Jeff Hall, MD

CASE 1 › Judy C is a newly employed 40-year-old health care worker who was born in China and received the bacille Calmette-Guérin (BCG) vaccination as a child. Her new employer requires her to undergo testing for tuberculosis (TB). Her initial tuberculin skin test (TST) is 0 mm, but on a second TST 2 weeks later, it is 8 mm. She is otherwise healthy, negative for human immunodeficiency virus (HIV), and has no constitutional symptoms. Does she have latent tuberculosis infection (LTBI)?

CASE 2 › A mom brings in her 3-year-old son, Patrick. She reports that a staff member at his day care center traveled outside the country for 3 months and was diagnosed with LTBI upon her return. She wants to know if her son should be tested.

More than 2 billion people—nearly one-third of the world’s population—are infected with Mycobacterium tuberculosis.¹ Most harbor the bacilli as LTBI, which means that while they have living TB bacilli within their bodies, these mycobacteria are kept dormant by an intact immune system. These individuals are not contagious, nor are they likely to become ill from active TB unless something adversely affects their immune system and increases the likelihood that LTBI will progress to active TB.

Two tests are available for diagnosing LTBI: the TST and the newer interferon gamma release assay (IGRA). Each test has advantages and disadvantages, and the best test to use depends on various patient-specific factors. This article describes whom you should test for LTBI, which test to use, and how to diagnose active TB.

Why test for LTBI?

LTBI is an asymptomatic infection; patients with LTBI have a 5% to 10% lifetime risk of developing active TB.² The risk of developing active TB is approximately 5% within the first 18 months of infection, and the remaining risk is spread out over the rest of the patient’s life.² Screening for LTBI is desirable because early diagnosis and treatment can reduce the activation risk to 1% to 2%,³ and treatment for LTBI is simpler, less costly, and less toxic than treatment for active TB.

Whom to test. Screening for LTBI should target patients for whom the benefits of treatment outweigh the cost and risks of treatment.⁴ A decision to screen for LTBI implies that the patient will be treated if he or she tests positive.³

The benefit of treatment increases in people who have a significant risk of progression to active TB—primarily those with recently acquired LTBI, or with co-existing conditions that increase their likelihood of progression (TABLE 1).⁵

Screening for latent TB infection is desirable because early diagnosis and treatment can reduce the activation risk to 1% to 2%.

All household contacts of patients with active TB and recent immigrants from countries with a high TB prevalence should be tested for LTBI.⁶ Those with a negative test and recent exposure should be retested in 8 to 12 weeks to allow for the delay in conversion to a positive test after recent infection.⁷ Health care workers and others who are potentially exposed to active TB on an ongoing basis should be tested at the time of employment, with repeat testing done periodically based on their risk of infection.^8,9

Individuals with coexisting conditions should be tested for LTBI as long as the benefit of treatment outweighs the risk of drug-induced hepatitis. Because the risk of drug-induced hepatitis increases with age, the decision to test/treat is affected by age as well as the individual’s risk of progression. Patients with the highest risk conditions would benefit from testing/treating regardless of age, while treatment may not be justified in those with lower-risk conditions. A reasonable strategy is as follows:¹⁰
• high-risk conditions: test regardless of age
• moderate-risk conditions: test those <65 years
• low-risk conditions: test those <50 years.

Children with LTBI are at particularly high risk of progression to active TB.⁵ The American Academy of Pediatrics (AAP) recommends assessing a child’s risk for TB at first contact with the child and once every 6 months for the first year of life. After one year, annual assessment is recommended, but specific TB testing is not required for children who don’t have risk factors.¹¹ The AAP suggests using a TB risk assessment questionnaire that consists of 4 screening questions with follow-up questions if any of the screening questions are positive (TABLE 2).¹¹

Use of TST is well established

To perform a TST, inject 5 tuberculin units (0.1 mL) of purified protein derivative (PPD) intradermally into the inner surface of the forearm using a 27- to 30-gauge needle. (In the United States, PPD is available as Aplisol or Tubersol.) Avoid the former practice of “control” or anergy testing with mumps or Candida antigens because this is rarely helpful in making TB treatment decisions, even in HIV-positive patients.¹²

To facilitate intradermal injection, gently stretch the skin taut during injection. Raising a wheal confirms correct placement. The test should be read 48 to 72 hours after it is administered by measuring the greatest diameter of induration at the administration site. (Erythema is irrelevant to how the test is interpreted.) Induration is best read by using a ballpoint pen held at a 45-degree angle pointing toward the injection site. Roll the point of the pen over the skin with gentle pressure toward the injection site until induration causes the pen to stop rolling freely (FIGURE). The induration should be measured with a rule that has millimeter measurements and interpreted as positive or negative based on the individual’s risk factors (TABLE 3).³

Watch for these 2 factors that can affect TST results

Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis, is (or has been) used as a routine childhood immunization in many parts of the world, although not in the United States.¹³ It is ordinarily given as a single dose shortly after birth, and has some utility in preventing serious childhood TB infection. The antigens in PPD and those in BCG are not identical, but they do overlap.

BCG administered after an individual’s first birthday resulted in false positive TSTs >10 mm in 21% of those tested more than 10 years after BCG was administered.¹⁴ However, a single BCG vaccine in infancy causes little if any change in the TST result in individuals who are older than age 10 years. When a TST is performed for appropriate reasons, a positive TST in people previously vaccinated with BCG is generally more likely to be the result of LTBI than of BCG.¹⁵ Current guidelines from the Centers for Disease Control and Prevention (CDC) recommend that previous BCG status not change the cutoffs used for interpreting TST results.¹⁶

Booster phenomenon. In many adults who have undiagnosed LTBI that they acquired in the distant past, or who received BCG vaccination as a child, immunity wanes after several decades. This can result in an initial TST being negative, but because the antigens in the PPD itself stimulate antigenic memory, the next time a TST is performed, it may be positive.

In people who will have annual TST screenings, such as health care workers or nursing home residents, a 2-step PPD can help discriminate this “booster” phenomenon from a new LTBI acquired during the first year of annual TST testing. A second TST is placed 1 to 2 weeks after the initial test, a time interval during which acquisition of LTBI would be unlikely. The result of the second test should be considered the person’s baseline for evaluation of subsequent TSTs. A subsequent TST would be considered positive if the induration is >10 mm and has increased by ≥6 mm since the previous baseline.¹⁷

IGRA offers certain benefits

IGRA uses antigens that are more specific for Mycobacterium tuberculosis than the TST, and as a result, this test is not influenced by previous BCG vaccination. It requires only one blood draw, and interpretation does not depend on the patient’s risk category or interpretation of skin induration. The primary disadvantage of IGRAs is high cost (currently $200 to $300 per test), and the need for a laboratory with adequate equipment and personnel trained in performing the test. IGRAs must be collected in special blood tubes, and the samples must be processed within 8 to 16 hours of collection, depending on the test used.⁵

Currently, 2 IGRAs are approved for use in the United States—the QuantiFERON-TB Gold In-Tube (QFT-GIT) and the T-SPOT.TB assay. Both tests may produce false positives in patients infected with Mycobacterium marinum or Mycobacterium kansasii, but otherwise are highly specific for Mycobacterium tuberculosis. IGRA results may be “boosted” by recent TST (ie, a TST given within the previous 3 months may cause a false positive IGRA result), and this effect may begin as early as 3 days after a TST is administered.¹⁸ Therefore, if an IGRA is needed to clarify a TST result, it should be drawn on the day the TST is read.¹⁹

CDC guidelines (2010) recommend that IGRAs may be used in place of—but not routinely in addition to—TSTs in all cases in which TST is otherwise indicated.²⁰ There are a few situations where one test may be preferred over the other.²¹

IGRA may be preferred over TST in individuals in one of 2 categories:
• those who have received BCG immunization. If a patient is unsure of their BCG status, the World Atlas of BCG Policies and Practices, available at www.bcgatlas.org,²² can aid clinicians in determining which patients likely received BCG as part of their routine childhood immunizations.
• those in groups that historically have poor rates of return for TST reading, such as individuals who are homeless or suffer from alcoholism or a substance use disorder.

Individuals in whom TST is preferred over IGRA include:
• children age <5 years, because data guiding use of IGRAs in this age group are limited.²³ Both TST and IGRA may be falsely negative in children under the age of 3 months.²⁴
• patients who require serial testing, because individuals with positive IGRAs have been shown to commonly test negative on subsequent tests, and there are limited data on interpretation and prognosis of positive IGRAs in people who require serial testing.²⁵

Individuals in whom performing both tests simultaneously could be helpful include:
• those with an initial negative test, but with a high risk for progression to active TB or a poor outcome if the first result is falsely negative (eg, patients with HIV infection or children ages <5 years who have been exposed to a person with active TB)
• those with an initial positive test who don’t believe the test result and are reluctant to be treated for LTBI.

TST and IGRA have comparable sensitivities—around 80% to 90%, respectively—for diagnosing LTBI. IGRAs have a specificity >95% for diagnosing LTBI. While TST specificity is approximately 97% in patients not vaccinated with BCG, it can be as low as 60% in people previously vaccinated with BCG.²⁶ IGRAs have been shown to have higher positive and negative predictive values than TSTs in high-risk patients.²⁷ A recent study suggested that the IGRAs might have a higher rate of false-positive results compared to TSTs in a low-risk population of health care workers.²⁸

Both the TST and IGRA have lag times of 3 to 8 weeks from the time of a new infection until the test becomes positive. It is therefore best to defer testing for LTBI infection until at least 8 weeks after a known TB exposure to decrease the likelihood of a false-negative test.³

Diagnose active TB based on symptoms, culture

The CDC reported 9412 new cases of active TB in the United States in 2014, for a rate of 3 new cases per 100,000 people.²⁹ This is the lowest rate reported since national reporting began in 1953, when the incidence in the United States was 53 cases per 100,000.

Who should you test for active TB? The risk factors for active TB are the same as those for LTBI: recent exposure to an individual with active TB, and other disease processes or medications that compromise the immune system. Consider active TB when a patient with one of these risk factors presents with:²
• persistent fever
• weight loss
• night sweats
• cough, especially if there is any blood.

