Lesson 20, Volume 15—A Current Approach to the Diagnosis and Treatment of Latent Tuberculosis Infection

By Robert M. Jasmer, MD

Objectives

1. List the main risk factors for developing tuberculosis once a person is infected with Mycobacterium tuberculosis.
2. Describe how to evaluate a person with a positive tuberculin skin test for active tuberculosis.
3. Identify the two main options for treatment of latent tuberculosis infection (LTBI).
4. Explain how to treat LTBI in HIV-infected patients.
5. Describe how patients being treated for LTBI should be monitored.

Key words

HIV infection; isoniazid; latent tuberculosis infection; pyrazinamide; rifampin; tuberculosis infection

Abbreviations

BCG = bacille Calmette-Guérin; LTBI = latent tuberculosis infection

Tuberculosis remains the leading cause of mortality from a single infectious agent throughout the world.¹ Approximately 1.7 billion persons, one third of the world's population, are infected with Mycobacterium tuberculosis.² Unlike diseases caused by many other infectious agents, disease due to M tuberculosis often occurs only after a variable but often long latent period. Although tuberculosis cases in the United States are again decreasing, the previous decade of increased case rates has created a large reservoir of infected persons who represent the potential cases of the future. The focus of tuberculosis control efforts in the next decade will therefore be on the identification of persons at increased risk for the development of tuberculosis and on the treatment of latent tuberculosis infection (LTBI) to prevent new cases from occurring. Treatment of LTBI is now the preferred terminology and has replaced "preventive therapy" and "prophylaxis"; it refers to the treatment of persons already infected with M tuberculosis in order to prevent active tuberculosis from developing.

In this review, current recommendations will be reviewed, including a discussion of which persons should be tested, how testing is conducted and interpreted, and the use of isoniazid and alternative approaches to the treatment of LTBI.

Current Diagnosis of Tuberculosis Infection

Persons Who Should Be Screened by Tuberculin Testing

The essential principle underlying the entire topic of LTBI is that the overall goal is to identify persons who, because they are at high risk for tuberculosis, would benefit by treatment of LTBI. Following that principle, tuberculin skin testing should be targeted to persons in groups at highest risk for recent infection with M tuberculosis and those who are at increased risk for progression to active tuberculosis. Therefore, testing for tuberculosis infection in low-risk persons should not be conducted because the benefit of treatment is quite small and because many in the low-risk group who test positive by the tuberculin test may have false-positive tests. Another way to think about this key principle of LTBI is that a decision to test is, in essence, a decision to treat, because only those who would benefit from treatment should be tested for LTBI.

Given these goals, persons who should be screened include those at increased risk of exposure to active tuberculosis cases, members of populations with a high prevalence of tuberculosis infection, and those who have medical conditions associated with an increased risk of developing tuberculosis once infected. These recommendations are summarized in Table 1.

Examples of persons at increased risk of exposure to active tuberculosis cases include those who have recently had close contact with such cases, especially at a time when case patients are infectious, and health-care workers. Persons or populations having a high prevalence of tuberculosis include, for example, those born in countries with a high prevalence of tuberculosis, homeless persons, and those living or working in nursing homes. Persons with an abnormal chest radiograph consistent with tuberculosis and/or symptoms such as hemoptysis or weight loss would also be included in this category.

A variety of medical conditions increase the risk of the development of active tuberculosis for any given prevalence of tuberculosis infection. The strongest risk factor yet identified is HIV infection.^3,4 Tuberculosis in persons with HIV infection can result from reactivation of long-standing LTBI or recent infection followed by rapid progression to clinical disease.^5,6 Other medical conditions that increase the risk of tuberculosis once infected include end-stage renal disease, injection drug use, insulin-requiring diabetes, malignancies such as Hodgkin's disease, and diseases that are treated with immunosuppressive medications such as corticosteroids. The underlying reason that all of these conditions predispose to the development of tuberculosis is likely related to their effects on cell-mediated immunity.

Administration and Reading of the Tuberculin Skin Test

The only proven method to diagnose LTBI is the tuberculin skin test. Other tests, such as the tine test, should not be used. The tuberculin skin test is based on the observation that infection with M tuberculosis leads to sensitivity to antigens contained in culture filtrate extracts called tuberculins. The reaction to intracutaneously injected tuberculin is a classic example of a delayed-type hypersensitivity reaction. This type of reaction is characterized by a peak reaction at 48 to 72 h marked by induration and, rarely, vesiculation and necrosis. Sensitization is induced by infection with M tuberculosis or other cross-reacting mycobacteria. In some individuals, the peak reaction is delayed and may not occur until > 72 h after the test is performed. The tuberculin skin test should be read by trained readers 48 to 72 h after injection. The basis of the reading is the degree of induration present, not erythema.

