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Tuberculosis

Susan Walters Schmid, BA, MA, PhD candidate

Our courses fulfill continuing nursing education requirements in all 50 states. For more accreditation information, click here. Nurse practitioners may apply these contact hours to pharmacy continuing education and prescriptive authorization.

Unless otherwise cited, this course was based on material provided by the Centers for Disease Control and Prevention (CDC).

Tuberculosis (TB) is an airborne disease caused by Mycobacterium tuberculosis (M. tuberculosis). It is spread primarily by droplet nuclei—tiny airborne particles—expelled by an individual who has infectious TB disease (CDC, 2004). If another person inhales air containing these droplet nuclei, transmission may occur.

People who are infected but do not have TB disease are asymptomatic and not infectious; they usually have a positive reaction to the tuberculin skin test. About 10% of those infected will develop TB disease later in life, but the risk is considerably higher for those who are immunosuppressed, especially those who are HIV-positive. Although the majority of TB cases are pulmonary, TB can occur in almost any anatomical site, or as disseminated disease (CDC, 2001).

Though Robert Koch announced his discovery of M. tuberculosis in 1882, TB remains one of the leading causes of death worldwide from infectious disease. An estimated 2 billion individuals—one-third of the world's population—are infected with M. tuberculosis. Each year, approximately 9 million people become ill from TB, and about 2 million die. Yet, TB is preventable and, in most cases, curable (CDC, 2006a; CDC, 2004).

TB IN THE UNITED STATES

In the United States the vast majority of TB cases are caused by M. tuberculosis. There are four closely related mycobacterial species (M. bovis, M. africanum, M. microti, and M. canetti) that can also cause tuberculous disease, and together with M. tuberculosis they comprise what is known as the M. tuberculosis complex. Mycobacteria other than those comprising the M. tuberculosis complex are called nontuberculous mycobacteria (NTM). Nontuberculous mycobacteria may cause pulmonary disease resembling TB; however, NTM are not usually spread from person to person (CDC, 2004).

In 1989 the Centers for Disease Control and Prevention (CDC) announced the goal of eliminating 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 (CDC, 2001).

Implementation of this plan was delayed by the TB resurgence that occurred in the late 1980s and early 1990s. This resurgence was fueled by the onset of the HIV epidemic, increases in immigration of individuals from countries where TB was common, outbreaks in congregate settings, and the transmission of deadly multidrug-resistant (MDR) TB strains. These occurred at a time when decades of cuts in TB funding had resulted in the deterioration of TB control programs, and federal, state and local TB control officials had very few resources (CDC, 2004).

In 1992 a federal task force was convened to address the problem of increasing outbreaks of MDR TB. This task force developed the National Action Plan to Combat Multidrug-Resistant Tuberculosis. The original strategic plan was reassessed in 1999 to identify actions necessary to achieve elimination. Both plans stressed the need to increase clinical knowledge about TB disease and infection (CDC, 2001).

Since 1993 there has been a decrease in the number of new TB cases in the United States (CDC, 2004). In late 1998, CDC commissioned the Institute of Medicine (IOM) to determine if TB elimination was still feasible as a national goal and to provide recommendations on how to make that goal a reality. The IOM stated that TB elimination is possible. To break the "cycle of neglect" that has characterized U.S. tuberculosis control efforts, the report recommended an aggressive strategy to:

• Maintain control of TB
• Speed the decline in TB incidence
• Develop new tools for TB diagnosis, treatment, and prevention
• Increase U.S. efforts to help fight the global epidemic
• Mobilize and sustain public support for TB elimination and track its progress (CDC, 2004)

Although current activities to control TB are yielding significant results nationwide, TB elimination will require sustained effort, long-term commitment, new tools, and strong partnerships with other federal health agencies and state and local health departments (CDC, 2004). Even though the 2005 TB rate was the lowest recorded in the United States since national reporting began in 1953, the average annual decline has slowed during the past three years, MDR TB remains a threat, and disparate rates of TB persist among certain racial, ethnic, and foreign-born populations (CDC, 2006a).

TRANSMISSION AND PATHOGENESIS

Transmission

Mycobacterium tuberculosis is spread from person to person through the air. When a person with pulmonary or laryngeal TB coughs, sneezes, speaks, or sings, droplet nuclei containing tubercle bacilli (M. tuberculosis organisms) are expelled into the air. Depending on the environment, these tiny particles can remain suspended in the air for prolonged periods (CDC, 2004; CDC, 2001).

When a susceptible individual inhales droplet nuclei containing the tubercle bacilli, TB transmission may occur. The probability that TB will be transmitted depends on the

• Infectiousness of the individual with TB disease
• Environment in which exposure occurred
• Duration of exposure
• Virulence of the organism

Infectiousness is directly related to the number of tubercle bacilli a individual expels into the air. Individuals who expel many tubercle bacilli are more infectious than those who expel few or no bacilli (CDC, 2004; Curry, 2004).

The best way to stop transmission is to isolate patients with suspected or confirmed infectious TB disease immediately and start effective TB therapy. Infectiousness declines rapidly after adequate standardized therapy is started, as long as the patient adheres to the prescribed regimen (CDC, 2004).

Close contacts are at the highest risk of becoming infected with M. tuberculosis. They may be family members, roommates, friends, coworkers, or others. Close contacts are more likely to become infected with M. tuberculosis than contacts who spent less time with a individual while he or she was infectious (CDC, 2004).

Drug-resistant TB is transmitted in the same way as drug-susceptible TB, although it is no more infectious than drug-susceptible TB. However, delay in the recognition of drug resistance and resultant prolonged periods of infectiousness may facilitate increased transmission (CDC, 2004).

Except for laryngeal TB, extrapulmonary TB is rarely contagious; however, transmission from extrapulmonary sites has been reported to occur during aerosol-producing procedures such as autopsies and tissue irrigation (CDC, 2004).

Pathogenesis

Infection occurs when a susceptible individual inhales droplet nuclei containing tubercle bacilli and the droplet nuclei reach the alveoli (small air sacs) of the lungs. The tubercle bacilli that reach the alveoli are ingested by alveolar macrophages and the majority of these bacilli are destroyed or inhibited.

A small number of the bacilli multiply intracellularly and are released when the macrophages die. If they are alive, these bacilli may spread through the bloodstream to more distant tissues and organs, including areas in which TB is most likely to develop: the apex of the lung, the kidneys, the brain, and bone and through the lymphatic channels to regional lymph nodes.

This process of dissemination primes the immune system for a systemic response (CDC, 2004; CDC, 2001). Immune responses soon develop to thwart the bacilli. Within weeks after infection, the immune system is usually able to halt the multiplication of the tubercle bacilli, preventing further progression.

LATENT TB INFECTION AND TB DISEASE

An individual can thus have TB infection without progressing to TB disease. The initial stage is called latent TB infection (LTBI), and it may be detected by using the Mantoux tuberculin skin test or the QuantiFERON-TB test (see below). Individuals who are infected with M. tuberculosis, but who do not have TB disease, cannot spread the infection to other people. A individual with LTBI is not regarded as a "case" of TB for public health reporting (CDC, 2004).

In some people, the tubercle bacilli overcome the defenses of the immune system and begin to multiply, resulting in the progression from LTBI to TB disease. This process may occur soon after, or many years after, infection. In the United States, unless treated, approximately 5% of individuals who have been infected with M. tuberculosis will develop TB disease in the first year or two after infection and another 5% will develop TB disease at some time later in life. Thus, approximately 10% of individuals with normal immune systems who are infected with M. tuberculosis will develop TB disease at some point in their lives (CDC, 2004).

Tuberculosis disease most commonly affects the lungs (pulmonary TB). Patients with pulmonary TB usually have a cough and an abnormal chest x-ray, and may be infectious. Tuberculosis disease may also occur outside the lungs (extrapulmonary) in the following ways: as a pleural effusion; in the central nervous, lymphatic, or genitourinary systems; in the bones and joints; or as disseminated disease (miliary TB). Extrapulmonary TB is more common in immunosuppressed individuals and in young children; lymphatic TB and miliary disease are particularly common in immunosuppressed individuals. Extrapulmonary TB is often accompanied by pulmonary TB (CDC, 2004).