Routine laboratory and radiographic studies that should prompt you to consider TB include:²
• upper lobe infiltrates on chest x-ray
• sterile pyuria on urinalysis with a negative culture for routine pathogens
• elevated levels of C-reactive protein or an elevated erythrocyte sedimentation rate without another obvious cause.

Active TB typically presents as pulmonary TB, but it can also affect nearly every other body system. Other common presentations include:³⁰
• vertebral destruction and collapse (“Pott's disease”)
• subacute meningitis
• peritonitis
• lymphadenopathy (especially in children).

IGRAs have been shown to have higher positive and negative predictive values than TSTs in high-risk patients.

Culture is the gold standard. Neither TST or IGRA should ever be relied upon to make or exclude the diagnosis of active TB, as these tests are neither sensitive nor specific for diagnosing active TB.^31,32 Instead, the gold standard for the diagnosis of active TB remains a positive culture from infected tissue—commonly sputum, pleura or pleural fluid, cerebrospinal fluid, urine, or peritoneal fluid. Cultures are crucial not only to confirm the diagnosis, but to guide therapy, because of the rapidly increasing resistance to firstline antibiotics used to treat TB.³³

Culture results and drug sensitivities are ordinarily not available until 2 to 6 weeks after the culture was obtained. A smear for acid-fast bacilli as well as newer rapid diagnostic tests such as nucleic acid amplification (NAA) tests are generally performed on the tissue sample submitted for culture, and these results, while less trustworthy, are generally available within 24 to 48 hours. The CDC recommends that an NAA test be performed in addition to microscopy and culture for specimens submitted for TB diagnosis.³⁴

A single BCG vaccine in infancy causes little if any change in the TST result in individuals who are older than 10 years of age.

Since 2011, the World Health Organization has endorsed the use of a new molecular diagnostic test called Xpert MTB/RIF in settings with high prevalence of HIV infection or multidrug-resistant TB (MDR-TB).³⁵ This test is able to detect M. tuberculosis as well as rifampin resistance, a surrogate for MDR-TB, within 2 hours, with sensitivity and specificity approaching that of culture.³⁶

“Culture-negative” TB? A small but not insignificant proportion of patients will present with risk factors for, and clinical signs and symptoms of, active TB; their cultures, however, will be negative. In such cases, consultation with an infectious disease or pulmonary specialist may be warranted. If no alternative diagnosis is found, such patients are said to have “culture-negative active TB” and should be continued on anti-TB drug therapy, although the course may be shortened.³⁷ This highlights the fact that while cultures are key to diagnosing and treating active TB, the condition is—practically speaking—a clinical diagnosis; treatment should not be withheld or stopped simply because of a negative culture or rapid diagnostic test.

CASE 1 › Based on her risk factors (being a health care worker, born in a country with a high prevalence of TB), Ms. C’s cutoff for a positive test is >10 mm, so her TST result is negative and she is not considered to have LTBI. The increase to 8 mm seen on the second TST probably represents either childhood BCG vaccination or previous infection with nontuberculous Mycobacterium.

CASE 2 › Strictly speaking, 3-year-old Patrick does not need testing, because he was exposed only to LTBI, which is not infectious. However, because children under age 5 are at particularly high risk for progressing to active TB and poor outcomes, it would be best to confirm the mother’s story with the day care center and/or health department. If it turns out that Patrick had, in fact, been exposed to active TB, much more aggressive management would be required.

CORRESPONDENCE
Jeff Hall, MD, Family Medicine Center, 3209 Colonial Drive Columbia, SC 29203; [email protected]

CASE 1 › Judy C is a newly employed 40-year-old health care worker who was born in China and received the bacille Calmette-Guérin (BCG) vaccination as a child. Her new employer requires her to undergo testing for tuberculosis (TB). Her initial tuberculin skin test (TST) is 0 mm, but on a second TST 2 weeks later, it is 8 mm. She is otherwise healthy, negative for human immunodeficiency virus (HIV), and has no constitutional symptoms. Does she have latent tuberculosis infection (LTBI)?

CASE 2 › A mom brings in her 3-year-old son, Patrick. She reports that a staff member at his day care center traveled outside the country for 3 months and was diagnosed with LTBI upon her return. She wants to know if her son should be tested.

More than 2 billion people—nearly one-third of the world’s population—are infected with Mycobacterium tuberculosis.¹ Most harbor the bacilli as LTBI, which means that while they have living TB bacilli within their bodies, these mycobacteria are kept dormant by an intact immune system. These individuals are not contagious, nor are they likely to become ill from active TB unless something adversely affects their immune system and increases the likelihood that LTBI will progress to active TB.

Two tests are available for diagnosing LTBI: the TST and the newer interferon gamma release assay (IGRA). Each test has advantages and disadvantages, and the best test to use depends on various patient-specific factors. This article describes whom you should test for LTBI, which test to use, and how to diagnose active TB.

Why test for LTBI?

LTBI is an asymptomatic infection; patients with LTBI have a 5% to 10% lifetime risk of developing active TB.² The risk of developing active TB is approximately 5% within the first 18 months of infection, and the remaining risk is spread out over the rest of the patient’s life.² Screening for LTBI is desirable because early diagnosis and treatment can reduce the activation risk to 1% to 2%,³ and treatment for LTBI is simpler, less costly, and less toxic than treatment for active TB.

Whom to test. Screening for LTBI should target patients for whom the benefits of treatment outweigh the cost and risks of treatment.⁴ A decision to screen for LTBI implies that the patient will be treated if he or she tests positive.³

The benefit of treatment increases in people who have a significant risk of progression to active TB—primarily those with recently acquired LTBI, or with co-existing conditions that increase their likelihood of progression (TABLE 1).⁵

Screening for latent TB infection is desirable because early diagnosis and treatment can reduce the activation risk to 1% to 2%.

All household contacts of patients with active TB and recent immigrants from countries with a high TB prevalence should be tested for LTBI.⁶ Those with a negative test and recent exposure should be retested in 8 to 12 weeks to allow for the delay in conversion to a positive test after recent infection.⁷ Health care workers and others who are potentially exposed to active TB on an ongoing basis should be tested at the time of employment, with repeat testing done periodically based on their risk of infection.^8,9

Individuals with coexisting conditions should be tested for LTBI as long as the benefit of treatment outweighs the risk of drug-induced hepatitis. Because the risk of drug-induced hepatitis increases with age, the decision to test/treat is affected by age as well as the individual’s risk of progression. Patients with the highest risk conditions would benefit from testing/treating regardless of age, while treatment may not be justified in those with lower-risk conditions. A reasonable strategy is as follows:¹⁰
• high-risk conditions: test regardless of age
• moderate-risk conditions: test those <65 years
• low-risk conditions: test those <50 years.

Children with LTBI are at particularly high risk of progression to active TB.⁵ The American Academy of Pediatrics (AAP) recommends assessing a child’s risk for TB at first contact with the child and once every 6 months for the first year of life. After one year, annual assessment is recommended, but specific TB testing is not required for children who don’t have risk factors.¹¹ The AAP suggests using a TB risk assessment questionnaire that consists of 4 screening questions with follow-up questions if any of the screening questions are positive (TABLE 2).¹¹

Use of TST is well established

To perform a TST, inject 5 tuberculin units (0.1 mL) of purified protein derivative (PPD) intradermally into the inner surface of the forearm using a 27- to 30-gauge needle. (In the United States, PPD is available as Aplisol or Tubersol.) Avoid the former practice of “control” or anergy testing with mumps or Candida antigens because this is rarely helpful in making TB treatment decisions, even in HIV-positive patients.¹²

To facilitate intradermal injection, gently stretch the skin taut during injection. Raising a wheal confirms correct placement. The test should be read 48 to 72 hours after it is administered by measuring the greatest diameter of induration at the administration site. (Erythema is irrelevant to how the test is interpreted.) Induration is best read by using a ballpoint pen held at a 45-degree angle pointing toward the injection site. Roll the point of the pen over the skin with gentle pressure toward the injection site until induration causes the pen to stop rolling freely (FIGURE). The induration should be measured with a rule that has millimeter measurements and interpreted as positive or negative based on the individual’s risk factors (TABLE 3).³

Watch for these 2 factors that can affect TST results

Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis, is (or has been) used as a routine childhood immunization in many parts of the world, although not in the United States.¹³ It is ordinarily given as a single dose shortly after birth, and has some utility in preventing serious childhood TB infection. The antigens in PPD and those in BCG are not identical, but they do overlap.

BCG administered after an individual’s first birthday resulted in false positive TSTs >10 mm in 21% of those tested more than 10 years after BCG was administered.¹⁴ However, a single BCG vaccine in infancy causes little if any change in the TST result in individuals who are older than age 10 years. When a TST is performed for appropriate reasons, a positive TST in people previously vaccinated with BCG is generally more likely to be the result of LTBI than of BCG.¹⁵ Current guidelines from the Centers for Disease Control and Prevention (CDC) recommend that previous BCG status not change the cutoffs used for interpreting TST results.¹⁶

Booster phenomenon. In many adults who have undiagnosed LTBI that they acquired in the distant past, or who received BCG vaccination as a child, immunity wanes after several decades. This can result in an initial TST being negative, but because the antigens in the PPD itself stimulate antigenic memory, the next time a TST is performed, it may be positive.

