should be continued throughout the 4-month regimen.

The recommendations for the duration of TB treatment for HIV-infected persons are the same as for persons not infected with HIV. However, in HIV-infected patients, it is critically important to assess the clinical and bacteriologic response to therapy. Treatment should be prolonged if the response is slow or otherwise suboptimal. Because the effect of patient adherence on the outcome is much more crucial, DOT is strongly recommended for this group.

Click here to return to Table of Contents

Extrpulmonary TB

As a general rule, regimens that are adequate for treating pulmonary TB in adults and children are also effective for treating extrapulmonary disease. However, infants and children who have miliary TB, bone and joint TB, or TB meningitis should receive a minimum of 12 months of therapy.

The use of adjunctive therapies such as surgery and corticosteroids is more commonly required for extrapulmonary TB than for pulmonary disease. Surgery may be necessary to obtain specimens for diagnosis and to treat such processes as constrictive pericarditis and spinal cord compression from Pott's disease. Corticosteroids have been shown to be beneficial in preventing cardiac constriction from tuberculous pericarditis and in decreasing the neurologic sequelae of all stages of TB meningitis, especially when administered early in the course of disease.

In patients with extrapulmonary TB, the type of follow-up examinations should be determined by the site of the disease. Bacteriologic evaluation may be limited by the relative inaccessibility of the site. Thus, the response to treatment must often be judged on the basis of clinical and radiographic findings.

Click here to return to Table of Contents

Pregnant or Lactating Women

Pregnant women with TB must be given adequate therapy as soon as TB is suspected. The preferred initial treatment regimen is isoniazid, rifampin, and ethambutol (ethambutol may be excluded if primary isoniazid resistance is unlikely). Streptomycin should not be used because it has been shown to have harmful effects on the fetus. In addition, pyrazinamide should not be used routinely because its effect on the fetus is unknown. Because the 6-month treatment regimen cannot be used, a minimum of 9 months of therapy should be given. To prevent peripheral neuropathy, it is advisable to give pyridoxine to pregnant women who are taking isoniazid. See table 3 for information on the use of TB drugs to treat pregnant women.

The small concentrations of TB drugs in breast milk do not have a toxic effect on nursing newborns, and breast feeding should not be discouraged. Conversely, drugs in breast milk should not be considered effective treatment for disease or infection in a nursing infant.

Click here to return to Table of Contents

Children and Adolescents

Infants and children with TB should be treated with one of the regimens mentioned in the section Treatment of Pulmonary TB. The specific intermittent regimens have not been studied in children. However, the success of other intermittent regimens in children suggests that these regimens would be effective. Ethambutol is generally not used for young children whose visual acuity cannot be monitored. If ethambutol must be used to treat a young child (e.g., because of drug-resistant TB), the minimum dose should be used.

In infants, TB is much more likely to disseminate; therefore, prompt and vigorous treatment should be started as soon as the diagnosis is suspected.

Sputum specimens collected from children are often inadequate. In these situations, it may be necessary to rely on the results of cultures and susceptibility tests of specimens from the adult source case to confirm the diagnosis in the child and to guide the choice of drugs. When drug-resistant TB is suspected or isolates from a source case are not available, it may be necessary to perform gastric aspiration, bronchoalveolar lavage, or tissue diagnosis.

Furthermore, for children, bacteriologic examinations are less useful for evaluating the response to treatment than for adults; thus, clinical and radiographic examinations are more important for children. However, the chest radiographs of children with hilar adenopathy may not become normal for 2 to 3 years after treatment. In this situation, a normal chest radiograph is not a criterion for discontinuing TB drugs.

In general, extrapulmonary TB in children can be treated with the same regimens as pulmonary TB. The exceptions are bone and joint disease, disseminated (miliary) disease, and meningitis, for which a minimum of 12 months of therapy is recommended.