Conditions that increase the risk that latent TB infection will progress to TB disease include:

• Human immunodeficiency virus (HIV) infection
• Previous TB (in a individual who received inadequate or no treatment) indicated by chest x-ray
• Prolonged corticosteroid therapy and other immunosuppressive therapy
• Recent infection with M. tuberculosis (within the past two years)
• Substance abuse (especially intravenous drug use)
• Silicosis
• Diabetes mellitus
• End-stage renal disease
• Cancer of the head and neck
• Hematologic and reticuloendothelial diseases
• Intestinal bypass or gastrectomy
• Chronic malabsorption syndromes
• Low body weight (10% or more below ideal) (CDC, 2004)

The risk may be approximately three times greater (eg, diabetes) to more than 100 times greater (eg, HIV infection) for individuals who have these conditions than for those who do not. HIV infection is the strongest known risk factor for development of TB disease in individuals with LTBI. The risk of developing TB is 7% to 10% each year for those who are infected with both M. tuberculosis and HIV, whereas it is 10% over a lifetime for those infected only with M. tuberculosis (CDC, 2004).

DRUG RESISTANCE

There are two types of drug resistance: primary and secondary. Primary resistance develops in individuals who are initially infected with resistant organisms. Secondary resistance, or acquired resistance, develops during TB therapy, either because the patient was treated with an inadequate regimen or because the patient did not take the prescribed regimen appropriately (CDC, 2004).

Patients at increased risk for drug resistance include:

• Those whose cultures remain positive despite 2 months of therapy with TB drugs
• Those receiving inadequate treatment regimens for >2 weeks
• Those who have a history of treatment with TB drugs
• Contacts of individuals known to have drug-resistant TB
• Foreign-born people from areas where the prevalence of drug-resistant TB is high (CDC, 2004)

CLASSIFICATION BY PATHOGENESIS

The current clinical classification system for TB is based on the pathogenesis of the disease (Table 1). This classification system allows clinicians to track the development of TB in their patients. Healthcare providers must comply with state and local laws and regulations requiring the reporting of TB. A patient should not have a Class 5 classification for more than three months. All individuals with Class 3 or Class 5 TB are to be reported promptly to the local or state health department (CDC, 2004).

TABLE 1

CLASSIFICATION SYSTEM FOR TUBERCULOSIS

Class	Type	Description
0	No TB exposure Not infected	No history of exposure Negative reaction to tuberculin skin test or QFT-G*
1	TB exposure No evidence of infection	History of exposure Negative reaction to tuberculin skin test or QFT-G
2	TB infection No disease	Positive reaction to tuberculin skin test or QFT-G Negative bacteriologic studies (if done) No clinical, bacteriologic, or x-ray evidence of active TB
3	TB Clinically active	M. tuberculosis cultured (if done) Clinical, bacteriologic, or x-ray evidence of current disease
4	TB Not clinically active	History of episode(s) of TB or Abnormal but stable x-ray findings Positive reaction to the tuberculin skin test or        QFT-G Negative bacteriologic studies (if done) and No clinical or x-ray evidence of current disease
5	TB suspected	Diagnosis pending
*See Testing, next section. Source: CDC, 2004.

TESTING

Targeted testing for TB infection is done to identify individuals who are at high risk of developing TB disease and who would benefit from treatment. All testing activities should be accompanied by a plan for follow-up medical evaluation and treatment for individuals with TB infection or TB disease. Individuals with a positive test for TB infection should be evaluated for TB disease and, if disease is ruled out, considered for treatment for LTBI (CDC, 2004).

In the United States, the two preferred methods for detecting TB infection are the Mantoux tuberculin skin test (TST) and the QuantiFERON-TB gold test (QFT-G). The latter replaced the original QuantiFERON-TB test (QFT) in 2005 (CDC, 2005a; CDC, 2004).

Mantoux tuberculin skin test interpretation depends on (1) the measurement in millimeters (mm) of the induration, and (2) the individual's risk of being infected with TB and progression to disease if infected. Special considerations, such as live virus vaccination, boosted reaction, and two-step testing, should be acknowledged when conducting and interpreting TB tests (CDC, 2004).

Who Should Be Tested?

Healthcare providers should identify individuals who are in a high-risk category and test them for TB infection as part of a routine evaluation. Flexibility is needed in defining high-priority groups for testing. The changing epidemiology of TB indicates that groups currently considered high-risk for TB disease or infection may be less so over time, and groups currently not identified as high-risk may come to be so (CDC, 2004).

High-priority groups can be divided into two categories:

• Individuals at risk for TB exposure or infection
• Individuals at risk for TB disease, once infected (CDC, 2004)

People at higher risk for TB exposure or infection include the following:

• Close contacts of people known or suspected to have TB
• Foreign-born individuals, including children, who have immigrated within the last five years from areas that have a high TB incidence or prevalence
• Residents and employees of high-risk congregate settings
• Healthcare workers who serve high-risk clients
• Some medically underserved, low-income populations as defined locally
• High-risk racial or ethnic minority populations defined locally as having an increased prevalence of TB
• Infants, children, and adolescents exposed to adults in high-risk categories
• Individuals who inject illicit drugs or any other locally identified high-risk substance users (CDC, 2004)

Individuals at higher risk for TB disease once infected include the following:

• Those with human immunodeficiency virus (HIV) infection
• Those who were recently infected with M. tuberculosis (within the past two years), particularly infants and very young children
• Those who have medical conditions known to increase the risk for disease if infection occurs
• Those who inject illicit drugs or other groups of high-risk substance users
• Those who have a history of inadequately treated TB (CDC, 2004)

Healthcare agencies or other facilities should consult with the local health department before starting a testing program for TB infection. This will ensure that adequate provisions are made for the evaluation and treatment of individuals whose test results for TB infection are positive. Individuals with a positive test for TB infection should be evaluated for TB disease and, if disease is ruled out, considered for treatment of LTBI (CDC, 2004).

For individuals who have a positive test for TB infection, who have had TB disease ruled out, and who refuse treatment for LTBI, routine follow-up tests for LTBI and chest x-rays are unnecessary. These patients should be instructed to seek medical attention if they experience symptoms and signs suggestive of active TB disease (CDC, 2004).

The Tests

MANTOUX TUBERCULIN SKIN TEST (TST)

The Mantoux tuberculin skin test, or TST, is performed by placing an intradermal injection of 0.1 ml of purified protein derivative containing 5 tuberculin units (TU) into the volar surface of the forearm. The injection should be made with a disposable 27-gauge tuberculin syringe, just beneath the surface of the skin, with the needle bevel facing upward. This should produce a wheal 6 mm to 10 mm in diameter. Institutional guidelines regarding universal precautions for infection control (eg, use of gloves) should be followed (CDC, 2004).

Infection with M. tuberculosis produces a delayed-type hypersensitivity reaction to the tuberculin. This means an increased reactivity to specific antigens mediated by lymphocytes and not by antibodies. The reaction to the TST should be read 48 to 72 hours after the injection by a trained healthcare worker. Healthcare workers should not ask patients to read their own skin test results (CDC, 2004).

The skin test is read by palpating the site of injection to find an area of induration. The diameter of the indurated area should be measured across the forearm (perpendicular to the long axis). Erythema should not be measured. Indurations should be recorded in millimeters—even those classified as negative. If no induration is found, "0 mm" should be recorded. Reading the TST requires training and experience (CDC, 2004). It is never left to the patient or caregiver.

Interpreting TST Reactions

Skin test interpretation depends on (1) the measurement in millimeters (mm) of the induration, and (2) the individual's risk of being infected with TB or progression to disease if infected.