In people who will have annual TST screenings, such as health care workers or nursing home residents, a 2-step PPD can help discriminate this “booster” phenomenon from a new LTBI acquired during the first year of annual TST testing. A second TST is placed 1 to 2 weeks after the initial test, a time interval during which acquisition of LTBI would be unlikely. The result of the second test should be considered the person’s baseline for evaluation of subsequent TSTs. A subsequent TST would be considered positive if the induration is >10 mm and has increased by ≥6 mm since the previous baseline.¹⁷

IGRA offers certain benefits

IGRA uses antigens that are more specific for Mycobacterium tuberculosis than the TST, and as a result, this test is not influenced by previous BCG vaccination. It requires only one blood draw, and interpretation does not depend on the patient’s risk category or interpretation of skin induration. The primary disadvantage of IGRAs is high cost (currently $200 to $300 per test), and the need for a laboratory with adequate equipment and personnel trained in performing the test. IGRAs must be collected in special blood tubes, and the samples must be processed within 8 to 16 hours of collection, depending on the test used.⁵

Currently, 2 IGRAs are approved for use in the United States—the QuantiFERON-TB Gold In-Tube (QFT-GIT) and the T-SPOT.TB assay. Both tests may produce false positives in patients infected with Mycobacterium marinum or Mycobacterium kansasii, but otherwise are highly specific for Mycobacterium tuberculosis. IGRA results may be “boosted” by recent TST (ie, a TST given within the previous 3 months may cause a false positive IGRA result), and this effect may begin as early as 3 days after a TST is administered.¹⁸ Therefore, if an IGRA is needed to clarify a TST result, it should be drawn on the day the TST is read.¹⁹

CDC guidelines (2010) recommend that IGRAs may be used in place of—but not routinely in addition to—TSTs in all cases in which TST is otherwise indicated.²⁰ There are a few situations where one test may be preferred over the other.²¹

IGRA may be preferred over TST in individuals in one of 2 categories:
• those who have received BCG immunization. If a patient is unsure of their BCG status, the World Atlas of BCG Policies and Practices, available at www.bcgatlas.org,²² can aid clinicians in determining which patients likely received BCG as part of their routine childhood immunizations.
• those in groups that historically have poor rates of return for TST reading, such as individuals who are homeless or suffer from alcoholism or a substance use disorder.

Individuals in whom TST is preferred over IGRA include:
• children age <5 years, because data guiding use of IGRAs in this age group are limited.²³ Both TST and IGRA may be falsely negative in children under the age of 3 months.²⁴
• patients who require serial testing, because individuals with positive IGRAs have been shown to commonly test negative on subsequent tests, and there are limited data on interpretation and prognosis of positive IGRAs in people who require serial testing.²⁵

Individuals in whom performing both tests simultaneously could be helpful include:
• those with an initial negative test, but with a high risk for progression to active TB or a poor outcome if the first result is falsely negative (eg, patients with HIV infection or children ages <5 years who have been exposed to a person with active TB)
• those with an initial positive test who don’t believe the test result and are reluctant to be treated for LTBI.

TST and IGRA have comparable sensitivities—around 80% to 90%, respectively—for diagnosing LTBI. IGRAs have a specificity >95% for diagnosing LTBI. While TST specificity is approximately 97% in patients not vaccinated with BCG, it can be as low as 60% in people previously vaccinated with BCG.²⁶ IGRAs have been shown to have higher positive and negative predictive values than TSTs in high-risk patients.²⁷ A recent study suggested that the IGRAs might have a higher rate of false-positive results compared to TSTs in a low-risk population of health care workers.²⁸

Both the TST and IGRA have lag times of 3 to 8 weeks from the time of a new infection until the test becomes positive. It is therefore best to defer testing for LTBI infection until at least 8 weeks after a known TB exposure to decrease the likelihood of a false-negative test.³

Diagnose active TB based on symptoms, culture

The CDC reported 9412 new cases of active TB in the United States in 2014, for a rate of 3 new cases per 100,000 people.²⁹ This is the lowest rate reported since national reporting began in 1953, when the incidence in the United States was 53 cases per 100,000.

Who should you test for active TB? The risk factors for active TB are the same as those for LTBI: recent exposure to an individual with active TB, and other disease processes or medications that compromise the immune system. Consider active TB when a patient with one of these risk factors presents with:²
• persistent fever
• weight loss
• night sweats
• cough, especially if there is any blood.

Routine laboratory and radiographic studies that should prompt you to consider TB include:²
• upper lobe infiltrates on chest x-ray
• sterile pyuria on urinalysis with a negative culture for routine pathogens
• elevated levels of C-reactive protein or an elevated erythrocyte sedimentation rate without another obvious cause.

Active TB typically presents as pulmonary TB, but it can also affect nearly every other body system. Other common presentations include:³⁰
• vertebral destruction and collapse (“Pott's disease”)
• subacute meningitis
• peritonitis
• lymphadenopathy (especially in children).

IGRAs have been shown to have higher positive and negative predictive values than TSTs in high-risk patients.

Culture is the gold standard. Neither TST or IGRA should ever be relied upon to make or exclude the diagnosis of active TB, as these tests are neither sensitive nor specific for diagnosing active TB.^31,32 Instead, the gold standard for the diagnosis of active TB remains a positive culture from infected tissue—commonly sputum, pleura or pleural fluid, cerebrospinal fluid, urine, or peritoneal fluid. Cultures are crucial not only to confirm the diagnosis, but to guide therapy, because of the rapidly increasing resistance to firstline antibiotics used to treat TB.³³

Culture results and drug sensitivities are ordinarily not available until 2 to 6 weeks after the culture was obtained. A smear for acid-fast bacilli as well as newer rapid diagnostic tests such as nucleic acid amplification (NAA) tests are generally performed on the tissue sample submitted for culture, and these results, while less trustworthy, are generally available within 24 to 48 hours. The CDC recommends that an NAA test be performed in addition to microscopy and culture for specimens submitted for TB diagnosis.³⁴

A single BCG vaccine in infancy causes little if any change in the TST result in individuals who are older than 10 years of age.

Since 2011, the World Health Organization has endorsed the use of a new molecular diagnostic test called Xpert MTB/RIF in settings with high prevalence of HIV infection or multidrug-resistant TB (MDR-TB).³⁵ This test is able to detect M. tuberculosis as well as rifampin resistance, a surrogate for MDR-TB, within 2 hours, with sensitivity and specificity approaching that of culture.³⁶

“Culture-negative” TB? A small but not insignificant proportion of patients will present with risk factors for, and clinical signs and symptoms of, active TB; their cultures, however, will be negative. In such cases, consultation with an infectious disease or pulmonary specialist may be warranted. If no alternative diagnosis is found, such patients are said to have “culture-negative active TB” and should be continued on anti-TB drug therapy, although the course may be shortened.³⁷ This highlights the fact that while cultures are key to diagnosing and treating active TB, the condition is—practically speaking—a clinical diagnosis; treatment should not be withheld or stopped simply because of a negative culture or rapid diagnostic test.

CASE 1 › Based on her risk factors (being a health care worker, born in a country with a high prevalence of TB), Ms. C’s cutoff for a positive test is >10 mm, so her TST result is negative and she is not considered to have LTBI. The increase to 8 mm seen on the second TST probably represents either childhood BCG vaccination or previous infection with nontuberculous Mycobacterium.

CASE 2 › Strictly speaking, 3-year-old Patrick does not need testing, because he was exposed only to LTBI, which is not infectious. However, because children under age 5 are at particularly high risk for progressing to active TB and poor outcomes, it would be best to confirm the mother’s story with the day care center and/or health department. If it turns out that Patrick had, in fact, been exposed to active TB, much more aggressive management would be required.

CORRESPONDENCE
Jeff Hall, MD, Family Medicine Center, 3209 Colonial Drive Columbia, SC 29203; [email protected]

CASE 1 › Judy C is a newly employed 40-year-old health care worker who was born in China and received the bacille Calmette-Guérin (BCG) vaccination as a child. Her new employer requires her to undergo testing for tuberculosis (TB). Her initial tuberculin skin test (TST) is 0 mm, but on a second TST 2 weeks later, it is 8 mm. She is otherwise healthy, negative for human immunodeficiency virus (HIV), and has no constitutional symptoms. Does she have latent tuberculosis infection (LTBI)?

CASE 2 › A mom brings in her 3-year-old son, Patrick. She reports that a staff member at his day care center traveled outside the country for 3 months and was diagnosed with LTBI upon her return. She wants to know if her son should be tested.

More than 2 billion people—nearly one-third of the world’s population—are infected with Mycobacterium tuberculosis.¹ Most harbor the bacilli as LTBI, which means that while they have living TB bacilli within their bodies, these mycobacteria are kept dormant by an intact immune system. These individuals are not contagious, nor are they likely to become ill from active TB unless something adversely affects their immune system and increases the likelihood that LTBI will progress to active TB.

Two tests are available for diagnosing LTBI: the TST and the newer interferon gamma release assay (IGRA). Each test has advantages and disadvantages, and the best test to use depends on various patient-specific factors. This article describes whom you should test for LTBI, which test to use, and how to diagnose active TB.

Why test for LTBI?

LTBI is an asymptomatic infection; patients with LTBI have a 5% to 10% lifetime risk of developing active TB.² The risk of developing active TB is approximately 5% within the first 18 months of infection, and the remaining risk is spread out over the rest of the patient’s life.² Screening for LTBI is desirable because early diagnosis and treatment can reduce the activation risk to 1% to 2%,³ and treatment for LTBI is simpler, less costly, and less toxic than treatment for active TB.

Whom to test. Screening for LTBI should target patients for whom the benefits of treatment outweigh the cost and risks of treatment.⁴ A decision to screen for LTBI implies that the patient will be treated if he or she tests positive.³

The benefit of treatment increases in people who have a significant risk of progression to active TB—primarily those with recently acquired LTBI, or with co-existing conditions that increase their likelihood of progression (TABLE 1).⁵

Screening for latent TB infection is desirable because early diagnosis and treatment can reduce the activation risk to 1% to 2%.

All household contacts of patients with active TB and recent immigrants from countries with a high TB prevalence should be tested for LTBI.⁶ Those with a negative test and recent exposure should be retested in 8 to 12 weeks to allow for the delay in conversion to a positive test after recent infection.⁷ Health care workers and others who are potentially exposed to active TB on an ongoing basis should be tested at the time of employment, with repeat testing done periodically based on their risk of infection.^8,9

Individuals with coexisting conditions should be tested for LTBI as long as the benefit of treatment outweighs the risk of drug-induced hepatitis. Because the risk of drug-induced hepatitis increases with age, the decision to test/treat is affected by age as well as the individual’s risk of progression. Patients with the highest risk conditions would benefit from testing/treating regardless of age, while treatment may not be justified in those with lower-risk conditions. A reasonable strategy is as follows:¹⁰
• high-risk conditions: test regardless of age
• moderate-risk conditions: test those <65 years
• low-risk conditions: test those <50 years.