Click here to return to Table of Contents

Drug-Resistant TB

A 6-month regimen of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin has been demonstrated to be effective for the treatment of TB resistant only to isoniazid. When resistance to isoniazid is documented during the recommended initial four-drug therapy, the regimen should be adjusted by discontinuing isoniazid and continuing the other three drugs for the entire 6 months of therapy. TB resistant only to isoniazid may also be treated with rifampin and ethambutol for 12 months.

When isoniazid resistance is documented in the 9-month regimen without pyrazinamide, isoniazid should be discontinued. If ethambutol was included in the initial regimen, treatment with rifampin and ethambutol should be continued for a minimum of 12 months. If ethambutol was not included initially, susceptibility tests should be repeated, isoniazid should be discontinued, and two drugs (e.g., ethambutol and pyrazinamide) should be added. The regimen can be adjusted when the results of the susceptibility tests become available.

Multidrug-resistant TB (i.e., TB resistant to at least isoniazid and rifampin) presents difficult treatment problems. Treatment must be individualized and based on the patient's medication history and susceptibility studies.

Unfortunately, adequate data are not available on the effectiveness of various regimens and the necessary duration of treatment for patients with organisms resistant to both isoniazid and rifampin. Moreover, many of these patients also have resistance to other first-line drugs (e.g., ethambutol and streptomycin) when drug resistance is discovered. Because of the poor outcome in such cases, it is preferable to give at least three new drugs to which the organism is susceptible. This regimen should be continued until culture conversion is documented, followed by at least 12 months of two-drug therapy. Often, a total of 24 months of therapy is given empirically.

Clinicians who are unfamiliar with the treatment of drug-resistant TB should seek expert consultation. Because second-line drugs can cause serious adverse reactions, patients taking these drugs should be monitored closely throughout the course of treatment. The role of new agents, such as the quinolone derivatives and amikacin, in the treatment of multidrug-resistant disease is not known, although these drugs are commonly being used in such cases.

Surgery seems to offer considerable benefit and a significantly improved cure rate for patients who have multidrug-resistant TB if the bulk of disease can be resected.

Click here to return to Table of Contents

Persons with Additional Medical Problems

A number of medical conditions may alter immune responsiveness and predispose a person to TB. Such disorders include HIV infection, immunosuppressive therapy, hematologic or reticuloendothelial malignancies, chronic renal failure, and malnutrition. These conditions may influence the outcome of therapy. Therapeutic decisions for the impaired host must be individualized.

For patients with partial impairment of renal function, avoid streptomycin, kanamycin, and capreomycin if possible. If renal function is severely impaired, reduced doses or increased dosing intervals of other TB drugs may be necessary (see table 3). Measurement of blood concentrations may be helpful in adjusting dosage.

For patients who may abuse alcohol or who have neuropsychiatric disorders, close supervision--preferably using DOT--is necessary to ensure adherence and monitor for adverse reactions to medications.

Click here to return to Table of Contents

Monitoring

Adverse reactions to TB drugs are relatively rare, but in some patients they may be severe. Clinicians who treat TB should be familiar with the methods of monitoring for adverse reactions and response to treatment. In some situations (e.g., drug-resistant TB, pregnant patients, HIV-infected patients), expert consultation may be required.

Adverse Reactions (See tables 2 and 4)

Monitoring for adverse reactions to TB medications must be individualized. The type and frequency of monitoring should depend on the drugs used in a given regimen and the patient's risk factors for adverse reactions (e.g., age, alcohol use). At a minimum, patients should be seen monthly during therapy and questioned by medical personnel concerning adverse reactions, even if no problems are apparent. Patients should be specifically instructed to look for symptoms associated with the most common reactions to the medications they are taking. They should also be instructed to seek medical attention immediately should these symptoms occur. If the symptoms suggest adverse reactions, appropriate laboratory testing should be performed.

All patients receiving isoniazid, rifampin, or pyrazinamide should be instructed to report immediately any symptoms suggesting hepatitis (nausea, loss of appetite, vomiting, persistently dark urine, yellowish skin, malaise, unexplained elevated temperature for more than 3 days, or abdominal tenderness). Patients receiving rifampin should be monitored for possible manifestations of thrombocytopenia (bleeding tendency, easy bruising, blood in urine) or flu-like syndromes.