Interpreting Tuberculin Reactions >5 mm

A TST reaction greater than or equal to 5 mm of induration is interpreted as a positive result in the following groups:

• HIV-infected individuals
• Recent contacts of someone with TB
• Those with fibrotic changes on chest x-ray consistent with old healed TB
• Patients with organ transplants and other immunosuppressed patients (receiving the equivalent of >15 mg/day of prednisone for >1 month

Interpreting Tuberculin Reactions >10 mm

A TST reaction greater than or equal to 10 mm of induration is interpreted as a positive result in individuals who do not meet the preceding criteria but who have other risk factors for TB. These include the following:

• Recent arrivals to the United States (< 5 yr) from high-prevalence countries
• Injection drug users
• Residents and employees of high-risk congregate settings
• Mycobacteriology laboratory personnel
• Individuals with medical conditions that place them at high risk
• Children <4 years of age
• Children and adolescents exposed to adults in high-risk categories

Interpreting Tuberculin Reactions >15 mm

A TST reaction greater than or equal to 15 mm of induration is interpreted as a positive result in individuals with no known risk factors for TB who, except for certain screening programs required by local law or regulation, would not otherwise be tested. Targeted skin testing programs should only be conducted among high-risk groups.

Guidelines for interpreting tuberculin skin test reactions should also be applied to individuals who may have occupational exposure to TB (eg, staff of nursing homes, drug treatment centers, correctional facilities). Thus, the appropriate cutoff for defining a positive reaction depends on the employee's individual risk factors for TB, including recent TB exposure and the prevalence of TB in the facility. In facilities where the risk of exposure is very low, >15 mm may be an appropriate cutoff for employees with no other risk factors (CDC, 2004).

False Positives, False Negatives

The TST is a valuable tool, but it is not perfect. Several factors can lead to false-positive and false-negative skin test reactions. False-positive reaction may be caused by:

• Nontuberculous mycobacteria
• BCG vaccination
• Incorrect interpretation
• Administration of incorrect antigen

False-negative reaction may be caused by:

• Cutaneous anergy
• Recent TB infection
• Very young age (<6 months old)
• Recent live-virus vaccination (including smallpox)
• Overwhelming TB disease
• Some viral illnesses (eg, measles, chickenpox)
• Incorrect method of administration
• Too little antigen
• Subcutaneous injection
• Incorrect interpretation (CDC, 2004)

QuantiFERON-TB Gold test (QFT-G)

In May 2005 a new in vitro test, QuantiFERON-TB Gold (QFT-G), received final approval from the FDA as an aid in diagnosing M. tuberculosis infection (CDC, 2005a).

The new QuantiFERON test differs from the original QFT, which was first approved in 2001, in the antigens used, the methods of measurement, and the approaches to test interpretation. The earlier test had been approved as an aid for diagnosing LTBI, whereas the QFT-G is approved for diagnosing both LTBI and TB disease. The QFT is no longer commercially available (CDC, 2005a).

The QFT-G can be used in all circumstances in which the TST is currently used, including contact investigations, evaluation of recent immigrants who have had BCG vaccination, and TB screening of healthcare workers and others undergoing serial evaluation for M. tuberculosis infection. The QFT-G is generally used in place of—not in addition to—the TST (CDC, 2005a; CDC, 2006b).

A positive QFT-G result should prompt the same public health and medical interventions as a positive TST result. No reason exists to follow a positive QFT-G result with a TST. Individuals who have a positive QFT-G result, regardless of symptoms or signs, should be evaluated for TB disease before LTBI is diagnosed (CDC, 2005a; CDC, 2006b).

The majority of healthy adults who have negative QFT-G results are unlikely to have M. tuberculosis infection and do not require further evaluation. However, for people who have had recent contact with individuals having infectious TB, negative QFT-G results should be confirmed with a repeat test performed 8 to 10 weeks after the end of exposure, as is recommended for a negative TST result. Studies to determine the best time to retest contacts with negative QFT-G results have not been reported. Until more information is available, the timing of QFT-G testing should be the same as that used for the TST (CDC, 2005a).

Advantages to using the QFT-G include:

• It requires a single patient visit to draw a blood sample.
• Results can be available within 24 hours.
• It does not boost responses measured by subsequent tests, which can happen with tuberculin skin tests (TST).
• It is not subject to reader bias, which can occur with TST.
• It is not affected by prior BCG vaccination.

Disadvantages and limitations to using the QFT-G include:

• Blood samples must be processed within 12 hours after collection while white blood cells are still viable.
• There are limited data on the use of QFT-G in children younger than 17 years of age, among individuals recently exposed to M. tuberculosis, and in immunocompromised individuals (eg, impaired immune function caused by HIV/AIDS, current treatment with immunosuppressive drugs, selected hematologic disorders, specific malignancies, diabetes, silicosis, and chronic renal failure).
• Errors in collecting or transporting blood specimens or in running and interpreting the assay can decrease the accuracy of QFT-G.
• Limited data exist on the use of QFT-G to determine who is at risk for developing TB disease (CDC, 2005a).

Special Testing Situations

PREGNANT WOMEN

Even though tuberculin skin testing is both safe and reliable throughout the course of pregnancy, pregnant women should be targeted for tuberculin skin testing only if they have a specific risk factor for TB infection or for progression of infection to TB disease (CDC, 2004).

LIVE VIRUS VACCINATION

Vaccination with live viruses may interfere TST reactivity and cause false-negative reactions. For individuals scheduled to receive tuberculin skin testing, the testing should be done:

• On the same day as vaccination with live-virus measles vaccine or 4–6 weeks after measles vaccination
         OR
• At least one month after smallpox vaccination (CDC, 2004)

ANERGY

Anergy is the inability to react to a TST because of a weakened immune system. The absence of a reaction to the TST does not rule out the diagnosis of TB infection. Anergy may be caused by many factors, such as HIV infection, severe or febrile illness, measles or other viral infections, Hodgkin's disease, sarcoidosis, live-virus vaccination, the administration of corticosteroids or immunosuppressive drugs, and the underdeveloped immune system in young children. The use of anergy testing in conjunction with tuberculin skin testing is not routinely recommended (CDC, 2004).

BOOSTED REACTION

In some people who are infected with M. tuberculosis, hypersensitivity to tuberculin may wane over the years. When these people are tuberculin skin-tested many years after infection, they may have a negative reaction. However, the skin test itself may stimulate ("boost") their ability to react to tuberculin, causing a positive reaction in subsequent tests. This boosted reaction can be misinterpreted as a new infection. The booster phenomenon may occur at any age; its prevalence increases with age and it is highest among older adults. Boosted reactions may occur in individuals infected with nontuberculous mycobacteria or in individuals who have had a BCG vaccination (CDC, 2004).

TWO-STEP TESTING

When serial testing is anticipated, two-step testing is a strategy used to reduce the likelihood that a boosted reaction will be misinterpreted as a recent infection. Two-step testing should be used for the initial skin testing of adults and children who will be retested periodically (eg, healthcare workers) (CDC, 2004).

OCCUPATIONAL SETTINGS

Residents and employees of high-risk congregate facilities should be tested for TB upon employment or entry into the facility and thereafter at intervals determined by the risk of transmission in that facility. This testing is done for two reasons:

• Detection of TB infection or disease in staff or residents so that they may be given treatment
• Surveillance for TB transmission in the facility

High-risk congregate facilities are settings where there is a high risk of TB transmission; examples may include correctional facilities, nursing homes, homeless shelters, hospitals, residential facilities for individuals living with AIDS, and other healthcare facilities (CDC, 2004).

DIAGNOSIS

The signs and symptoms of pulmonary TB may include the following:

• Cough (duration of >3 weeks)
• Chest pain
• Hemoptysis (expectoration of blood or of blood-stained sputum)
• Systemic signs and symptoms
• Fever
• Chills
• Night sweats
• Appetite loss
• Weight loss
• Easy fatigability (CDC, 2004)

Symptoms of extrapulmonary TB depend on the site affected. Tuberculosis 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 individuals who have systemic symptoms and are at high risk for TB (CDC, 2004).

