Respiratory Problems

Diagnostic Blood Tests for TB

Within the last decade, two interferon gamma release assays (IGRAs) have been developed as new diagnostic tests for TB. They are the QuantiFERON–TB Gold In-Tube test (QFT–GIT) and the T–SPOT.TB test (T–Spot).

Although a positive IGRA means that the person has been infected with TB bacteria, it cannot distinguish if the person has LTBI or TB disease. However, it is not subject to reader bias as the case may be with the TST and is not affected by prior BCG vaccination. They are the preferred method testing for LTBI for anyone who has received the BCG shot or will have a difficult time returning for a second appointment to read the TST.^3,5–7

Treatment Regimens for LTBI

Although 90% of active cases of TB in non-HIV-infected individuals are secondary to endogenous reactivation, treatment that diminishes or eradicates the bacterial population in “healed” or radiographically invisible lesions is an important means of reducing progression to active disease. There are several treatment regimens available for the treatment of LTBI and providers should choose the appropriate regimen based on the following: drug susceptibility results of the presumed source case (if known), coexisting medical illness and potential for drug–drug interactions, who are at especially high risk for TB disease and are either suspected of nonadherence or given an intermittent dosing regimen, and directly observed therapy (DOT) for LTBI should be considered.

Isoniazid Regimen

Since 1965, isoniazid (INH) for 6 to 12 months has been the mainstay of therapy of individuals with LTBI infection, as it can reduce the rate of reactivation by at least 70%. However, adherence to therapy has been problematic because of the long duration of therapy and concerns about toxicity. The current CDC recommendations for treatment with INH include a 6- and 9-month regimen.

The 9-month regimen is preferred because it is more efficacious. However, treatment for 6 months may be more cost-effective and result in greater adherence by patients. Accordingly, health care providers may prefer to implement the 6-month regimen rather than the 9-month regimen. Every effort should be made to ensure that patients adhere to LTBI treatment for at least 6 months. The preferred regimen for children aged 2 to 11 years is 9 months of daily INH.³

New: 12-Dose Weekly Isoniazid and Rifapentine

Rifapentine (RPT) is a rifamycin derivative with a long half-life and greater potency against M. tuberculosis than rifampin. A new directly observed 12-dose, once-weekly regimen of INH and RPT for 3 months is recommended as an option equal to the standard INH 9-month daily regimen for treating LTBI in otherwise healthy people, age 12 or above, who had recent contact with infectious TB, or had tuberculin skin test or blood test for TB infection recent conversions of a TST or IGRA, or those with radiologic findings consistent with healed pulmonary TB.^5,8

The regimen may be used in otherwise healthy HIV-infected persons, 12 years of age and older, who are not on antiretroviral medications. Further, it may also be considered for children aged 2 to 11 years if completion of 9 months of INH is unlikely and hazard of TB disease is great.

The 12-dose regimen is NOT recommended for the following individuals:

• Children younger than 2 years of age

• People with HIV/AIDS who are taking antiretroviral therapy (ART)

• People presumed to be infected with INH or rifampin-resistant M. tuberculosis

• Pregnant women or women expecting to become pregnant while taking this regimen

Rifampin (RIF) Regimen

A 4-month regimen of up to 600 mg daily can be considered for persons who cannot tolerate INH or who have been exposed to INH-resistant TB. It should not be used to treat HIV-infected persons taking some combinations of ART. The choice between the 12-dose regimen and other recommended LTBI treatment regimens depends on several factors, including:

• Feasibility of DOT

• Resources for drug procurement and patient monitoring

• Considerations of medical and social circumstances that could affect patient adherence

• Preferences of the patient and prescribing health care provider

Anergic patients or those with a previous history of a positive PPD and HIV infection should be treated if they are close contacts. Before initiating treatment, physicians must ensure that active disease is ruled out with a normal CXR. After that the decision to treat hinges on an analysis of risks and benefits.^3,5

• For pregnant, HIV-negative women, INH given daily or twice weekly for 9 months is recommended. For women at risk for progression of LTBI to disease, especially those who are infected with HIV or who have likely been infected recently, initiation of therapy should not be delayed on the basis of pregnancy alone, even during the first trimester. For women whose risk for active TB is lower, some experts recommend waiting 3 months postpartum because of the risk of INH hepatotoxicity.