Peripheral neuropathy is associated with the use of isoniazid but is uncommon at doses of 5 mg/kg. Persons with conditions in which neuropathy is common (e.g., diabetes, uremia, alcoholism, malnutrition), as well as pregnant women and persons with a seizure disorder, may be given pyridoxine (10-50 mg/day) with isoniazid. As little as 6 mg/day of pyridoxine has been shown to prevent isoniazid-associated neuropathy.

Hyperuricemia may occur in patients receiving pyrazinamide, but acute gout is uncommon. Asymptomatic hyperuricemia is not an indication for discontinuing the drug.

Audiometry should be performed at periodic intervals during streptomycin therapy. If vertigo, dizziness, or ataxia occur in patients taking streptomycin, the drug should be discontinued immediately.

The interaction of isoniazid and phenytoin increases the serum concentration of both drugs. When these drugs are given concomitantly, the serum level of phenytoin should be monitored.

Rifampin may accelerate the clearance of drugs metabolized by the liver. These include methadone, coumadin derivatives, glucocorticoids, estrogens, oral hypoglycemic agents, digitalis, anticonvulsants, ketoconazole, fluconazole, and cyclosporin. For patients who are in a drug treatment program, it may be necessary to increase the methadone dose by as much as 50%. Rifampin may also render oral contraceptives and contraceptive implants (e.g., Norplant) ineffective by accelerating estrogen metabolism. Women taking rifampin should use an alternative birth control method.

Current literature and package inserts should be consulted for other possible drug reactions.

Response to Treatment

For patients whose sputum cultures are positive before treatment, the best way to measure the effectiveness of therapy is to obtain specimens for culture at least monthly until the cultures convert to negative. Patients whose sputum no longer contains M. tuberculosis after 2 months of treatment should have at least one further sputum smear and culture performed at the completion of therapy. Patients with multidrug-resistant TB should have cultures performed monthly for the entire course of treatment.

Radiographic evaluations during treatment are of less importance than sputum evaluation. However, a chest film at completion of treatment provides a baseline for comparison with any future films.

More than 85% of patients taking isoniazid and rifampin become culture negative within 2 months of starting treatment. Patients whose cultures have not become negative or whose symptoms do not resolve after 2 months of therapy should be reevaluated for drug-resistant disease, as well as for failure to adhere to the regimen. If the patient is receiving self-administered therapy, the remainder of treatment should be directly observed.

While the results of drug susceptibility testing are pending, the original drug regimen may be continued or may be augmented by at least three drugs not given previously. Never add one drug at a time to a failing regimen. This may cause further drug resistance. If drug susceptibility results show resistance to any of the first-line drugs or if the patient remains symptomatic or smear or culture positive after 3 months, consult a TB medical expert.

In patients with negative sputum cultures before treatment, the major indicators of response to therapy are the chest radiograph and the clinical evaluation. The intervals at which chest radiography should be repeated depend on the clinical circumstances and the differential diagnosis that is being considered. If the radiograph does not improve after the patient has received 3 months of treatment, the abnormality may be the result of either previous (not current) TB or another process.

Routine follow-up after therapy is not necessary for patients who have had a satisfactory and prompt bacteriologic response to 6- or 9-month therapy with both isoniazid and rifampin. Patients whose organisms were fully susceptible to the drugs being used should be instructed to report promptly the development of any symptoms, particularly prolonged cough, fever, or weight loss. For patients with organisms resistant to isoniazid or rifampin or both, follow-up evaluation must be individualized.

Click here to return to Table of Contents

Chapter Eight: INFECTION CONTROL

Summary. The infectiousness of patients who have TB is directly related to the number of tubercle bacilli that they expel into the air. Infectiousness usually declines very rapidly after adequate therapy is started. The main goal of an infection control program is to detect TB disease early and to isolate and treat promptly persons who have TB. The infection control program should involve three types of controls--administrative controls, engineering controls, and personal respiratory protection. Administrative controls (e.g., the prompt detection of suspected cases, isolation of infectious patients, and appropriate treatment) are the primary strategy for infection control. Administrative controls include training and education and TB screening for health care workers. In addition, three types of engineering controls may be used to prevent the transmission of TB is health care facilities: ventilation, high-efficiency particulate air (HEPA) filtration, and ultraviolet germicidal irradiation (UVGI).