Children with LTBI are at particularly high risk of progression to active TB.⁵ The American Academy of Pediatrics (AAP) recommends assessing a child’s risk for TB at first contact with the child and once every 6 months for the first year of life. After one year, annual assessment is recommended, but specific TB testing is not required for children who don’t have risk factors.¹¹ The AAP suggests using a TB risk assessment questionnaire that consists of 4 screening questions with follow-up questions if any of the screening questions are positive (TABLE 2).¹¹

Use of TST is well established

To perform a TST, inject 5 tuberculin units (0.1 mL) of purified protein derivative (PPD) intradermally into the inner surface of the forearm using a 27- to 30-gauge needle. (In the United States, PPD is available as Aplisol or Tubersol.) Avoid the former practice of “control” or anergy testing with mumps or Candida antigens because this is rarely helpful in making TB treatment decisions, even in HIV-positive patients.¹²

To facilitate intradermal injection, gently stretch the skin taut during injection. Raising a wheal confirms correct placement. The test should be read 48 to 72 hours after it is administered by measuring the greatest diameter of induration at the administration site. (Erythema is irrelevant to how the test is interpreted.) Induration is best read by using a ballpoint pen held at a 45-degree angle pointing toward the injection site. Roll the point of the pen over the skin with gentle pressure toward the injection site until induration causes the pen to stop rolling freely (FIGURE). The induration should be measured with a rule that has millimeter measurements and interpreted as positive or negative based on the individual’s risk factors (TABLE 3).³

Watch for these 2 factors that can affect TST results

Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis, is (or has been) used as a routine childhood immunization in many parts of the world, although not in the United States.¹³ It is ordinarily given as a single dose shortly after birth, and has some utility in preventing serious childhood TB infection. The antigens in PPD and those in BCG are not identical, but they do overlap.

BCG administered after an individual’s first birthday resulted in false positive TSTs >10 mm in 21% of those tested more than 10 years after BCG was administered.¹⁴ However, a single BCG vaccine in infancy causes little if any change in the TST result in individuals who are older than age 10 years. When a TST is performed for appropriate reasons, a positive TST in people previously vaccinated with BCG is generally more likely to be the result of LTBI than of BCG.¹⁵ Current guidelines from the Centers for Disease Control and Prevention (CDC) recommend that previous BCG status not change the cutoffs used for interpreting TST results.¹⁶

Booster phenomenon. In many adults who have undiagnosed LTBI that they acquired in the distant past, or who received BCG vaccination as a child, immunity wanes after several decades. This can result in an initial TST being negative, but because the antigens in the PPD itself stimulate antigenic memory, the next time a TST is performed, it may be positive.

In people who will have annual TST screenings, such as health care workers or nursing home residents, a 2-step PPD can help discriminate this “booster” phenomenon from a new LTBI acquired during the first year of annual TST testing. A second TST is placed 1 to 2 weeks after the initial test, a time interval during which acquisition of LTBI would be unlikely. The result of the second test should be considered the person’s baseline for evaluation of subsequent TSTs. A subsequent TST would be considered positive if the induration is >10 mm and has increased by ≥6 mm since the previous baseline.¹⁷

IGRA offers certain benefits

IGRA uses antigens that are more specific for Mycobacterium tuberculosis than the TST, and as a result, this test is not influenced by previous BCG vaccination. It requires only one blood draw, and interpretation does not depend on the patient’s risk category or interpretation of skin induration. The primary disadvantage of IGRAs is high cost (currently $200 to $300 per test), and the need for a laboratory with adequate equipment and personnel trained in performing the test. IGRAs must be collected in special blood tubes, and the samples must be processed within 8 to 16 hours of collection, depending on the test used.⁵

Currently, 2 IGRAs are approved for use in the United States—the QuantiFERON-TB Gold In-Tube (QFT-GIT) and the T-SPOT.TB assay. Both tests may produce false positives in patients infected with Mycobacterium marinum or Mycobacterium kansasii, but otherwise are highly specific for Mycobacterium tuberculosis. IGRA results may be “boosted” by recent TST (ie, a TST given within the previous 3 months may cause a false positive IGRA result), and this effect may begin as early as 3 days after a TST is administered.¹⁸ Therefore, if an IGRA is needed to clarify a TST result, it should be drawn on the day the TST is read.¹⁹

CDC guidelines (2010) recommend that IGRAs may be used in place of—but not routinely in addition to—TSTs in all cases in which TST is otherwise indicated.²⁰ There are a few situations where one test may be preferred over the other.²¹

IGRA may be preferred over TST in individuals in one of 2 categories:
• those who have received BCG immunization. If a patient is unsure of their BCG status, the World Atlas of BCG Policies and Practices, available at www.bcgatlas.org,²² can aid clinicians in determining which patients likely received BCG as part of their routine childhood immunizations.
• those in groups that historically have poor rates of return for TST reading, such as individuals who are homeless or suffer from alcoholism or a substance use disorder.

Individuals in whom TST is preferred over IGRA include:
• children age <5 years, because data guiding use of IGRAs in this age group are limited.²³ Both TST and IGRA may be falsely negative in children under the age of 3 months.²⁴
• patients who require serial testing, because individuals with positive IGRAs have been shown to commonly test negative on subsequent tests, and there are limited data on interpretation and prognosis of positive IGRAs in people who require serial testing.²⁵

Individuals in whom performing both tests simultaneously could be helpful include:
• those with an initial negative test, but with a high risk for progression to active TB or a poor outcome if the first result is falsely negative (eg, patients with HIV infection or children ages <5 years who have been exposed to a person with active TB)
• those with an initial positive test who don’t believe the test result and are reluctant to be treated for LTBI.

TST and IGRA have comparable sensitivities—around 80% to 90%, respectively—for diagnosing LTBI. IGRAs have a specificity >95% for diagnosing LTBI. While TST specificity is approximately 97% in patients not vaccinated with BCG, it can be as low as 60% in people previously vaccinated with BCG.²⁶ IGRAs have been shown to have higher positive and negative predictive values than TSTs in high-risk patients.²⁷ A recent study suggested that the IGRAs might have a higher rate of false-positive results compared to TSTs in a low-risk population of health care workers.²⁸

Both the TST and IGRA have lag times of 3 to 8 weeks from the time of a new infection until the test becomes positive. It is therefore best to defer testing for LTBI infection until at least 8 weeks after a known TB exposure to decrease the likelihood of a false-negative test.³

Diagnose active TB based on symptoms, culture

The CDC reported 9412 new cases of active TB in the United States in 2014, for a rate of 3 new cases per 100,000 people.²⁹ This is the lowest rate reported since national reporting began in 1953, when the incidence in the United States was 53 cases per 100,000.

Who should you test for active TB? The risk factors for active TB are the same as those for LTBI: recent exposure to an individual with active TB, and other disease processes or medications that compromise the immune system. Consider active TB when a patient with one of these risk factors presents with:²
• persistent fever
• weight loss
• night sweats
• cough, especially if there is any blood.

Routine laboratory and radiographic studies that should prompt you to consider TB include:²
• upper lobe infiltrates on chest x-ray
• sterile pyuria on urinalysis with a negative culture for routine pathogens
• elevated levels of C-reactive protein or an elevated erythrocyte sedimentation rate without another obvious cause.

Active TB typically presents as pulmonary TB, but it can also affect nearly every other body system. Other common presentations include:³⁰
• vertebral destruction and collapse (“Pott's disease”)
• subacute meningitis
• peritonitis
• lymphadenopathy (especially in children).

IGRAs have been shown to have higher positive and negative predictive values than TSTs in high-risk patients.

Culture is the gold standard. Neither TST or IGRA should ever be relied upon to make or exclude the diagnosis of active TB, as these tests are neither sensitive nor specific for diagnosing active TB.^31,32 Instead, the gold standard for the diagnosis of active TB remains a positive culture from infected tissue—commonly sputum, pleura or pleural fluid, cerebrospinal fluid, urine, or peritoneal fluid. Cultures are crucial not only to confirm the diagnosis, but to guide therapy, because of the rapidly increasing resistance to firstline antibiotics used to treat TB.³³

Culture results and drug sensitivities are ordinarily not available until 2 to 6 weeks after the culture was obtained. A smear for acid-fast bacilli as well as newer rapid diagnostic tests such as nucleic acid amplification (NAA) tests are generally performed on the tissue sample submitted for culture, and these results, while less trustworthy, are generally available within 24 to 48 hours. The CDC recommends that an NAA test be performed in addition to microscopy and culture for specimens submitted for TB diagnosis.³⁴

A single BCG vaccine in infancy causes little if any change in the TST result in individuals who are older than 10 years of age.

Since 2011, the World Health Organization has endorsed the use of a new molecular diagnostic test called Xpert MTB/RIF in settings with high prevalence of HIV infection or multidrug-resistant TB (MDR-TB).³⁵ This test is able to detect M. tuberculosis as well as rifampin resistance, a surrogate for MDR-TB, within 2 hours, with sensitivity and specificity approaching that of culture.³⁶

“Culture-negative” TB? A small but not insignificant proportion of patients will present with risk factors for, and clinical signs and symptoms of, active TB; their cultures, however, will be negative. In such cases, consultation with an infectious disease or pulmonary specialist may be warranted. If no alternative diagnosis is found, such patients are said to have “culture-negative active TB” and should be continued on anti-TB drug therapy, although the course may be shortened.³⁷ This highlights the fact that while cultures are key to diagnosing and treating active TB, the condition is—practically speaking—a clinical diagnosis; treatment should not be withheld or stopped simply because of a negative culture or rapid diagnostic test.

CASE 1 › Based on her risk factors (being a health care worker, born in a country with a high prevalence of TB), Ms. C’s cutoff for a positive test is >10 mm, so her TST result is negative and she is not considered to have LTBI. The increase to 8 mm seen on the second TST probably represents either childhood BCG vaccination or previous infection with nontuberculous Mycobacterium.