Medical Evaluation

Individuals suspected of having TB should be referred for a medical evaluation that includes:

• Medical history
• Physical examination
• Test for TB infection
• Chest x-ray
• Appropriate bacteriologic or histologic examinations (CDC, 2004)

MEDICAL HISTORY

It is important to ask individuals suspected of having TB about their history of TB exposure, infection, or disease. Clinicians may also contact the local health department for information about whether a patient has received TB treatment in the past. If the treatment 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, gender, ethnic or racial group, occupation) that may increase the patient's risk for exposure to TB or to drug-resistant TB disease. In addition, clinicians should determine whether the patient has medical conditions, especially HIV infection, that increase the risk for latent TB infection to progress to TB disease. Patients who do not know their current HIV status should be referred for HIV counseling and testing (CDC, 2004).

PHYSICAL EXAM

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 (CDC, 2004).

TESTING

The two tests for detecting TB infection (TST, QFT-G) were introduced earlier. The TST may help clinicians differentiate infected from uninfected people with symptoms and signs of TB. However, a negative reaction to the TST does not exclude the diagnosis of TB, especially for patients with severe TB illness or infection with HIV (CDC, 2004).

CHEST X-RAY

A posterior-anterior x-ray of the chest is the standard view used for the detection and description of chest abnormalities. In some instances, other views (eg, lateral, lordotic) or additional studies (eg, CT scans) may be necessary (CDC, 2004).

DIAGNOSTIC MICROBIOLOGY

Individuals suspected of having pulmonary or laryngeal TB should have at least three sputum specimens examined by acid-fast bacilli (AFB) smear and culture. Detection of AFB in stained smears examined microscopically may provide the first bacteriologic clue of the existence of TB.

However, smear examination permits only the presumptive diagnosis of TB because the AFB in a smear may be acid-fast organisms other than M. tuberculosis. Furthermore, many TB patients have negative AFB smears. Positive cultures for M. tuberculosis confirm the 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 for the purpose of diagnosis should be done on all specimens, regardless of AFB smear results (CDC, 2004).

Laboratories should report initial positive smears and positive M. tuberculosis cultures within 24 hours by telephone or fax to the primary healthcare provider. Out-of-state laboratories who receive referral specimens must contact the healthcare provider in the patient's state of origin. Follow-up results may be reported by mail. It is the responsibility of the primary healthcare provider to promptly report all suspected or confirmed cases of TB to the state or local health department so that a contact investigation can be initiated quickly to interrupt the potential ongoing transmission (CDC, 2004).

Follow-up bacteriologic examinations are important for assessing the patient's infectiousness and response to therapy. Specimens should be obtained at monthly intervals until the culture results convert to negative. Laboratories should report initial positive smears and positive M. tuberculosis cultures within 24 hours by telephone or fax to the primary healthcare provider. Genotyping can be used to identify specific strains of M. tuberculosis and facilitate tracking of TB transmission during outbreaks (CDC, 2004).

For all patients, the initial M. tuberculosis isolate should be tested for resistance to the first-line antituberculosis medications. It is crucial to identify drug resistance as early as possible in order to ensure appropriate treatment (CDC, 2004).

LATENT TUBERCULOSIS INFECTION (LTBI)

Treatment of latent tuberculosis infection is essential to controlling and eliminating TB in the United States. Treatment of LTBI substantially reduces the risk that TB infection will progress to disease. Certain groups are at very high risk for developing TB disease once infected.

Targeted testing programs should be designed to identify individuals who are at high risk for TB and who would benefit from treatment of LTBI. Careful assessment to rule out the possibility of TB disease is necessary before treatment for LTBI is started (CDC, 2004).

There are several regimens available for the treatment of LTBI, and providers should discuss options with their patients (CDC, 2004). In general, individuals with no known risk factors for TB should not be tested for LTBI. However, testing is occasionally performed among certain population groups for surveillance purposes or where cases of active TB may result in extensive transmission.

If testing is performed in these populations, they may be considered for treatment of LTBI if their reaction to the tuberculin test is >15 mm of induration. This group should be given a lower priority for prevention efforts than the groups listed previously (CDC, 2004).

Some close contacts who have a negative tuberculin skin test reaction (<5 mm of induration) should be evaluated for treatment of LTBI. Treatment for LTBI should be given after TB disease has been ruled out. These contacts include children less than 4 years of age, immunosuppressed people, and others who may develop TB disease quickly after infection (CDC, 2004).

Close contacts who have a negative reaction to an initial skin test should be retested 10 to 12 weeks after they were last exposed to TB. Treatment may be discontinued if the skin test result is again negative and if the individual is no longer exposed to TB (CDC, 2004). However, close contacts known to have or suspected of having HIV infection and other immunocompromised individuals should be given treatment for LTBI regardless of their skin test reaction (CDC, 2004).

Because of their age, infants and young children with a positive skin test are known to have been infected recently, and are at high risk of their infection progressing to disease. Infants and young children are also more likely than older children and adults to develop life-threatening forms of TB disease (CDC, 2004).

Children less than 4 years of age who are close contacts to someone with infectious TB should receive treatment for LTBI even if the tuberculin skin test result and chest x-ray do not suggest TB. A second tuberculin test should be placed 10 to 12 weeks after the last exposure to infectious TB. Treatment of LTBI can be discontinued at that time if all of the following conditions are met:

• The second tuberculin test is negative.
• The second test was performed at least 10 weeks after the child was last exposed to infectious TB.
• The child is at least 6 months of age. (CDC, 2004)

Treatment Regimens

Antituberculosis drugs currently in use in the United States are listed in Table 2, below. Healthcare providers should discuss treatment options with their patients. Providers acting in a case management or similar capacity who are not the primary determiners of a patient's regimen should still be fully versed in drug basics, components of the regimen, proper dosing instructions, adverse reactions, and all other relevant information. Treatment of LTBI can be complex and lengthy; a fully informed healthcare provider will greatly aid patient understanding, which in turn will facilitate compliance and recovery.

There are several treatment regimens available for the treatment of LTBI. For individuals who are at especially high risk for TB, are on an intermittent dosing regimen, or where nonadherence is suspected, directly observed therapy (DOT) of LTBI should be considered. This method of treatment is especially appropriate when a household member is on DOT for active disease, or in institutions and facilities where a staff member can observe infection treatment (CDC, 2004).

Table 2 presents the antituberculosis drugs currently in use in the United States.

TABLE 2

CURRENT U.S. ANTITUBERCULOSIS DRUGS

First-line drugs	Second-line drugs
Isoniazid	Cycloserine
Rifampin	Ethionomide
Rifapentine	Levofloxacin*
Rifabutin*	Moxifloxacin*
Ethambutol	Gatifloxacin*
Pyrazinamide	ρ -Aminosalicylic acid
	Streptomycin Amikacin/kanamycin* Capreomycin
*Not approved by the FDA for use in the treatment of tuberculosis. Source: CDC, 2004.

Suggested regimens include the following:

• A 9-month regimen of isoniazid (INH) is considered optimal treatment for both HIV-infected and HIV-negative adults.
• A 4-month regimen of daily rifampin (RIF) is an alternative option, and for individuals known to be contacts of patients with INH-resistant, RIF-susceptible TB.
• The 2-month regimen of a rifamycin and pyrazinamide (PZA) should generally not be used due to increased risk of severe liver injury and death.

For individuals likely to have been infected with a strain of M. tuberculosis resistant to both INH and RIF, alternative regimens considered should consist of drug(s) to which the infecting organism has demonstrated susceptibility.

Isoniazid (INH) is normally used alone for treatment of LTBI. Isoniazid can be given daily or two times a week (as DOT of LTBI). For individuals suspected of having LTBI, treatment should not begin until active TB disease has been excluded by history, physical examination, chest x-ray, and, when indicated, bacteriologic studies. When INH is given alone to individuals with active TB disease, resistance to INH is more likely to develop. For this reason, individuals suspected of having TB disease should receive the recommended multidrug regimen for treatment of disease until the diagnosis is confirmed or ruled out.