In places where administrative and engineering controls may not fully protect health care workers from infectious droplet nuclei, health care workers should use personal respirators. Precautions to prevent airborne transmission are particularly important during and immediately after procedures that stimulate coughing (e.g., sputum collection, bronchoscopy, and aerosolized pentamidine treatments). Such procedures should be carried out in rooms designated for these procedures and with appropriate ventilation. Coordination with the health department is necessary in order to report all confirmed or suspected TB patients, conduct contact investigations, and plan for follow-up care for patients known to have or suspected of having TB.

Click here to return to Table of Contents

Infectiousness

Infectiousness is directly related to the number of tubercle bacilli expelled into the air. In general, persons who have or who are suspected of having pulmonary or laryngeal TB should be considered infectious if (1) they are coughing, they are undergoing cough-inducing or aerosol-generating procedures, or their sputum smears contain acid-fast bacilli; and (2) they are not receiving therapy, have just started therapy, or have a poor clinical or bacteriologic response to therapy.

• they have received adequate therapy for 2 to 3 weeks
• they have a favorable clinical response to therapy
• they have three consecutive negative sputum smear results from sputum collected on different days

Persons with extrapulmonary TB are usually not infectious. However, in several instances, TB has been transmitted from a draining skin or tissue abscess containing M. tuberculosis.

Patients with TB disease should be closely monitored for relapse. Smear examinations should be done regularly (e.g., every 1 to 2 weeks) while the patient is hospitalized. Persistent infectiousness is usually due to drug resistance or the patient's failure to take medication as prescribed. These possibilities should be considered for any patient who does not clinically respond to therapy within 2 to 3 weeks.

In patients with drug-resistant TB, infectiousness may last several weeks or even months. In these patients, the response to treatment should be closely monitored, and TB isolation should be maintained until infectiousness is ruled out. Continued isolation throughout hospitalization should be considered for patients with multidrug-resistant TB because these patients are more likely to experience treatment failure or relapse, which may prolong infectiousness.

Click here to return to Table of Contents

Infection Control

• the use of administrative measures to reduce the risk of exposure to persons with infectious TB
• the use of engineering controls to prevent the spread and reduce the concentration of infectious droplet nuclei in the air
• the use of personal respiratory protective equipment in areas where there is an increased risk of exposure to M. tuberculosis, such as in TB isolation rooms

Administrative Controls

All health care facilities must have guidelines for the prompt detection of suspected TB cases. These guidelines should include assigning supervisory responsibility for TB control.

In general, clinicians should suspect TB in any patient who has a persistent cough, bloody sputum, night sweats, fever, weight loss, or loss of appetite. The index of suspicion should be very high in areas or among groups of patients in which the prevalence of TB is high. In ambulatory and inpatient settings, designated personnel should develop a protocol for the early detection of persons with infectious TB, basing it on the prevalence and characteristics of TB in the population served.

In an outpatient setting, patients who have signs or symptoms of TB should be moved to an area away from other patients (preferably into a TB isolation room) and promptly given a diagnostic evaluation. These patients should be given a surgical mask and instructed to keep it on; they should also be given tissues and asked to cover the nose and mouth when coughing or sneezing.

After a thorough and timely diagnostic evaluation (see Diagnosis of TB), patients for whom TB has been confirmed or is suspected should start appropriate therapy at once.

TB should be considered in HIV-infected patients with undiagnosed pulmonary disease. If TB is suspected, appropriate precautions to prevent airborne transmission should be taken unless infectious TB is ruled out.

In hospitals and other inpatient settings, patients known to have TB or suspected of having TB should be placed in a TB isolation room right away. All TB isolation rooms must have negative pressure relative to other parts of the facility (air flow from the corridors into the isolation room) and must be checked periodically to ensure proper air flow.