CASE 2 › Strictly speaking, 3-year-old Patrick does not need testing, because he was exposed only to LTBI, which is not infectious. However, because children under age 5 are at particularly high risk for progressing to active TB and poor outcomes, it would be best to confirm the mother’s story with the day care center and/or health department. If it turns out that Patrick had, in fact, been exposed to active TB, much more aggressive management would be required.

CORRESPONDENCE
Jeff Hall, MD, Family Medicine Center, 3209 Colonial Drive Columbia, SC 29203; [email protected]

CASE  › Mitchell J, age 62, comes to see you because he’s had a cough with increasing dyspnea for a month. Mr. J has never smoked but has type 2 diabetes mellitus. He also tells you that over the past month, he’s had occasional night sweats and has lost 8 pounds, although he’s not changed his diet. During the past week, he’s noticed blood-tinged sputum. Physical examination reveals a thin, chronically ill appearing man with an oral temperature of 100.6°F and mild tachypnea. You order a complete blood count, chest x-ray, and metabolic profile, administer a tuberculin skin test (TST), and initiate levofloxacin 500 mg/d for a presumed bacterial pneumonia. His lab work reveals mild leukocytosis and hyperglycemia, and the chest x-ray shows a left upper lobe infiltrate. The TST reaction—4 mm 50 hours after placement—was negative.

Mr. J returns a week later and says he feels worse. Your examination reveals worsened tachypnea, with tachycardia and crackles over the left upper lung fields.

How would you proceed with his care?

More people die of tuberculosis (TB) each year than any other infectious disease except human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. In 2013, an estimated 9 million people worldwide developed active TB and 1.5 million died of the disease.¹ Many of these deaths could have been prevented if patients had received a diagnosis and treatment during the latent phase (when the patient was infected, but had no active disease), or as soon as the patient developed active disease. In this article we describe treatment for both latent and active TB.

Before treating latent TB infection, first rule out active TB

Patients with latent tuberculosis infection (LTBI) have a 5% to 10% lifetime risk of developing active TB disease.² Treatment of LTBI can reduce this risk to 1% to 2%.³

Assess patients with latent TB infection for signs of active TB, such as weight loss, unexplained fever, night sweats, or hemoptysis. Although not the focus of this article, diagnosis of LTBI is made by using either a TST, in which the patient receives an intradermal injection of purified protein derivative and the size of the skin induration is measured 48 to 72 hours after administration, or an interferon-gamma release assay (IGRA), which requires a blood draw. After receiving a positive test result for LTBI, the next step is to rule out active TB.⁴ This is necessary because the primary treatment regimen for LTBI involves only one drug, whereas treating active TB with one drug is strongly associated with treatment failure and future resistance to that drug.⁵

To rule out active TB, perform a brief, problem-focused history and physical, and obtain a chest x-ray.⁴ Pertinent findings that suggest active disease include:

• any history of recent weight loss, unexplained fever, night sweats, cough or hemoptysis
• fever or any unexpected lung findings on physical exam
• any parenchymal infiltrates on chest x-ray. (Granulomas and scarring may be signs of previously healed TB infection, but do not indicate active TB.)

Any of these findings should prompt a further investigation to either confirm or definitively rule out active TB disease. In the absence of these findings, the physician may proceed with treatment for LTBI.

Latent TB infection treatment: Isoniazid alone, or another regimen?

The current preferred regimen for most patients with LTBI is 9 months of isoniazid (INH) 5 mg/kg/d (10 mg/kg/d in children) up to a maximum of 300 mg/d. This regimen has been recommended by the Centers for Disease Control and Prevention (CDC), the American Thoracic Society, and the Infectious Diseases Society of America.³ However, there are 3 other CDC-recommended LTBI treatment regimens that include INH, INH plus rifapentine (RPT), or rifampin (RIF) for 6, 3, or 4 months, respectively (TABLE 1).⁶ These other regimens may be considered under certain circumstances. For example, INH and rifapentine might be used to treat an otherwise healthy patient who has had recent exposure to an individual with active, contagious TB.

If the patient is pregnant. INH is a pregnancy category C drug. Treatment for LTBI during pregnancy is generally regarded as safe and should be strongly considered if the patient has risk factors for progression to active TB, such as a recent exposure to someone with active TB.⁷ In otherwise healthy patients, treatment for LTBI may be deferred until after delivery.

Take steps to avoid complications of drug therapy

Drug-induced hepatitis is the primary adverse effect of INH treatment. Risk increases with age, previous hepatic injury, or concomitant use of other hepatotoxic medications. The risk is very small (<0.1%) for healthy children but may be over 10% for adults with multiple risk factors.⁸ Hepatitis is generally preceded by asymptomatic elevation of liver function tests (LFTs), which is much more common than clinical hepatitis.

Baseline LFTs should be obtained in patients who:

• have underlying liver disease, such as hepatitis B or C⁹
• consume ≥2 alcoholic drinks daily or >5 drinks at a time on any occasion
• take other medications with potential hepatotoxicity, such as statins
• have HIV infection¹⁰
• are pregnant or postpartum.

If a patient being considered for INH treatment has not had serologic testing for HIV, hepatitis B, or hepatitis C, these tests should be done prior to initiating INH. LFTs should be monitored every 1 to 2 months during INH therapy for patients who have ≥1 of these conditions and normal baseline LFTs. If baseline transaminases are >3 times the upper limit of normal, treatment for LTBI should probably be withheld, though might be considered in those whose LFTs return to normal after withdrawal of a modifiable risk factor, such as alcohol or a statin medication.

Patients with latent TB infection who are receiving isoniazid should be monitored regularly for signs and symptoms of hepatitis. After beginning LTBI treatment, patients should be monitored regularly for signs and symptoms of hepatitis, including anorexia, nausea, abdominal pain, icterus, and dark urine, and LFTs performed if these develop. If during treatment transaminases increase to >3 times normal in a symptomatic patient (or >5 times normal in an asymptomatic patient), INH should be stopped and generally not resumed, even after LFTs return to normal. (Such patients would be considered to have partially treated LTBI, and their physicians should be alert to signs and symptoms of active TB, such as unexplained fever, weight loss, or blood-tinged sputum, during subsequent patient encounters.)

Peripheral neuropathy is a less common adverse effect of INH. It occurs in up to 2% of patients and is caused by interference with vitamin B6 (pyridoxine) metabolism. It can be prevented by supplementation with pyridoxine 25 to 50 mg/d. Vitamin B6, however, does not prevent INH-induced hepatotoxicity.

Noncompliance is a concern with INH therapy because treatment typically requires a 9-month course of daily medication.¹¹ Patients for whom compliance is likely to be an issue might be considered for a 3-month, 12-dose course of once-weekly, directly-observed therapy (DOT) with INH and RPT administered by a public health agency. (See “Which patients with TB should receive directly observed therapy?” on page 32.^12-14) A randomized, open-label trial involving nearly 8000 patients in 4 low-risk countries found this regimen was as effective as 9 months of self-administered INH.¹⁵ The CDC has published recommendations for using this regimen.¹⁶

Suspect active TB? Don’t wait for cultures to begin Tx

Unlike LTBI, for which the results of diagnostic testing are available within a few days, active TB is diagnosed by culture, which may take as long as 6 to 8 weeks. Don’t wait to receive culture results to initiate treatment in a patient you suspect may have active TB. However, if you suspect your patient has active TB, do not delay treatment while waiting for culture results, or defer treatment for a patient who has a negative acid-fast bacilli (AFB) smear or rapid nucleic acid amplification test.¹⁷ These 2 tests, which are routinely performed during TB cultures, look for other evidence of the presence of TB bacilli; they are not as accurate as cultures, but results are available within days. Likewise, a negative TST or IGRA should not prevent empiric treatment for active TB. Treatment for active TB should be begun empirically based on risk factors and clinical presentation, and can be modified or stopped if cultures are negative, the patient fails to improve, or an alternative diagnosis is found to explain the patient’s symptoms.

Rapid testing for evidence of active TB disease—as well as resistance to medications commonly used to treat TB—can be performed using newer modalities such as MODS (Microscopic-Observation Drug-Susceptibility)^18,19 or Xpert MTB/RIF²⁰ testing. However, these tests are not available in many hospitals, and culture and drug sensitivity testing remain the gold standard.²¹

CASE › Mr. J’s clinical history and chest x-ray findings are highly suggestive of active TB. It was not unreasonable to initially treat him for a bacterial pneumonia, although fluoroquinolones should be used cautiously in this setting, because they are one of the most effective second-line drugs for TB, and using them as a single agent will often invoke drug resistance. Because he failed to respond to treatment for bacterial pneumonia and his presentation suggests TB or another serious cause of nonresponsiveness to standard treatment for community-acquired pneumonia (CAP), you admit him to the hospital.

Treatment for active TB requires multiple drugs in 2 phases

While all family physicians should suspect active TB in appropriate clinical situations and be comfortable with obtaining cultures and initiating empiric treatment, most will want to seek consultation with an infectious disease (ID) specialist especially in the scenarios listed in TABLE 2.^5,22 Delayed or inappropriate treatment of active TB remains a major public health problem and cause of multidrug-resistant TB. Inappropriate treatment has been shown to be associated with a 27-fold increase in treatment failure.²³ TB treatment guidelines are available from the CDC,²⁴ World Health Organization,²⁵ and International Union Against Tuberculosis and Lung Disease.²⁶

In the initial phase of treatment for active TB, patients should begin 4 drugs—INH, RIF, EMB, and PZA—for 2 months. Appropriate treatment requires the use of multiple medications administered in 2 phases. In the initial phase, a patient with suspected TB should begin 4 drugs—usually INH, RIF, ethambutol (EMB), and pyrazinamide (PZA)—for 2 months.^1,2,27 The daily pediatric and adult doses and common adverse effects of these medications are summarized in TABLE 3.²⁸ Although most cases of TB can be adequately treated with 2 drugs to which the organism is susceptible, 4 drugs are used initially while awaiting drug sensitivity test results because of the risk of inadequately treating a strain of drug-resistant TB. Before beginning these medications, a chest x-ray, LFTs, HIV antibody test, hepatitis B and C serologies, a serum creatinine, and complete blood count should be obtained in all patients.⁵ If EMB is prescribed, the patient should also undergo testing for red-green color discrimination, because red-green color vision disturbance is a potential adverse effect of this medication.