Over time, delayed-type hypersensitivity resulting from mycobacterial infection may wane in some individuals, resulting in a nonreactive tuberculin skin test despite the fact that they are truly infected. However, the stimulus of this initial negative tuberculin test in these persons may "boost" or increase the size of the reaction to a second test administered later, resulting in a positive tuberculin test and incorrectly suggesting tuberculin conversion. This ability of the tuberculin test to recall the waned reactivity is known as the booster phenomenon.^7,8

Because of the difficulty in distinguishing boosting (indicating prior infection many years ago) from tuberculin conversion (indicating recent infection), it is recommended that persons who will undergo annual tuberculin skin testing and persons > 55 years old receive two-step testing. To perform two-step testing, the first tuberculin test is placed and the test read at 48 to 72 h. If the test is negative, a second test is placed, usually 1 week later, and again read 48 to 72 h later. If the second test is also negative, then the person is considered to be tuberculin skin test–negative. If the second test is positive, it is interpreted as a boosted response indicative of prior infection with M tuberculosis. Only the initial evaluation requires two-step testing, and subsequent testing that is conducted can be accomplished with the standard single-step method.

Because the tuberculin skin test is not 100% specific for the diagnosis of infection with M tuberculosis, false-positive tests can occur from either infection with nontuberculous mycobacteria or bacille Calmette-Guérin (BCG) vaccination. With respect to BCG vaccination, it can be difficult to distinguish between a tuberculin test reaction that is caused by LTBI and one due to prior BCG vaccination. The likelihood that a positive skin test reaction is due to M tuberculosis rather than BCG increases (1) as the size of the reaction increases, (2) when the patient is a close contact of a person with tuberculosis, (3) when the patient's country of origin has a high prevalence of tuberculosis, and (4) as the time between vaccination and tuberculin testing increases.⁹ In practice, most clinicians ignore prior BCG vaccination when interpreting the results of tuberculin skin tests, if it has been at least several years since the time of vaccination.

Interpretation of the Results of the Tuberculin Skin Test

Given these concerns about false-positive tuberculin tests, the current guidelines endorsed by the American Thoracic Society and Centers for Disease Control and Prevention¹⁰ are intended to increase the likelihood that persons at high risk for tuberculosis will be candidates for treatment of LTBI and that persons whose tuberculin reactions are not due to M tuberculosis will not receive unnecessary treatment. Thus, the appropriate criterion for defining a positive skin test reaction depends not only on the likelihood of tuberculosis infection, but also on the risk of developing tuberculosis if infection has occurred.

The interpretation of the tuberculin skin test requires an assessment of the probability that tuberculosis infection is present so that a definition of a significant reaction can be adjusted depending on the clinical circumstances. From a practical standpoint, this means that the least restrictive criteria should be applied to diagnose LTBI among persons at highest risk for having tuberculosis infection, eg, a close contact of an infectious case. On the other hand, the most restrictive criteria should be applied to diagnose tuberculosis infection in a person who is at low risk, for example, a US-born suburban office worker without known contacts.

Based on these considerations, three different thresholds (5, 10, and 15 mm) have been set for defining a positive tuberculin reaction, depending on the individual or population being tested (Table 2). For persons at highest risk of developing tuberculosis, a cutoff of > 5 mm is recommended. This group includes persons known or suspected to be HIV-infected, close contacts of active tuberculosis cases, persons with an abnormal chest radiograph showing fibrosis consistent with prior tuberculosis, and immunosuppressed patients who are receiving the equivalent of at least 15 mg/d of prednisone for > 1 month. A cutoff of > 10 mm is classified as positive for individuals at intermediate risk for tuberculosis. Examples of such individuals include persons with medical conditions known to increase the risk of progressing from latent to active tuberculosis, persons from countries with a high prevalence of tuberculosis, and residents and employees of prisons, nursing homes, and homeless shelters. The remaining group consists of persons at low risk for tuberculosis who have none of the risk factors listed in Table 1. These persons are classified as positive if the tuberculin reaction is > 15 mm. As mentioned previously, it is not recommended that these persons be screened in the first place.

Recent tuberculin skin test converters are also at high risk of tuberculosis and have therefore been identified as a high-priority group for treatment of LTBI. Conversion is defined as an increase in induration of at least 10 mm within a 2-year period.