Treatment of LTBI for 6 months rather than 9 months may be more cost-effective and result in greater adherence by patients; therefore, local TB programs may prefer to implement the 6-month regimen. The 6-month regimen is not recommended for children, HIV-infected individuals, or those with stable fibrotic lesions on the chest x-ray consistent with prior TB (CDC, 2004).

Peripheral neuropathy is associated with the use of INH, but is uncommon at doses of 5 mg/kg. Individuals with conditions in which neuropathy is common (eg, diabetes, uremia, alcoholism, malnutrition, HIV infection), as well as pregnant women and individuals with a seizure disorder, may be given pyridoxine (vitamin B6) 10–25 mg/day with INH (CDC, 2004).

The following individuals or situations may require adjusted treatment regimens. Consult with appropriate healthcare providers and or LTBI/TB experts for guidance.

• Contacts of isoniazid-resistant TB
• Contacts of multidrug-resistant TB
• Immunocompromised contacts
• Individuals with fibrotic lesions
• Women who are pregnant or breastfeeding

For pregnant women who are at high risk of the progression of LTBI to active disease (eg, HIV-positive, recently infected), initiation of therapy should not be delayed on the basis of pregnancy alone, even during the first trimester. Careful clinical monitoring and laboratory monitoring for hepatitis is indicated (CDC, 2004).

Breastfeeding is not contraindicated when a mother is being treated for LTBI. Likewise, the amount of INH provided by breast milk is inadequate for the treatment of an infant. Infants whose breastfeeding mothers are taking INH should receive supplemental pyridoxine (CDC, 2004).

Patient Monitoring

HISTORY

Before treatment for LTBI is started, clinicians should conduct a careful medical history to:

• Rule out the possibility of TB disease
• Determine the history of treatment for LTBI or TB disease
• Determine if there are any pre-existing medical conditions that are contraindications to treatment or are associated with an increased risk of adverse effects of treatment
• Obtain information about current and previous drug therapy, including any previous adverse reactions to drugs considered for treatment of LTBI and to current drugs that have known interactions with drugs used for the treatment of LTBI
• Recommend voluntary HIV testing and counseling (CDC, 2004)

In addition, conducting a history provides an opportunity to establish rapport with the patient and to highlight important aspects of treatment, such as:

• Benefits of treatment
• Importance of adherence to the treatment regimen
• Possible adverse side effects of the regimen
• Establishment of an optimal follow-up plan (CDC, 2004)

BASELINE AND ROUTINE LABORATORY TESTING

Baseline laboratory testing is not routinely indicated for all patients at the start of LTBI treatment. Baseline hepatic measurements of serum aminotransferase and bilirubin are indicated for patients whose initial evaluation suggests a liver disorder. Baseline testing is also indicated for patients with HIV infection, women who are pregnant or in the immediate postpartum period, individuals with a history of liver disease, individuals who use alcohol regularly, and others who are at risk for chronic liver disease (CDC, 2004).

Baseline laboratory testing is not routinely indicated in older adults. However, testing may be considered on an individual basis, particularly for patients who are taking other medications for chronic medical conditions. Active hepatitis and end-stage liver disease are relative contraindications to the use of INH (CDC, 2004).

Routine laboratory monitoring during treatment of LTBI with INH or RIF is indicated only for those whose baseline tests suggest a liver disorder and for other individuals with a risk of hepatic disease, or for patients with symptoms compatible with hepatotoxicity, to allow for the evaluation of possible adverse reactions that might occur during treatment (CDC, 2004).

MONTHLY EVALUATIONS

During treatment of LTBI, patients should be clinically evaluated at least once a month for:

• Adherence to the prescribed regimen
• Signs and symptoms of active TB disease
• Signs and symptoms of hepatitis

Patients should be instructed to stop taking medication immediately and seek medical consultation if abdominal pain, emesis, jaundice, or other hepatitis symptoms develop (CDC, 2004).

TREATMENT OF TB DISEASE

Tuberculosis disease must be treated over a long period of time compared to 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 (CDC, 2004). Overall public health goals for the treatment of TB are to:

• Cure the individual, thus minimizing death and disability from TB
• Interrupt the transmission of M. tuberculosis to other individuals (CDC, 2004)

Tuberculosis treatment regimens must contain multiple drugs to which the organisms are susceptible. Treatment with 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 antituberculosis regimen can lead to drug resistance (CDC, 2004).

For each patient with newly diagnosed TB, a specific treatment and monitoring plan should be developed in collaboration with the local health department within one week of the presumptive diagnosis. This plan should include a description of the treatment regimen, the methods of assessing and ensuring adherence to the antituberculosis regimen, and the methods of monitoring for adverse reactions (CDC, 2004).

Nonadherence to TB treatment is a major problem in TB control. Inadequate treatment can lead to relapse, continued transmission, and the development of drug resistance (CDC, 2004).

Adherence Strategies

PATIENT EDUCATION

All patients should be educated about:

• TB
• Dosing of medications
• Possible adverse reactions to the medications
• Importance of taking their medication

Healthcare providers 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 directly observed therapy (see below). Written instructions should also be provided. All patients with TB should be advised to undergo voluntary counseling and testing for HIV infection (CDC, 2004).

CASE MANAGEMENT

A strategy that may be used to ensure that patients complete TB treatment is case management. There are three elements of case management:

• Assignment of responsibility
• Systematic regular review
• Plan to address barriers to adherence

In case management, a health department employee (case manager) is assigned primary responsibility for the management of specific patients and is held accountable for ensuring that each of those patients is educated about TB and its treatment, that therapy is continuous, and that contacts are examined. Some specific responsibilities may be assigned to other individuals (eg, clinic supervisors, outreach workers, health educators, social workers). 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 (CDC, 2004).

DIRECTLY OBSERVED THERAPY (DOT)

Directly observed therapy is a component of case management designed to ensure that patients adhere to therapy. Directly observed therapy means that a healthcare worker or another designated individual watches the patient swallow each dose of TB medication. Directly observed therapy can significantly reduce the development of drug resistance and treatment failure or relapse when treatment ends (CDC, 2004).

Directly observed therapy is the preferred core management strategy for all patients with TB. Establishing a relationship with the patient and addressing barriers to adherence is the core of a successful DOT program. It takes good case management to make DOT programs effective (CDC, 2004).

It is important that DOT be carried out at times and in locations that are as convenient as possible for the patient. Therapy may be directly observed in a medical office or clinic setting, but can also be observed by an outreach worker in the field. In some situations, staff of correctional facilities or of drug treatment programs, home healthcare workers, maternal and child health staff, or designated community members may provide DOT (CDC, 2004).

Incentives should be used to enhance adherence to therapy. This may be as simple as offering a cup of coffee and talking with a patient who is waiting in the clinic or as complex as providing food and housing for a homeless patient (CDC, 2004).

Directly observed therapy should be used for all children and adolescents with TB. Even when drugs are given under DOT, tolerance of the medications must be monitored closely. Parents should not be relied on to supervise DOT (CDC, 2004).

FIXED-DOSE COMBINATION DRUGS

The use of fixed-dose combination capsules or tablets may enhance patient adherence and reduce the risk of inappropriate monotherapy when treatment is self-administered. Clinicians should become familiar with the management of TB using FDA-approved fixed-dose combination drugs. In addition, incentives should be used to enhance adherence to self-administered therapy (CDC, 2004).

SELF-ADMINISTERED THERAPY

Patients should be asked routinely about adherence at follow-up visits. Pill counts should be routine and urine tests can be used periodically to check for the presence of drug metabolites. In addition, the response to treatment should be monitored closely for all patients. If the patient's sputum remains positive after two months of treatment, the patient should be reevaluated and DOT considered for the remainder of treatment (CDC, 2004).