All 4 drugs may be administered as a single daily dose, and may be taken together.²⁹ They are ordinarily given either daily for 8 weeks, or daily for 2 weeks followed by a twice-weekly schedule for the remaining 6 weeks in higher doses, although the twice-weekly dose of RIF is the same as the daily dose. All are pregnancy category C, although for active TB, the benefit of treatment is almost always greater than the potential harm.

The continuation phase of treatment starts at 8 weeks, when the results of initial cultures and drug sensitivity tests should be available to guide therapy. A second set of cultures and AFB smears is obtained at 8 weeks to document clearing of the initial infection and guide duration of the continuation phase. If the initial culture was positive for Mycobacterium tuberculosis and the organism was sensitive to both INH and RIF, these 2 drugs should be continued for another 4 months (for a total of 6 months of treatment). PZA and EMB may be stopped at 2 months if the organism is sensitive to both INH and RIF. Thus, for most patients with active TB, the standard regimen will be 4 drugs for 2 months, then 2 drugs for 4 months.²

When should the standard treatment regimen be modified?

If a patient with active TB has persistently positive cultures and cavitary disease on an initial chest x-ray, treatment should be extended to 9 months. If the second set of cultures obtained 2 months after beginning drug treatment is positive and there was cavitary disease on the initial chest x-ray, the continuation phase should be extended by 7 months (for a total of 9 months of treatment).³⁰ If a patient has either cavitary disease or persistently positive cultures (but not both), then the length of therapy is determined on an individual basis in consultation with an ID specialist.

Should a patient’s cultures show resistance to any of the first-line drugs, obtain consultation with an ID specialist. Treatment of multidrug-resistant TB (resistant to INH and RIF) and its subset, extensively drug-resistant TB (resistant to INH and RIF, plus any fluoroquinolone, plus either an aminoglycoside or capreomycin) requires prolonged courses of therapy with multiple drugs administered by DOT.^31,32

If at any point during treatment a patient shows clinical deterioration that’s believed to be due to a resurgence of his or her TB disease, obtain a new set of cultures and, in consultation with an ID specialist, add at least 2 drugs to which the patient has not been exposed. Never add only one drug to a failing regimen; active TB always requires 2 drugs to cure, and the patient may have developed resistance to all of the drugs he or she is currently receiving.

If initial cultures are negative for Mycobacterium tuberculosis but the patient responds to treatment, he or she is considered to have “culture-negative TB,” and should generally be continued on INH and RIF for 2 more months after completion of the initial treatment phase (for a total of 4 months of INH and RIF).³³

Remember to report. In the United States, active TB must be reported to your local health department, which can be invaluable in coordinating care and administering DOT.

CASE › In the hospital, Mr. J was placed in respiratory isolation, had prompt sputum cultures for TB, and was started on empiric treatment for active TB with INH, RIF, PZA, and EMB in standard doses. A search for other causes of nonresponsiveness to CAP showed no evidence of malignancy or HIV infection. He improved steadily and was discharged from the hospital after 2 weeks to complete 2 months of 4-drug therapy, with follow-up care coordinated by the local health department, including a home health nurse experienced in administering DOT. Cultures were positive for Mycobacterium tuberculosis sensitive to all drugs tested. After his initial 2 months of 4-drug therapy, he completed 4 months of additional treatment with INH and RIF, given by DOT, and recovered completely. 

CORRESPONDENCE
Jeff Hall, MD, University of South Carolina Department of Family and Preventive Medicine, 3209 Colonial Drive, Columbia, SC 29203; [email protected]

CASE  › Mitchell J, age 62, comes to see you because he’s had a cough with increasing dyspnea for a month. Mr. J has never smoked but has type 2 diabetes mellitus. He also tells you that over the past month, he’s had occasional night sweats and has lost 8 pounds, although he’s not changed his diet. During the past week, he’s noticed blood-tinged sputum. Physical examination reveals a thin, chronically ill appearing man with an oral temperature of 100.6°F and mild tachypnea. You order a complete blood count, chest x-ray, and metabolic profile, administer a tuberculin skin test (TST), and initiate levofloxacin 500 mg/d for a presumed bacterial pneumonia. His lab work reveals mild leukocytosis and hyperglycemia, and the chest x-ray shows a left upper lobe infiltrate. The TST reaction—4 mm 50 hours after placement—was negative.

Mr. J returns a week later and says he feels worse. Your examination reveals worsened tachypnea, with tachycardia and crackles over the left upper lung fields.

How would you proceed with his care?

More people die of tuberculosis (TB) each year than any other infectious disease except human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. In 2013, an estimated 9 million people worldwide developed active TB and 1.5 million died of the disease.¹ Many of these deaths could have been prevented if patients had received a diagnosis and treatment during the latent phase (when the patient was infected, but had no active disease), or as soon as the patient developed active disease. In this article we describe treatment for both latent and active TB.

Before treating latent TB infection, first rule out active TB

Patients with latent tuberculosis infection (LTBI) have a 5% to 10% lifetime risk of developing active TB disease.² Treatment of LTBI can reduce this risk to 1% to 2%.³

Assess patients with latent TB infection for signs of active TB, such as weight loss, unexplained fever, night sweats, or hemoptysis. Although not the focus of this article, diagnosis of LTBI is made by using either a TST, in which the patient receives an intradermal injection of purified protein derivative and the size of the skin induration is measured 48 to 72 hours after administration, or an interferon-gamma release assay (IGRA), which requires a blood draw. After receiving a positive test result for LTBI, the next step is to rule out active TB.⁴ This is necessary because the primary treatment regimen for LTBI involves only one drug, whereas treating active TB with one drug is strongly associated with treatment failure and future resistance to that drug.⁵

To rule out active TB, perform a brief, problem-focused history and physical, and obtain a chest x-ray.⁴ Pertinent findings that suggest active disease include:

• any history of recent weight loss, unexplained fever, night sweats, cough or hemoptysis
• fever or any unexpected lung findings on physical exam
• any parenchymal infiltrates on chest x-ray. (Granulomas and scarring may be signs of previously healed TB infection, but do not indicate active TB.)

Any of these findings should prompt a further investigation to either confirm or definitively rule out active TB disease. In the absence of these findings, the physician may proceed with treatment for LTBI.

Latent TB infection treatment: Isoniazid alone, or another regimen?

The current preferred regimen for most patients with LTBI is 9 months of isoniazid (INH) 5 mg/kg/d (10 mg/kg/d in children) up to a maximum of 300 mg/d. This regimen has been recommended by the Centers for Disease Control and Prevention (CDC), the American Thoracic Society, and the Infectious Diseases Society of America.³ However, there are 3 other CDC-recommended LTBI treatment regimens that include INH, INH plus rifapentine (RPT), or rifampin (RIF) for 6, 3, or 4 months, respectively (TABLE 1).⁶ These other regimens may be considered under certain circumstances. For example, INH and rifapentine might be used to treat an otherwise healthy patient who has had recent exposure to an individual with active, contagious TB.

If the patient is pregnant. INH is a pregnancy category C drug. Treatment for LTBI during pregnancy is generally regarded as safe and should be strongly considered if the patient has risk factors for progression to active TB, such as a recent exposure to someone with active TB.⁷ In otherwise healthy patients, treatment for LTBI may be deferred until after delivery.

Take steps to avoid complications of drug therapy

Drug-induced hepatitis is the primary adverse effect of INH treatment. Risk increases with age, previous hepatic injury, or concomitant use of other hepatotoxic medications. The risk is very small (<0.1%) for healthy children but may be over 10% for adults with multiple risk factors.⁸ Hepatitis is generally preceded by asymptomatic elevation of liver function tests (LFTs), which is much more common than clinical hepatitis.

Baseline LFTs should be obtained in patients who:

• have underlying liver disease, such as hepatitis B or C⁹
• consume ≥2 alcoholic drinks daily or >5 drinks at a time on any occasion
• take other medications with potential hepatotoxicity, such as statins
• have HIV infection¹⁰
• are pregnant or postpartum.

If a patient being considered for INH treatment has not had serologic testing for HIV, hepatitis B, or hepatitis C, these tests should be done prior to initiating INH. LFTs should be monitored every 1 to 2 months during INH therapy for patients who have ≥1 of these conditions and normal baseline LFTs. If baseline transaminases are >3 times the upper limit of normal, treatment for LTBI should probably be withheld, though might be considered in those whose LFTs return to normal after withdrawal of a modifiable risk factor, such as alcohol or a statin medication.

Patients with latent TB infection who are receiving isoniazid should be monitored regularly for signs and symptoms of hepatitis. After beginning LTBI treatment, patients should be monitored regularly for signs and symptoms of hepatitis, including anorexia, nausea, abdominal pain, icterus, and dark urine, and LFTs performed if these develop. If during treatment transaminases increase to >3 times normal in a symptomatic patient (or >5 times normal in an asymptomatic patient), INH should be stopped and generally not resumed, even after LFTs return to normal. (Such patients would be considered to have partially treated LTBI, and their physicians should be alert to signs and symptoms of active TB, such as unexplained fever, weight loss, or blood-tinged sputum, during subsequent patient encounters.)

Peripheral neuropathy is a less common adverse effect of INH. It occurs in up to 2% of patients and is caused by interference with vitamin B6 (pyridoxine) metabolism. It can be prevented by supplementation with pyridoxine 25 to 50 mg/d. Vitamin B6, however, does not prevent INH-induced hepatotoxicity.