Among persons having any of the conditions listed in Table 2, treatment of LTBI is recommended regardless of age. An important caveat is that not all persons in a given population group (eg, health-care workers) who have LTBI need to be treated unless they have been infected recently, as demonstrated by tuberculin test conversion, or local epidemiologic circumstances dictate that they are in a group at high risk for the development of tuberculosis. Prior to beginning treatment of LTBI, it is essential that active tuberculosis be excluded by a chest radiograph and symptom review in all persons who have a positive tuberculin skin test (Fig 1). If either the chest radiograph or symptoms are consistent with active tuberculosis, the clinician should evaluate sputum for the presence of acid-fast bacilli and withhold treatment for LTBI until active disease has been ruled out. Treatment of LTBI should be administered only after the cultures are negative and tuberculosis is no longer clinically suspected. Full treatment for presumptive tuberculosis can be initiated pending cultures, of course, if the clinical suspicion for active tuberculosis is high.

Figure 1. Tuberculosis screening flowchart. *See Table 1. †Treatment of LTBI may be indicated for close contacts to infectious cases, even if the initial tuberculin skin test is negative.

Current Treatment of Tuberculosis Infection

Isoniazid

The first option for treatment of LTBI is isoniazid given in a single daily dose of 300 mg/d for adults and 10 mg/kg/d (up to a maximum of 300 mg/d) in children and adolescents. Current guidelines recommend that treatment last at least 6 months and preferably 9 months in adults (Table 3). a 9-month course of isoniazid is currently recommended because prospective randomized trials of up to 12 months in HIV-uninfected persons suggest that the maximal benefit of isoniazid is achieved by 9 months.¹¹ For persons whose adherence to treatment is poor, directly observed preventive therapy is an alternative approach that can be accomplished by either daily directly observed isoniazid therapy at 300 mg/d or twice-weekly isoniazid given at 15 mg/kg/d (maximum twice-weekly dose of 900 mg).

Completion of treatment is based on the total number of doses administered and not on duration of therapy alone. This means that the 9-month isoniazid regimen should consist of 270 doses taken within 12 months, allowing for short interruptions in treatment. The 6-month regimen should consist of 180 doses taken within 9 months.

The most important side effect of isoniazid is hepatitis. Although liver function abnormalities are relatively common in persons taking isoniazid,^12,13 symptomatic hepatitis is uncommon. In fact, a recent study has estimated the rate of isoniazid-related hepatitis to be 1 per 1,000 persons.¹⁴ The most important cofactor for the development of isoniazid hepatitis is alcohol consumption, so it is important to advise patients not to drink alcohol when they are taking isoniazid. In addition, all persons taking isoniazid should be educated about the symptoms of hepatitis, including nausea, vomiting, extreme fatigue, abdominal pain, dark urine, and jaundice so that they can be evaluated before the hepatitis becomes severe.

The other potential side effect of isoniazid is peripheral neuropathy, which is caused by interference with the metabolism of pyridoxine. In persons predisposed to neuropathy (such as patients with diabetes, uremia, malnutrition, and HIV infection), pregnant women, and persons with seizure disorders, pyridoxine (at a dose of 25 or 50 mg/d) should be given with isoniazid.

Rifampin

A 4-month course of rifampin alone is the second option for treatment of LTBI (Table 3), although this should clearly be the option of last resort. This is the regimen that has been the least studied, and in the only study evaluating its use, 10% of the patients taking rifampin alone for 3 months still developed active tuberculosis later. In addition, the use of rifampin alone for LTBI in a patient with undiagnosed active tuberculosis could lead to rifampin-resistant tuberculosis, which is very difficult to treat. This is clearly the least attractive option; the use of rifampin should be reserved for persons who cannot tolerate isoniazid or pyrazinamide.

Rifampin and Pyrazinamide

The third major option to treat LTBI is rifampin and pyrazinamide for 2 months (Table 3). These drugs have been as effective and safe as isoniazid when studied in HIV-infected persons with LTBI.^15-17 However, there is relatively little experience using a regimen of rifampin and pyrazinamide for treating tuberculosis infection in persons without HIV infection, and case reports of severe hepatitis with 5 deaths have raised concerns about the safety of the regimen.¹⁸ Because of the potential for hepatotoxicity with rifampin and pyrazinamide, patients need to be monitored closely and given no more than a 2-week supply of medications. For rifampin and pyrazinamide, completion of treatment is defined as taking 60 doses within 3 months. Rifampin and pyrazinamide are not currently recommended for treatment of LTBI in pregnant women or children. In terms of side effects, rifampin can cause hepatitis, rash, thrombocytopenia, and flulike symptoms. Because rifampin induces hepatic microsomal enzymes, it can accelerate the metabolism of many drugs including coumadin, digitalis, and oral contraceptives, to name a few. This often necessitates dosage increases of these medications to maintain their effect. Pyrazinamide can also cause hepatitis, GI upset, rash, and arthralgias.