Patients should be educated about the transmission of TB, the reasons for TB isolation, and the importance of staying in their rooms. Every effort should be made to help the patient follow the isolation policy--including the use of incentives, such as providing telephones or televisions or allowing special dietary requests. As few persons as possible should enter the TB isolation room, and anyone entering the room should wear respiratory protection (see Personal Respirators).

Because TB is transmitted through the air rather than by fomites or direct contact, the sterilization of personal items or eating utensils and the cleaning of walls are unnecessary.

Health care workers, including home health nurses and emergency medical technicians, should be included in a TB screening and prevention program. This means tuberculin skin testing for all health care workers upon employment and at intervals determined by their risk of exposure thereafter. Any worker who develops symptoms of TB disease or whose tuberculin skin test result converts to positive should be evaluated promptly.

In addition, all health care workers should be educated about the basic concepts of TB transmission and pathogenesis, infection control practices, the signs and symptoms of TB, and the importance of participating in the employee skin testing program.

Health care facilities should work closely with the health department to report all confirmed or suspected cases of TB, to ensure that contact investigations are carried out for all cases, and to develop an appropriate discharge plan for TB patients or persons suspected of having TB.

Patients who are suspected of having infectious TB may be discharged to their home after starting TB therapy, even though they may still be infectious. It is important to note that after treatment has started, persons who have TB are less likely to transmit the disease to members of their household. However, before the patient is discharged to home, clinicians and discharge planners should consider whether any household members were previously exposed or are at very high risk for TB disease if infected (e.g., HIV infected or otherwise severely immunocompromised persons or children 5 years of age or younger).

Engineering Controls

Engineering Controls are based primarily on the use of adequate ventilation systems; these may be supplemented with high-efficiency particulate air (HEPA) filtration and ultraviolet germicidal irradiation (UVGI) in high-risk areas. These strategies are designed to reduce the concentration of infectious droplet nuclei in the air, to prevent the dissemination of droplet nuclei throughout the facility, or to render droplet nuclei noninfectious by killing the tubercle bacilli they contain.

In isolation rooms, ventilation systems are necessary to maintain negative pressure and to exhaust the air properly. Isolation rooms should be monitored daily when in use to ensure the negative pressure maintained. Isolation room doors should be kept closed, except when patients or personnel must enter or exit the room, in order to maintain negative pressure. Ventilation systems can also be designed to minimize the spread of TB in other areas of the health care facility.

HEPA filters can be used in ventilation systems to remove droplet nuclei from the air. These filters can be installed in ventilation ducts to filter air for recirculation into the same room or recirculation to other areas of a facility. The effectiveness of portable HEPA filtration units has not been adequately evaluated. All HEPA filters must be carefully installed and meticulously maintained to ensure adequate function.

UVGI, or ultraviolet lighting, may kill M. tuberculosis contained in droplet nuclei. Because exposure to ultraviolet light can be harmful to the skin and eyes, the lamps must be installed in the upper part of rooms or corridors or placed in exhaust vents. The effectiveness of UVGI in preventing the transmission of TB is not known.

Personal Respirators

In some settings--for example, TB isolation rooms and rooms where cough-inducing procedures are done--administrative and engineering controls may not fully protect health care workers from infectious droplet nuclei. Health care workers should use personal respirators to filter out droplet nuclei in these settings. They should also use personal respirators when visiting the home of an infectious TB patient. A respiratory protection program that teaches health care workers how and when to use personalrespirators should be included in all infection control programs.

Precautions to prevent the airborne transmission of tubercle bacilli are particularly important during and immediately after procedures that stimulate coughing (e.g., sputum collection, sputum induction, bronchoscopy, and aerosolized pentamidine treatments) by persons at risk for TB. Persons who carry out these procedures should wear personal respirators, and the procedures should be done in rooms or booths with negative air pressure in relation to adjacent rooms or hallways. The air from these rooms should be exhausted directly to the outside and away from intake sources.