TB Control Programs

Responsibility for successful TB treatment is assigned to the healthcare provider, not the patient. Healthcare providers who note that a particular TB patient has demonstrated the inability or unwillingness to adhere to a prescribed treatment regimen, should consult the health department TB control program. The TB control program then assists in evaluating the patient for causes of nonadherence and provides additional services, such as the provision of outreach workers, to enable the patient to complete the recommended therapy.

If these efforts are unsuccessful, the TB control program should take appropriate action, such as seeking court-ordered DOT or, if all other measures fail, 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 (CDC, 2004).

Treatment Regimens

Currently, there are ten drugs approved by the U.S. Food and Drug Administration (FDA) for treating TB. Of the approved drugs, isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA) are considered first-line antituberculosis agents and form the core of initial treatment regimens (CDC, 2004). (See Table 2 in previous section.)

PULMONARY TB

There are four regimens recommended for treating adults with culture-positive TB caused by organisms known or presumed to be susceptible to INH, RIF, PZA, and EMB. Each treatment regimen consists of an initial two-month treatment phase followed by a continuation phase. The continuation phase is generally four months, although the continuation phase should be extended to seven months (an additional three months) for certain patients.

All TB drugs should be given together rather than in divided doses. Although these regimens are broadly applicable, there are modifications that should be made under specified circumstances (CDC, 2004).

Treatment completion is defined primarily by the number of doses ingested within a specified time period. 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. All 6-month regimens must contain INH, RIF, and initially, PZA; all regimens of 9 months or less must contain INH and RIF (CDC, 2004).

Interruptions in the treatment of TB are common. Healthcare providers are responsible for deciding whether to restart a complete course of treatment or to continue as originally planned. These decisions should be based on when the interruption occurred and the duration of the interruption (CDC, 2004).

HIV-Positive Individuals

Management of HIV-related TB disease is complex, and the clinical and public health consequences associated with the failure of treatment are serious. Care for HIV-related TB should be provided by, or in consultation with, experts in the management of both TB and HIV disease (CDC, 2004). Choice of drugs, timing of treatment, and other factors may vary for HIV-positive individuals.

This is especially challenging in the care of pulmonary TB in children and adolescents with HIV-infection for whom the optimal treatment is unknown (CDC, 2004). Clinicians who are supervising care of HIV-positive individuals should consult with appropriate medical staff so that they can convey accurate details to the client and provide appropriate supervision of care.

A major concern in treating TB in the setting of HIV infection is the interaction of RIF with antiretroviral agents. Antiretroviral therapy should not be withheld because the patient is being treated for TB. However, it is not advisable to begin both antiretroviral therapy and combination chemotherapy for TB at the same time (CDC, 2004).

Pregnant Women and Breastfeeding Mothers

Untreated TB represents a greater hazard to a pregnant woman and her fetus than does treatment of the disease. Treatment of a pregnant woman with suspected TB should be started if the probability of TB is moderate to high (CDC, 2004).

In general, administration of antituberculosis drugs is not an indication for termination of pregnancy. However, in women who are being treated for drug-resistant TB, counseling concerning the risk to the fetus should be provided because of the known and unknown risks of the second-line antituberculosis drugs (CDC, 2004).

Breastfeeding should not be discouraged for women being treated with first-line antituberculosis drugs because the small concentrations of these drugs in breast milk do not produce toxic effects in the nursing infant. Conversely, drugs in breast milk should not be considered to serve as effective treatment for active TB or latent TB infection in a nursing infant.

Supplementary pyridoxine (Vitamin B6) is recommended both for the nursing mother and her infant. Due to the potential toxicity to the newborn, the administration of the fluoroquinolones during breastfeeding is not recommended (CDC, 2004).

Children and Adolescents

TB in infants and children younger than 4 years of age is more likely to disseminate; treatment should be started as soon as the diagnosis is suspected. Children commonly develop primary TB, but both children and adolescents may develop adult-type TB (CDC, 2004).

The lack of pediatric dosage forms of most antituberculosis medications may necessitate using crushed pills and suspensions, and drug regimens will need to be adjusted for children (CDC, 2004).

Individuals with Additional Medical Problems

A number of medical conditions may alter immune responsiveness and predispose a individual to TB. Two of the medical conditions that require additional treatment considerations are:

• Renal insufficiency and end-stage renal disease
• Hepatic disease (CDC, 2004)

EXTRAPULMONARY TB

As a general rule, principles that underlie the treatment of pulmonary TB also apply to extrapulmonary forms of the disease (CDC, 2004).

DRUG-RESISTANT TB

Drug resistance in a patient with newly diagnosed TB may be suspected if there was previous treatment, contact with a known drug-resistant case, or time spent in a region in which drug resistance is very common. Drug resistance can be proven only by drug-susceptibility testing (CDC, 2004).

Patients with strains of M. tuberculosis resistant to both INH and RIF (multidrug-resistant) are at high risk for treatment failure and further acquired resistance. These patients must be referred immediately to a specialist, or consultation obtained from specialized treatment centers (CDC, 2004).

PATIENT MONITORING

Clinicians who treat TB should be familiar with the methods of monitoring for adverse reactions and patients' response to treatment. In some situations (drug-resistant TB, pregnancy, HIV-positive patients), expert consultation may be required (CDC, 2004).

Baseline Monitoring

When TB treatment is initiated, the following examinations are conducted:

• Serologic testing for people at risk for hepatitis B or C (eg, injection drug use, birth in Asia or Africa, HIV infection)
• Measurements of aminotransferases, bilirubin, alkaline phosphatase, and serum creatinine, and a platelet count for all patients
• Testing of visual acuity (Snellen chart) and color vision (Ishihara) should be performed when EMB is to be used
• Obtain CD4+ lymphocyte count measurement for HIV-positive individuals (CDC, 2004)

Monitoring During Treatment

Patients should have clinical evaluations at least monthly to identify possible adverse reactions to medications and to assess adherence (CDC, 2004). As a routine, it is not necessary to monitor liver or renal function or platelet count for patients being treated with first-line antituberculosis drugs unless there were abnormalities at baseline or there are clinical reasons to obtain measurements. Patients who have stable abnormalities of hepatic or renal function at baseline should have repeat measurements early in the course of treatment, then less frequently to ensure that there has not been worsening (CDC, 2004).

Monthly repeat testing of visual acuity and color vision is recommended for patients receiving an EMB dose exceeding 15 to 20 mg/kg (the recommended range) and for patients receiving the drug for more than two months. Patients receiving EMB should be questioned regarding visual disturbances at monthly intervals. Patients should be educated regarding the possible visual side effects of EMB and should be instructed to immediately report vision changes to their healthcare provider (CDC, 2004).

For patients with extrapulmonary TB, the frequency and kinds of evaluations will depend on the sites involved and the ease with which specimens can be obtained (CDC, 2004).

Response to Treatment

For patients whose sputum culture is positive before treatment, the best way to measure the effectiveness of therapy is to obtain specimens for culture at least monthly until two consecutive specimens are negative on culture. Patients whose sputum no longer contains M. tuberculosis after two months of treatment should have at least one additional sputum smear and culture performed at the completion of therapy (CDC, 2004).

Patients with multidrug-resistant TB should have cultures performed monthly for the entire course of treatment (CDC, 2004).

For patients with negative sputum cultures before treatment, the major indicators of response to therapy are the chest x-ray and the clinical evaluation. A presumptive diagnosis can be made if x-ray improvement is noted, generally by the time two months of treatment has been completed. If the x-ray does not improve after the patient has received three months of treatment, the abnormality may be the result of either previous (not current) TB or another process (CDC, 2004).

Important treatment decisions concerning the continuation phase regimen are based on the microbiologic status at the end of the initial phase of treatment (ie, at two months). Patients whose cultures have not become negative or whose symptoms do not resolve despite three months of therapy should be reevaluated for potential drug-resistant disease, as well as for potential failure to adhere to the regimen (CDC, 2004).