Noncompliance is a concern with INH therapy because treatment typically requires a 9-month course of daily medication.¹¹ Patients for whom compliance is likely to be an issue might be considered for a 3-month, 12-dose course of once-weekly, directly-observed therapy (DOT) with INH and RPT administered by a public health agency. (See “Which patients with TB should receive directly observed therapy?” on page 32.^12-14) A randomized, open-label trial involving nearly 8000 patients in 4 low-risk countries found this regimen was as effective as 9 months of self-administered INH.¹⁵ The CDC has published recommendations for using this regimen.¹⁶

Suspect active TB? Don’t wait for cultures to begin Tx

Unlike LTBI, for which the results of diagnostic testing are available within a few days, active TB is diagnosed by culture, which may take as long as 6 to 8 weeks. Don’t wait to receive culture results to initiate treatment in a patient you suspect may have active TB. However, if you suspect your patient has active TB, do not delay treatment while waiting for culture results, or defer treatment for a patient who has a negative acid-fast bacilli (AFB) smear or rapid nucleic acid amplification test.¹⁷ These 2 tests, which are routinely performed during TB cultures, look for other evidence of the presence of TB bacilli; they are not as accurate as cultures, but results are available within days. Likewise, a negative TST or IGRA should not prevent empiric treatment for active TB. Treatment for active TB should be begun empirically based on risk factors and clinical presentation, and can be modified or stopped if cultures are negative, the patient fails to improve, or an alternative diagnosis is found to explain the patient’s symptoms.

Rapid testing for evidence of active TB disease—as well as resistance to medications commonly used to treat TB—can be performed using newer modalities such as MODS (Microscopic-Observation Drug-Susceptibility)^18,19 or Xpert MTB/RIF²⁰ testing. However, these tests are not available in many hospitals, and culture and drug sensitivity testing remain the gold standard.²¹

CASE › Mr. J’s clinical history and chest x-ray findings are highly suggestive of active TB. It was not unreasonable to initially treat him for a bacterial pneumonia, although fluoroquinolones should be used cautiously in this setting, because they are one of the most effective second-line drugs for TB, and using them as a single agent will often invoke drug resistance. Because he failed to respond to treatment for bacterial pneumonia and his presentation suggests TB or another serious cause of nonresponsiveness to standard treatment for community-acquired pneumonia (CAP), you admit him to the hospital.

Treatment for active TB requires multiple drugs in 2 phases

While all family physicians should suspect active TB in appropriate clinical situations and be comfortable with obtaining cultures and initiating empiric treatment, most will want to seek consultation with an infectious disease (ID) specialist especially in the scenarios listed in TABLE 2.^5,22 Delayed or inappropriate treatment of active TB remains a major public health problem and cause of multidrug-resistant TB. Inappropriate treatment has been shown to be associated with a 27-fold increase in treatment failure.²³ TB treatment guidelines are available from the CDC,²⁴ World Health Organization,²⁵ and International Union Against Tuberculosis and Lung Disease.²⁶

In the initial phase of treatment for active TB, patients should begin 4 drugs—INH, RIF, EMB, and PZA—for 2 months. Appropriate treatment requires the use of multiple medications administered in 2 phases. In the initial phase, a patient with suspected TB should begin 4 drugs—usually INH, RIF, ethambutol (EMB), and pyrazinamide (PZA)—for 2 months.^1,2,27 The daily pediatric and adult doses and common adverse effects of these medications are summarized in TABLE 3.²⁸ Although most cases of TB can be adequately treated with 2 drugs to which the organism is susceptible, 4 drugs are used initially while awaiting drug sensitivity test results because of the risk of inadequately treating a strain of drug-resistant TB. Before beginning these medications, a chest x-ray, LFTs, HIV antibody test, hepatitis B and C serologies, a serum creatinine, and complete blood count should be obtained in all patients.⁵ If EMB is prescribed, the patient should also undergo testing for red-green color discrimination, because red-green color vision disturbance is a potential adverse effect of this medication.

All 4 drugs may be administered as a single daily dose, and may be taken together.²⁹ They are ordinarily given either daily for 8 weeks, or daily for 2 weeks followed by a twice-weekly schedule for the remaining 6 weeks in higher doses, although the twice-weekly dose of RIF is the same as the daily dose. All are pregnancy category C, although for active TB, the benefit of treatment is almost always greater than the potential harm.

The continuation phase of treatment starts at 8 weeks, when the results of initial cultures and drug sensitivity tests should be available to guide therapy. A second set of cultures and AFB smears is obtained at 8 weeks to document clearing of the initial infection and guide duration of the continuation phase. If the initial culture was positive for Mycobacterium tuberculosis and the organism was sensitive to both INH and RIF, these 2 drugs should be continued for another 4 months (for a total of 6 months of treatment). PZA and EMB may be stopped at 2 months if the organism is sensitive to both INH and RIF. Thus, for most patients with active TB, the standard regimen will be 4 drugs for 2 months, then 2 drugs for 4 months.²

When should the standard treatment regimen be modified?

If a patient with active TB has persistently positive cultures and cavitary disease on an initial chest x-ray, treatment should be extended to 9 months. If the second set of cultures obtained 2 months after beginning drug treatment is positive and there was cavitary disease on the initial chest x-ray, the continuation phase should be extended by 7 months (for a total of 9 months of treatment).³⁰ If a patient has either cavitary disease or persistently positive cultures (but not both), then the length of therapy is determined on an individual basis in consultation with an ID specialist.

Should a patient’s cultures show resistance to any of the first-line drugs, obtain consultation with an ID specialist. Treatment of multidrug-resistant TB (resistant to INH and RIF) and its subset, extensively drug-resistant TB (resistant to INH and RIF, plus any fluoroquinolone, plus either an aminoglycoside or capreomycin) requires prolonged courses of therapy with multiple drugs administered by DOT.^31,32

If at any point during treatment a patient shows clinical deterioration that’s believed to be due to a resurgence of his or her TB disease, obtain a new set of cultures and, in consultation with an ID specialist, add at least 2 drugs to which the patient has not been exposed. Never add only one drug to a failing regimen; active TB always requires 2 drugs to cure, and the patient may have developed resistance to all of the drugs he or she is currently receiving.

If initial cultures are negative for Mycobacterium tuberculosis but the patient responds to treatment, he or she is considered to have “culture-negative TB,” and should generally be continued on INH and RIF for 2 more months after completion of the initial treatment phase (for a total of 4 months of INH and RIF).³³

Remember to report. In the United States, active TB must be reported to your local health department, which can be invaluable in coordinating care and administering DOT.

CASE › In the hospital, Mr. J was placed in respiratory isolation, had prompt sputum cultures for TB, and was started on empiric treatment for active TB with INH, RIF, PZA, and EMB in standard doses. A search for other causes of nonresponsiveness to CAP showed no evidence of malignancy or HIV infection. He improved steadily and was discharged from the hospital after 2 weeks to complete 2 months of 4-drug therapy, with follow-up care coordinated by the local health department, including a home health nurse experienced in administering DOT. Cultures were positive for Mycobacterium tuberculosis sensitive to all drugs tested. After his initial 2 months of 4-drug therapy, he completed 4 months of additional treatment with INH and RIF, given by DOT, and recovered completely. 

CORRESPONDENCE
Jeff Hall, MD, University of South Carolina Department of Family and Preventive Medicine, 3209 Colonial Drive, Columbia, SC 29203; [email protected]

CASE  › Mitchell J, age 62, comes to see you because he’s had a cough with increasing dyspnea for a month. Mr. J has never smoked but has type 2 diabetes mellitus. He also tells you that over the past month, he’s had occasional night sweats and has lost 8 pounds, although he’s not changed his diet. During the past week, he’s noticed blood-tinged sputum. Physical examination reveals a thin, chronically ill appearing man with an oral temperature of 100.6°F and mild tachypnea. You order a complete blood count, chest x-ray, and metabolic profile, administer a tuberculin skin test (TST), and initiate levofloxacin 500 mg/d for a presumed bacterial pneumonia. His lab work reveals mild leukocytosis and hyperglycemia, and the chest x-ray shows a left upper lobe infiltrate. The TST reaction—4 mm 50 hours after placement—was negative.

Mr. J returns a week later and says he feels worse. Your examination reveals worsened tachypnea, with tachycardia and crackles over the left upper lung fields.

How would you proceed with his care?

More people die of tuberculosis (TB) each year than any other infectious disease except human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. In 2013, an estimated 9 million people worldwide developed active TB and 1.5 million died of the disease.¹ Many of these deaths could have been prevented if patients had received a diagnosis and treatment during the latent phase (when the patient was infected, but had no active disease), or as soon as the patient developed active disease. In this article we describe treatment for both latent and active TB.

Before treating latent TB infection, first rule out active TB

Patients with latent tuberculosis infection (LTBI) have a 5% to 10% lifetime risk of developing active TB disease.² Treatment of LTBI can reduce this risk to 1% to 2%.³

Assess patients with latent TB infection for signs of active TB, such as weight loss, unexplained fever, night sweats, or hemoptysis. Although not the focus of this article, diagnosis of LTBI is made by using either a TST, in which the patient receives an intradermal injection of purified protein derivative and the size of the skin induration is measured 48 to 72 hours after administration, or an interferon-gamma release assay (IGRA), which requires a blood draw. After receiving a positive test result for LTBI, the next step is to rule out active TB.⁴ This is necessary because the primary treatment regimen for LTBI involves only one drug, whereas treating active TB with one drug is strongly associated with treatment failure and future resistance to that drug.⁵

To rule out active TB, perform a brief, problem-focused history and physical, and obtain a chest x-ray.⁴ Pertinent findings that suggest active disease include:

• any history of recent weight loss, unexplained fever, night sweats, cough or hemoptysis
• fever or any unexpected lung findings on physical exam
• any parenchymal infiltrates on chest x-ray. (Granulomas and scarring may be signs of previously healed TB infection, but do not indicate active TB.)

Any of these findings should prompt a further investigation to either confirm or definitively rule out active TB disease. In the absence of these findings, the physician may proceed with treatment for LTBI.

Latent TB infection treatment: Isoniazid alone, or another regimen?

The current preferred regimen for most patients with LTBI is 9 months of isoniazid (INH) 5 mg/kg/d (10 mg/kg/d in children) up to a maximum of 300 mg/d. This regimen has been recommended by the Centers for Disease Control and Prevention (CDC), the American Thoracic Society, and the Infectious Diseases Society of America.³ However, there are 3 other CDC-recommended LTBI treatment regimens that include INH, INH plus rifapentine (RPT), or rifampin (RIF) for 6, 3, or 4 months, respectively (TABLE 1).⁶ These other regimens may be considered under certain circumstances. For example, INH and rifapentine might be used to treat an otherwise healthy patient who has had recent exposure to an individual with active, contagious TB.