Clinical Monitoring

Regular monitoring of persons given isoniazid for treatment of LTBI is an important aspect of their care. Prior to treatment for LTBI, it is critical that patients be educated about potential side effects. Education should concentrate on the symptoms of hepatitis so that patients will stop their medication immediately and return promptly for medical evaluation in the event these symptoms occur. Persons being treated for LTBI should be systematically questioned at least monthly regarding the presence or absence of symptoms such as nausea, vomiting, abdominal pain, anorexia, dark urine, jaundice, arthralgia, and paresthesias of the hands and feet. Persons having any symptoms of hepatitis should undergo laboratory testing with measurement of serum aspartate transaminase, alanine transaminase, bilirubin, and alkaline phosphatase to confirm whether biochemical evidence of hepatitis is present. It is recommended that clinical monitoring be performed at least monthly for isoniazid and at weeks 2, 4, and 8 for those taking rifampin and pyrazinamide. Regular follow-up also provides an opportunity to reinforce the benefits of treatment and adherence to the drug regimen.

Baseline laboratory testing of liver function is not routinely indicated, except in the following cases: HIV-infected persons; pregnant woman and those within 3 months postpartum; persons with a history of liver disease; and persons who use alcohol regularly. In addition, all persons who are treated with rifampin and pyrazinamide should have baseline testing of liver function and follow-up testing at 2, 4, and 6 weeks to assess for hepatotoxicity.¹⁸ Follow-up laboratory testing of liver function is indicated only if baseline liver function tests are abnormal or when symptoms of hepatitis occur. Providers commonly withhold medications if a patient's serum transaminase level is > 3 times normal if associated with symptoms and 5 times normal if asymptomatic. The doses of medications used for LTBI, their toxicities, and monitoring recommendations are summarized in Table 4.

Coinfection With HIV

HIV-infected persons are clearly at highest risk for developing active tuberculosis once infected. Therefore, all HIV-infected persons should be screened for tuberculosis and LTBI.¹⁹ In those with LTBI who also have HIV infection, isoniazid should be given for 9 months. With respect to rifampin and pyrazinamide, it is important to note that rifampin should be used with great caution in HIV-infected persons taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. This is because of a drug interaction in which rifampin induces the metabolism of the anti-HIV drugs. In HIV-infected persons who are taking these antiretroviral drugs and have LTBI, rifabutin (often at an adjusted dose) can be substituted for rifampin in some circumstances. As antiretroviral agents and more pharmacokinetic data become available, these recommendations may be modified. Thus, expert consultation is advisable in such cases.

Other Special Circumstances

In patients who have positive tuberculin tests and abnormal chest radiographs with parenchymal fibrotic lesions and have not been treated previously, sputum should be collected to exclude active tuberculosis. Once active tuberculosis has been excluded, treatment options for LTBI include isoniazid for 9 months, rifampin with or without isoniazid for 4 months, or rifampin and pyrazinamide for 2 months. Although isoniazid can be given safely during pregnancy, most clinicians wait until after delivery to begin treatment for LTBI, unless the woman has HIV infection or has been in known contact with an infectious case. Infants and children < 5 years are at high risk for progression to active tuberculosis once infected and should receive isoniazid for 9 months. Contacts of patients with isoniazid-resistant, rifampin-susceptible tuberculosis should be treated with rifampin and pyrazinamide for 2 months. The treatment of contacts of multidrug-resistant tuberculosis cases is challenging, however, and needs to be individualized.

Conclusion

In summary, the goal of testing for LTBI is to identify those individuals who would most benefit from treatment of LTBI. They consist of those who either (1) are at risk for having recently acquired infection, or (2) have a condition that increases the risk of progression to active tuberculosis once they are infected. These at-risk individuals should undergo an evaluation to exclude active tuberculosis, which usually consists of a chest radiograph and symptom review. After active disease has been excluded, several treatment options exist. These include isoniazid for 9 months (although 6 months is an acceptable minimum in adults who are not HIV-infected); rifampin and pyrazinamide for 2 months; or, if neither isoniazid nor pyrazinamide can be given, rifampin for 4 months. Importantly, health-care providers need to work closely with their patients being treated for LTBI to teach them about potential adverse drug effects, especially hepatitis, and to encourage adherence to their medication regimen.

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