For further details on the planning and implementation of an infection control program, please refer to the CDC's latest published infection control guidelines.

Click here to return to Table of Contents

Chapter Nine: COMMUNITY TB CONTROL

Summary. All new TB cases and suspected cases should be reported promptly to the health department by the clinician. Early reporting is essential for the prompt evaluation of persons who have been in contact with the TB patient (contacts). Contact investigations are done by the health department and should start with the close contacts who are most likely to be infected, as well as young children and HIV-infected persons. In addition to case finding, surveillance, and patient care, the health department is responsible for overall planning and policy for TB control efforts within its jurisdiction. This planning includes reviewing appropriate laws and regulations to support TB control activities, building networks and coalitions with community-based organizations, providing expert consultation to local institutions and practitioners, developing an overall TB control strategy, and ensuring adequate staffing and funding in order to carry out TB control objectives. In addition, voluntary organizations such as the American Lung Association and the American Thoracic Society can play a key role in mobilizing community resources for TB control.

Click here to return to Table of Contents

Role of the Health Department

The first priority of state and local health department TB programs is identifying and treating all persons who have TB disease. This means finding cases of TB and ensuring that patients complete appropriate therapy.

The second priority is finding and evaluating persons who have been in contact with TB patients to determine whether they have TB infection or disease, and treating them appropriately.

Screening high-risk groups for TB infection to identify candidates for preventive therapy is also an important function of state and local health departments (as well as hospitals, drug treatment facilities, nursing homes, correctional facilities, and other facilities caring for persons at high risk for TB). Such screening programs should always be targeted at specific groups known to be at high risk for TB (see Groups That Should Be Screened).

Surveillance

TB reporting is required by law in every state. All new TB cases and suspected cases should be reported promptly to the health department by the clinician. Cases may also be reported by infection control nurses or by pharmacies when TB drugs are dispensed. In addition, all positive TB smears and cultures should be reported promptly by laboratories.

Early reporting is important for the control of TB, and it gives clinicians access to the resources of the health department for assistance in case management and contact investigation. State and local health departments have different procedures for reporting TB and other infectious diseases. Health care providers should become familiar with the system used in their area.

All drug susceptibility results should be forwarded to the health department. These results are important for the evaluation and treatment of infected contacts. In addition, health departments use this information to determine drug resistance rates in their area.

Containment

Although TB care and treatment are often provided by other medical care providers, the health department has the ultimate responsibility for ensuring that TB patients do not transmit infection to others.

Health departments must ensure that medical services are available, accessible, and acceptable for TB patients, suspects, contacts, and others at high risk, without regard to the patient's ability to pay for such services.

As noted earlier, most health departments have public health nurses or community outreach workers who can work with patients and clinicians to help the patients adhere to and complete treatment. Often, health departments can assign a worker with the same cultural and linguistic background as the patient to assist in designing and implementing a treatment plan.

Contact Investigation

Prompt and thorough contact investigation is essential for the control of TB. Contact investigations should start with the persons who are most likely to be infected--those who most frequently come in contact with the person who has infectious TB. These close contacts are usually family members or other persons who live in the same household. Close contacts may also include friends, coworkers, or persons in a carpool with the patient. Close contacts constitute the inner circle of the TB contact investigation and should receive priority for examination.

High priority should be given to examining contacts who are children or who are HIV infected. Newly infected children are at high risk for miliary TB and possibly meningitis, which can develop within weeks unless the child is given preventive therapy. In HIV-infected persons, TB infection may progress rapidly to TB disease; in some instances, the interval between exposure and the development of disease has been as short as 20 days. Therefore, contacts who are children or who are HIV infected should be given preventive therapy regardless of skin test results.

Contacts should be given a Mantoux tuberculin skin test (5 TU). Contacts with a positive skin test result (5 mm or greater) or signs or symptoms of TB disease should be evaluated carefully to rule out disease before isoniazid preventive therapy is prescribed.

If the skin testing of close contacts reveals that the rate of positive skin test results (the infection level) in this group exceeds that