Patients who have positive cultures after four months of treatment should be considered as having failed treatment and managed accordingly (CDC, 2004).

For patients with positive cultures at diagnosis, a repeat chest x-ray at completion of two months of treatment may be useful but is not essential (CDC, 2004).

For patients with negative initial cultures, a chest x-ray is necessary after two months of treatment and a x-ray at completion of treatment is desirable. Generally, follow-up after completion of therapy is not necessary (CDC, 2004).

For patients with multidrug-resistant TB, a chest film at completion of treatment provides a baseline for comparison with any future films (CDC, 2004).

Adverse Reactions

In addition to the microbiologic evaluations, it is essential that patients have clinical evaluations to identify possible adverse effects of the antituberculosis medications. Monitoring for adverse reactions must be individualized. The type and frequency of monitoring should depend on the drugs used and the patient's risk for adverse reactions (eg, age, alcohol use). At minimum, patients should be seen monthly during therapy and questioned by healthcare providers concerning adverse reactions even if no problems are apparent (CDC, 2004).

Adverse reactions to TB drugs are relatively rare, but in some patients they may be severe. Mild adverse effects can generally be managed with symptomatic therapy. The drug or drugs must be discontinued if there are more severe effects. It is important that first-line drugs not be stopped without adequate justification. Proper management of serious adverse reactions often requires expert consultation (CDC, 2004).

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. All patients receiving INH, RIF, or PZA should be instructed to stop taking the medications and to immediately report any symptoms suggestive of hepatitis. If the symptoms suggest adverse reactions, appropriate laboratory testing should be performed (CDC, 2004).

Common adverse reactions to TB treatment include:

• Gastrointestinal upset (nausea, vomiting, poor appetite, abdominal pain)
• Rash
• Drug fever
• Hepatitis

Current literature and package inserts should be consulted for other possible drug reactions (CDC, 2004).

Follow-Up After Treatment

Routine follow-up after treatment is not necessary for patients who have had a satisfactory response to 6- or 9-month regimen with both INH and RIF. 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 INH or RIF or both, follow-up evaluation must be individualized (CDC, 2004).

INFECTION CONTROL IN HEALTHCARE SETTINGS

Effective TB infection control in healthcare settings depends on early detection, airborne infection isolation, and treatment of individuals with infectious TB. All healthcare settings should have a TB infection control program designed to detect TB disease early and to isolate and promptly refer or treat individuals who have TB. The TB infection control program should be based on a three-level hierarchy of controls: administrative controls, environmental controls, and individual respiratory protection (CDC, 2004).

Infectiousness

In general, patients who have suspected or confirmed TB disease should be considered infectious if they:

• Have disease in the lungs, airway, or larynx, or
• Are coughing, or
• Are undergoing cough inducing procedures, or
• Have positive AFB sputum smears,
         and
• Are not on anti-tuberculosis chemotherapy, or
• Have just started chemotherapy, or
• Have a poor clinical or bacteriologic response to chemotherapy (CDC, 2004)

Individuals with extrapulmonary TB are usually not infectious unless they have concomitant pulmonary disease, nonpulmonary disease located in the oral cavity or the larynx, or extrapulmonary disease that includes an open abscess or lesion in which the concentration of organisms is high, especially if drainage from the abscess or lesion is extensive or there is aerosolization of drainage fluid (CDC, 2004).

All patients with confirmed drug-susceptible TB disease should remain in airborne infection isolation while hospitalized until they:

• Have had three negative sputum smears collected on different days (one should be an early-morning specimen)
• Demonstrate clinical improvement
• Are on adequate anti-TB chemotherapy (CDC, 2004)

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 by culture (CDC, 2004).

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 (CDC, 2004).

Developing a TB Infection Control Program

An effective TB infection control program comprises the following three-level hierarchy of controls:

• Administrative controls, to reduce the risk of exposure to individuals with potentially infectious TB
• Environmental controls, to prevent the spread and reduce the concentration of infectious droplet nuclei
• Individual respiratory protection use in situations that pose a relatively high risk for exposure to TB (CDC, 2004)

Effective TB infection control in healthcare settings depends on early detection, airborne infection isolation, and treatment of individuals with infectious TB. All healthcare settings should have a TB infection control program designed to detect TB disease early and to isolate and promptly refer or treat individuals who have TB (CDC, 2004). The specifics of the TB infection-control program will differ depending on whether a setting will provide healthcare or will triage and transfer patients with suspected or confirmed TB disease (CDC, 2004).

ADMINISTRATIVE CONTROLS

The use of administrative controls is the primary strategy and the first level of the hierarchy for infection control. Administrative controls are measures intended primarily to reduce the risk of exposing uninfected individuals to those who have infectious TB. These controls include:

• Assigning responsibility for TB infection control in the setting
• Conducting a TB risk assessment
• Developing and implementing a written TB infection control plan
• Implementing effective work practices for the management of patients who may have TB
• Ensuring proper cleaning and sterilization/disinfection of potentially contaminated equipment
• Educating, training, and counseling healthcare workers about TB
• Testing and evaluating healthcare workers who are at risk for TB or may be exposed to TB
• Coordinating efforts with the local health department (CDC, 2004)

ENVIRONMENTAL CONTROLS

The second level of the hierarchy is the use of environmental controls to prevent the spread and reduce the concentration of infectious droplet nuclei. Environmental controls include technologies for the removal or inactivation of M. tuberculosis. These technologies include:

• Controlling the source of infection by use of local exhaust ventilation
• Diluting and removing contaminated air by use of general ventilation
• Cleaning the air by use of high efficiency particulate air (HEPA) filtration
• Cleaning the air by use of ultraviolet germicidal irradiation (UVGI) (CDC, 2004)

PERSONAL RESPIRATORY PROTECTION

The third level of the hierarchy is the use of personal respiratory protection in situations that pose a relatively high risk for exposure. The first two levels of the infection-control hierarchy, administrative and environmental controls, minimize the number of areas where exposure to infectious TB disease may occur. They also reduce, but do not eliminate, the risk in the few areas where exposures can still occur (CDC, 2004).

Personal respiratory protection should be used by individuals:

• Entering areas in which patients with suspected or confirmed infectious TB are being isolated
• Present during cough-inducing or aerosol-generating procedures performed on patients with suspected or confirmed infectious TB
• In other settings where administrative and environmental controls are not likely to protect them from inhaling infectious airborne droplet nuclei (CDC, 2004).

Laboratorians conducting aerosol-producing procedures may require respiratory protection; decisions concerning use of personal respiratory protection in this setting should be made on a case-by-case basis. Aerosol-producing procedures should be performed in biological safety cabinets (BSC); however, if for some reason it is being done outside of a BSC, laboratorians should wear a respirator (CDC, 2004).

The Occupational Safety and Health Administration (OSHA) requires healthcare settings that use respiratory protection to prevent the inhalation of infectious droplet nuclei to develop, implement, and maintain a personal respiratory protection program. All healthcare workers who use respiratory protection must be included in the program. The two most critical elements of a personal respiratory protection program are:

• Training of healthcare workers
• Selection of appropriate, well-fitting respirators (CDC, 2004).

Healthcare workers should participate in annual training to include the following:

• Nature, extent, and hazards of TB disease in the healthcare setting
• Risk assessment and its relationship to the respirator program
• Signs and symbols used to show that respirators are required in an area
• Reasons for using respirators
• Environmental controls
• Reasons for selecting a particular respirator for a given hazard
• Operation, capabilities, and limitations of respirators
• Cautions about facial hair
• OSHA regulations
• Provide opportunities for trainees to handle and wear a respirator until proficient
• Provide trainees with copies or summaries of lecture materials for use as a reference
• Provide instructions to refer all respirator problems immediately to the respirator program administrator (CDC, 2004).