• Risk of therapy. Treatment of LTBI is usually indicated, regardless of age, in patients who belong to high-risk groups. INH is associated with age-related hepatitis, beginning after age 19 and increasing significantly after age 35. Extensive use of alcohol enhances this association. Fatal INH-associated hepatitis has been reported. The risk is highest among women, particularly black and Hispanic women; it may also be increased during the postpartum period. Baseline studies are indicated in individuals at high risk for hepatotoxicity, such as those with HIV infection, alcoholism, chronic liver disease, pregnancy, or postpartum status. These patients should be monitored monthly and liver function tests (LFTs) obtained if clinically indicated. INH should be discontinued if liver enzymes reach THREE times the upper limit of normal levels in symptomatic patients or five times the upper limit of normal levels in asymptomatic patients. Because INH may increase the serum level of phenytoin (Dilantin), a decreased dosage of the latter may be necessary. Women receiving RIF and oral contraceptives should be advised to use a backup method of contraception to avoid pregnancy. Pyridoxine, 25 to 100 mg per day, is recommended in high-risk adults to reduce the risk of INH-induced peripheral neuropathy.³

DIAGNOSIS AND TREATMENT OF TB DISEASE

Initiation of a diagnostic evaluation for TB is usually based on suspicion for TB on epidemiologic, clinical, and radiographic grounds.

History and Physical Examination

• Although some patients may be asymptomatic, most present with chronic nonspecific symptoms, such as cough, fever, night sweats, weight loss, lassitude, and hemoptysis.

• Extrapulmonary disease may present as a fever of unknown origin. On examination, patients often appear chronically ill with weight loss.

Laboratory Studies

• Diagnosis depends on CXR findings and identification of the acid-fast bacillus (AFB) in the sputum.

• Radiographic findings. Classically, the CXR reveals fibrocavitary lesions of the upper lobes; however, a varied picture may be present, with infiltration, miliary nodules, or an effusion. Conversely it may be normal, especially with disseminated disease. HIV-infected patients tend to have atypical CXRs or normal CXRs as immunosuppressed individuals may lack the cellular immune response that causes cavitations.

Bacteriologic evaluation. The detection of AFB on microscopic examination of stained smears is the most rapid and inexpensive TB diagnostic tool. In many countries, smears are the only diagnostic test used. Stained sputum smears are not as sensitive as sputum cultures as at least 5,000 to 10,000 bacilli per mL are needed for detection of bacteria in stained smears; in contrast, 10 to 100 organisms are needed for a positive culture.

The sensitivity and positive predictive value of AFB smear microscopy is approximately 45% to 80% and 50% to 80%, respectively. AFB visualized on a slide may represent M. tuberculosis or nontuberculous mycobacteria, so species identification requires culture and/or nucleic acid amplification. A nucleic acid amplification system test (NAAT) provides rapid confirmation that the infecting mycobacteria are M. tuberculosis. In the setting of high clinical suspicion for TB, initiation of empiric therapy based on preliminary acid-fast staining results is appropriate.

Culture. All clinical specimens suspected of containing mycobacteria should be cultured. A culture is required for drug susceptibility testing: it can also be used for species identification. The sensitivity and specificity of sputum culture are about 80% and 98%, respectively. Cultures, which typically take 6 to 8 weeks, have a sensitivity of 81% and a specificity of 98%; these percentages are lower with noncavitary disease. The use of a liquid medium system can provide information in 7 to 14 days. A 2-hour test has been developed that detects M. tuberculosis, and resistance to rifampin. The test, known as the Xpert MTB/RIF assay, is an automated test that works directly from a patient’s sputum without requiring a lengthy bacterial culture. This rapid diagnostic assay is as sensitive as currently available culture methods.⁹ It enables patients to receive their diagnosis during a single clinic visit.

• Reporting and public health. TB is a reportable disease in the United States. As such, persons with confirmed or suspected TB must be reported to a state or local public health authority promptly; in many states, this period is 24 hours.

• Surgical and invasive diagnostic tools.

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