If the patient is pregnant. INH is a pregnancy category C drug. Treatment for LTBI during pregnancy is generally regarded as safe and should be strongly considered if the patient has risk factors for progression to active TB, such as a recent exposure to someone with active TB.⁷ In otherwise healthy patients, treatment for LTBI may be deferred until after delivery.

Take steps to avoid complications of drug therapy

Drug-induced hepatitis is the primary adverse effect of INH treatment. Risk increases with age, previous hepatic injury, or concomitant use of other hepatotoxic medications. The risk is very small (<0.1%) for healthy children but may be over 10% for adults with multiple risk factors.⁸ Hepatitis is generally preceded by asymptomatic elevation of liver function tests (LFTs), which is much more common than clinical hepatitis.

Baseline LFTs should be obtained in patients who:

• have underlying liver disease, such as hepatitis B or C⁹
• consume ≥2 alcoholic drinks daily or >5 drinks at a time on any occasion
• take other medications with potential hepatotoxicity, such as statins
• have HIV infection¹⁰
• are pregnant or postpartum.

If a patient being considered for INH treatment has not had serologic testing for HIV, hepatitis B, or hepatitis C, these tests should be done prior to initiating INH. LFTs should be monitored every 1 to 2 months during INH therapy for patients who have ≥1 of these conditions and normal baseline LFTs. If baseline transaminases are >3 times the upper limit of normal, treatment for LTBI should probably be withheld, though might be considered in those whose LFTs return to normal after withdrawal of a modifiable risk factor, such as alcohol or a statin medication.

Patients with latent TB infection who are receiving isoniazid should be monitored regularly for signs and symptoms of hepatitis. After beginning LTBI treatment, patients should be monitored regularly for signs and symptoms of hepatitis, including anorexia, nausea, abdominal pain, icterus, and dark urine, and LFTs performed if these develop. If during treatment transaminases increase to >3 times normal in a symptomatic patient (or >5 times normal in an asymptomatic patient), INH should be stopped and generally not resumed, even after LFTs return to normal. (Such patients would be considered to have partially treated LTBI, and their physicians should be alert to signs and symptoms of active TB, such as unexplained fever, weight loss, or blood-tinged sputum, during subsequent patient encounters.)

Peripheral neuropathy is a less common adverse effect of INH. It occurs in up to 2% of patients and is caused by interference with vitamin B6 (pyridoxine) metabolism. It can be prevented by supplementation with pyridoxine 25 to 50 mg/d. Vitamin B6, however, does not prevent INH-induced hepatotoxicity.

Noncompliance is a concern with INH therapy because treatment typically requires a 9-month course of daily medication.¹¹ Patients for whom compliance is likely to be an issue might be considered for a 3-month, 12-dose course of once-weekly, directly-observed therapy (DOT) with INH and RPT administered by a public health agency. (See “Which patients with TB should receive directly observed therapy?” on page 32.^12-14) A randomized, open-label trial involving nearly 8000 patients in 4 low-risk countries found this regimen was as effective as 9 months of self-administered INH.¹⁵ The CDC has published recommendations for using this regimen.¹⁶

Suspect active TB? Don’t wait for cultures to begin Tx

Unlike LTBI, for which the results of diagnostic testing are available within a few days, active TB is diagnosed by culture, which may take as long as 6 to 8 weeks. Don’t wait to receive culture results to initiate treatment in a patient you suspect may have active TB. However, if you suspect your patient has active TB, do not delay treatment while waiting for culture results, or defer treatment for a patient who has a negative acid-fast bacilli (AFB) smear or rapid nucleic acid amplification test.¹⁷ These 2 tests, which are routinely performed during TB cultures, look for other evidence of the presence of TB bacilli; they are not as accurate as cultures, but results are available within days. Likewise, a negative TST or IGRA should not prevent empiric treatment for active TB. Treatment for active TB should be begun empirically based on risk factors and clinical presentation, and can be modified or stopped if cultures are negative, the patient fails to improve, or an alternative diagnosis is found to explain the patient’s symptoms.

Rapid testing for evidence of active TB disease—as well as resistance to medications commonly used to treat TB—can be performed using newer modalities such as MODS (Microscopic-Observation Drug-Susceptibility)^18,19 or Xpert MTB/RIF²⁰ testing. However, these tests are not available in many hospitals, and culture and drug sensitivity testing remain the gold standard.²¹

CASE › Mr. J’s clinical history and chest x-ray findings are highly suggestive of active TB. It was not unreasonable to initially treat him for a bacterial pneumonia, although fluoroquinolones should be used cautiously in this setting, because they are one of the most effective second-line drugs for TB, and using them as a single agent will often invoke drug resistance. Because he failed to respond to treatment for bacterial pneumonia and his presentation suggests TB or another serious cause of nonresponsiveness to standard treatment for community-acquired pneumonia (CAP), you admit him to the hospital.

Treatment for active TB requires multiple drugs in 2 phases

While all family physicians should suspect active TB in appropriate clinical situations and be comfortable with obtaining cultures and initiating empiric treatment, most will want to seek consultation with an infectious disease (ID) specialist especially in the scenarios listed in TABLE 2.^5,22 Delayed or inappropriate treatment of active TB remains a major public health problem and cause of multidrug-resistant TB. Inappropriate treatment has been shown to be associated with a 27-fold increase in treatment failure.²³ TB treatment guidelines are available from the CDC,²⁴ World Health Organization,²⁵ and International Union Against Tuberculosis and Lung Disease.²⁶

In the initial phase of treatment for active TB, patients should begin 4 drugs—INH, RIF, EMB, and PZA—for 2 months. Appropriate treatment requires the use of multiple medications administered in 2 phases. In the initial phase, a patient with suspected TB should begin 4 drugs—usually INH, RIF, ethambutol (EMB), and pyrazinamide (PZA)—for 2 months.^1,2,27 The daily pediatric and adult doses and common adverse effects of these medications are summarized in TABLE 3.²⁸ Although most cases of TB can be adequately treated with 2 drugs to which the organism is susceptible, 4 drugs are used initially while awaiting drug sensitivity test results because of the risk of inadequately treating a strain of drug-resistant TB. Before beginning these medications, a chest x-ray, LFTs, HIV antibody test, hepatitis B and C serologies, a serum creatinine, and complete blood count should be obtained in all patients.⁵ If EMB is prescribed, the patient should also undergo testing for red-green color discrimination, because red-green color vision disturbance is a potential adverse effect of this medication.

All 4 drugs may be administered as a single daily dose, and may be taken together.²⁹ They are ordinarily given either daily for 8 weeks, or daily for 2 weeks followed by a twice-weekly schedule for the remaining 6 weeks in higher doses, although the twice-weekly dose of RIF is the same as the daily dose. All are pregnancy category C, although for active TB, the benefit of treatment is almost always greater than the potential harm.

The continuation phase of treatment starts at 8 weeks, when the results of initial cultures and drug sensitivity tests should be available to guide therapy. A second set of cultures and AFB smears is obtained at 8 weeks to document clearing of the initial infection and guide duration of the continuation phase. If the initial culture was positive for Mycobacterium tuberculosis and the organism was sensitive to both INH and RIF, these 2 drugs should be continued for another 4 months (for a total of 6 months of treatment). PZA and EMB may be stopped at 2 months if the organism is sensitive to both INH and RIF. Thus, for most patients with active TB, the standard regimen will be 4 drugs for 2 months, then 2 drugs for 4 months.²

When should the standard treatment regimen be modified?

If a patient with active TB has persistently positive cultures and cavitary disease on an initial chest x-ray, treatment should be extended to 9 months. If the second set of cultures obtained 2 months after beginning drug treatment is positive and there was cavitary disease on the initial chest x-ray, the continuation phase should be extended by 7 months (for a total of 9 months of treatment).³⁰ If a patient has either cavitary disease or persistently positive cultures (but not both), then the length of therapy is determined on an individual basis in consultation with an ID specialist.

Should a patient’s cultures show resistance to any of the first-line drugs, obtain consultation with an ID specialist. Treatment of multidrug-resistant TB (resistant to INH and RIF) and its subset, extensively drug-resistant TB (resistant to INH and RIF, plus any fluoroquinolone, plus either an aminoglycoside or capreomycin) requires prolonged courses of therapy with multiple drugs administered by DOT.^31,32

If at any point during treatment a patient shows clinical deterioration that’s believed to be due to a resurgence of his or her TB disease, obtain a new set of cultures and, in consultation with an ID specialist, add at least 2 drugs to which the patient has not been exposed. Never add only one drug to a failing regimen; active TB always requires 2 drugs to cure, and the patient may have developed resistance to all of the drugs he or she is currently receiving.

If initial cultures are negative for Mycobacterium tuberculosis but the patient responds to treatment, he or she is considered to have “culture-negative TB,” and should generally be continued on INH and RIF for 2 more months after completion of the initial treatment phase (for a total of 4 months of INH and RIF).³³

Remember to report. In the United States, active TB must be reported to your local health department, which can be invaluable in coordinating care and administering DOT.

CASE › In the hospital, Mr. J was placed in respiratory isolation, had prompt sputum cultures for TB, and was started on empiric treatment for active TB with INH, RIF, PZA, and EMB in standard doses. A search for other causes of nonresponsiveness to CAP showed no evidence of malignancy or HIV infection. He improved steadily and was discharged from the hospital after 2 weeks to complete 2 months of 4-drug therapy, with follow-up care coordinated by the local health department, including a home health nurse experienced in administering DOT. Cultures were positive for Mycobacterium tuberculosis sensitive to all drugs tested. After his initial 2 months of 4-drug therapy, he completed 4 months of additional treatment with INH and RIF, given by DOT, and recovered completely. 

CORRESPONDENCE
Jeff Hall, MD, University of South Carolina Department of Family and Preventive Medicine, 3209 Colonial Drive, Columbia, SC 29203; [email protected]