Respiratory protective devices used in healthcare settings for protection against M. tuberculosis should meet the following criteria:

• At least N-95 particulate filter respirators certified by the National Institute for Occupational Safety and Health (NIOSH)—adequate in most situations
• Ability adequately to fit respirator wearers who are included in a formal respiratory protection program
• Ability to fit differing facial sizes and characteristics of healthcare workers (can usually be met by making respirators available in a variety of sizes)
• Select respirator models shown by their manufacturers to have inherently well-fitting characteristics (CDC, 2004)

BCG VACCINATION

The Bacille Calmette-Guérin (BCG) vaccine is a live vaccine derived from a strain of M. bovis that was attenuated by Calmette and Guérin at the Pasteur Institute in Lille, France. An early version of BCG was first administered to humans in 1921. Since that time, many different strains have been derived and are used today throughout the world. The BCG vaccination is not generally recommended in the United States because of the low risk of infection with M. tuberculosis, the variable effectiveness of the BCG vaccine against pulmonary TB, and the vaccine's interference with the ability to determine tuberculin reactivity (CDC, 2004).

BCG Cautions

Use of the BCG vaccination as a TB prevention strategy in the United States is limited because its effectiveness in preventing infectious forms of TB is uncertain. The BCG vaccine should be considered only for selected individuals who meet specific criteria. The use of the BCG vaccine should be undertaken only after consultation with local health authorities and experts in the management of TB (CDC, 2004).

The BCG vaccination may cause a positive reaction to the tuberculin skin test. Thus, it may complicate decisions about prescribing treatment for LTBI for BCG-vaccinated individuals who have a positive skin-test result (CDC, 2004).

BCG FOR AN INFANT OR CHILD

In the United States, BCG vaccination should only be considered for an infant or child who has a negative tuberculin skin-test result in the following circumstances:

• The child is exposed continually to an untreated or ineffectively treated patient who has infectious pulmonary TB, and the child cannot be separated from the infectious patient or given long-term primary treatment for infection, or
• The child is exposed continually to a patient who has infectious pulmonary TB caused by M. tuberculosis strains resistant to isoniazid and rifampin, and the child cannot be separated from the infectious patient (CDC, 2004).

BCG FOR HEALTHCARE WORKERS

The BCG vaccination of healthcare workers should be considered on an individual basis in settings in which:

• A high percentage of TB patients are infected with M. tuberculosis strains resistant to both isoniazid and rifampin
• Transmission of such drug-resistant M. tuberculosis strains to healthcare workers and subsequent infection are likely
• Comprehensive TB infection-control precautions have been implemented and have not been successful (CDC, 2004)

The BCG vaccination should not be required for employment or for assignment of healthcare workers in specific work areas. Healthcare workers considered for BCG vaccination should be counseled regarding the risks and benefits associated with both BCG vaccination and treatment for LTBI (CDC, 2004).

Contraindications to BCG Vaccination

The BCG vaccine is contraindicated in individuals who have an impaired immune response from the following:

• HIV infection
• Congenital immunodeficiency
• Leukemia
• Lymphoma
• Generalized malignancy
• High-dose steroid therapy
• Alkylating agents
• Antimetabolites
• Radiation therapy

It is prudent to avoid giving BCG vaccination to pregnant women, although no harmful effects of BCG on the fetus have been observed (CDC, 2004).

Tuberculin Reactions in BCG-Vaccinated Individuals

Many highly endemic countries still appropriately vaccinate infants with BCG as part of their TB control programs. In individuals vaccinated with BCG, sensitivity to tuberculin is highly variable, depending upon the strain of BCG used and the group vaccinated (CDC, 2004).

The TST or QFT-G are not contraindicated for individuals who have been vaccinated with BCG. The presence or size of a postvaccination TST reaction does not predict whether BCG will provide any protection against TB disease. The size of a TST reaction in a BCG-vaccinated individual is not a factor in determining whether the reaction is caused by M. tuberculosis infection or by the prior BCG vaccination (CDC, 2005a; CDC, 2004).

The TST results are used to support or exclude the diagnosis of LTBI. The TST in individuals vaccinated with BCG should be interpreted using the same criteria as for those not BCG-vaccinated. The booster phenomenon may occur among individuals who have had a prior BCG vaccination (CDC, 2004).

COMMUNITY TUBERCULOSIS CONTROL

State and local health departments have the primary responsibility for preventing and controlling TB. However, those who provide TB services in settings such as private clinics, managed care organizations, HIV clinics, correctional facilities, and hospitals also have responsibility for preventing and controlling TB in their communities (CDC, 2004).

Priority Strategies

Prevention and control efforts are conducted through the coordination of healthcare providers in a variety of settings to ensure the provision of direct services for TB patients. Prevention and control should include three vital strategies:

1. Identifying and treating all individuals who have TB disease. This means finding cases of TB and ensuring that patients complete appropriate therapy.
2. Finding and evaluating individuals who have been in contact with TB patients to determine whether they have TB infection or disease, and treating them accordingly.
3. Testing high-risk groups for TB infection to identify candidates for treatment of latent infection and to ensure the completion of treatment (CDC, 2004).

The Local Health Department

The local health department should achieve the three critical strategies by working in cooperation with healthcare providers offering direct services for TB patients. It is crucial to coordinate care with other healthcare providers and facilities in the following areas:

• Overall planning and policy development
• Identification of individuals who have clinically active TB
• Management of individuals who have disease or who are suspected of having disease
• Finding and evaluating those who have been in contact with individuals infected with M. tuberculosis
• Identification and management of individuals infected with M. tuberculosis
• Laboratory and diagnostic services
• Data collection and analysis
• Training and education (CDC, 2004)

EPILOGUE

There is much being done around the globe to combat TB—to raise awareness, advocate for patients' rights, seek out new drugs and treatments, and provide practical aid to patients and healthcare providers.

For the first time in fifty years, six new TB drugs will soon be tested in humans. These drugs might reduce the duration of therapy by 30% to 70%, making treatment completion more likely, and might increase the probability of cure. If proven to be safe and efficacious, they will provide additional options in the treatment of multidrug-resistant TB (CDC, 2006a). (See Resources for more information.)

On the eve of World TB Day [March 24, 2006], a consortium of international health agencies led by the American Thoracic Society and the World Health Organization published the first International Standards for Tuberculosis Care (ISTC).

"The purpose of the ISTC," said Dr. Philip Hopewell, who co-chaired the committee that produced the standards and is a past president of the ATS, "is to establish a widely accepted level of care that all practitioners, public and private, should achieve in managing patients who have, or are suspected of having, tuberculosis."

The new standards were announced in Geneva and published simultaneously on both the ATS and the WHO Web sites on March 22. WHO officials also announced The Patients' Charter for Tuberculosis Care. The charter specifies patients' rights and responsibilities. (ATS, 2006)

Yet, despite all the advances and successes, TB remains an enormous threat around the globe. In the same issue of the MMWR in which the CDC announced the new drugs about to be tested it offered some chilling news.

During the 1990s, multidrug-resistant tuberculosis, defined as resistance to at least isoniazid and rifampin, emerged as a threat to TB control, both in the United States and worldwide. Multidrug-resistant tuberculosis treatment requires the use of second-line drugs that are less effective, more toxic, and costlier than first-line isoniazid- and rifampin-based regimens.

In 2000 the Stop TB Partnership's Green Light Committee was created to increase access to second-line drugs worldwide while ensuring their proper use to prevent increased drug resistance. While assisting multidrug-resistant tuberculosis treatment programs worldwide, the committee encountered reports of multiple cases of TB with resistance to virtually all second-line drugs. To assess the frequency and distribution of extensively drug- resistant TB cases, CDC and the World Health Organization surveyed an international network of TB laboratories.

Their findings?

Extensively drug-resistant TB has emerged worldwide as a threat to public health and TB control, raising concerns of a future epidemic of virtually untreatable TB. New anti-TB drug regimens, better diagnostic tests, and international standards for second-line-drug–susceptibility testing are needed for effective detection and treatment of drug-resistant TB. (CDC, 2006a)

Posted June 7, 2006

Expires July 1, 2008

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