TB

Epidemiology

Prevalence of TB, especially MDR-TB, has increased among the immigrants for SE Asia, Sub-Saharan Africa, the Indian subcontinent, and Central America. Also drug resistant TB (XDR-TB) is becoming increasingly prevalent in Sub-Saharan Africa.

Etiology

TB is a systemic disease caused by M. tuberculosis. Most cases are the result of reactivation of prior infection.

Risk Factors

HIV infection, silicosis, DM, CKD, malignancy, malnutrition, and other forms of immunosuppression, especially therapy with TNF antagonist like infliximab and entanercept.

Dx

Drug suseptibility testing done on initial testing as well as on follow-up testing of Pts who do not respond to standard therapy.

Clinical Presentation

Pulmonary disease is the most frequent presentation. Focal infiltrates are classically in the upper lobes for reactivation disease. It can present as disseminated "miliary" pattern. Lower lobe disease can be seen in primary infection.

DDx

Extrapulmonary disease may present as cervical LAD, GU disease, OM, "miliary" dissemination, meningitis, peritonitis, or pericarditis.

Labs

Dx is usually made with positive fluorochrome or AFB smears of sputum, which are presumptive evidence of active TB, although nontuberculous mycobacteria and some Nocardia species may give positive results with these techniques.

TB can take several wks to grow in culture so if the clinical suspicion is high, presumptive therapy even with negative smears may be indicated until cultures are negative. Use of radiometric culture systems and species-specific DNA probes can provide results faster than traditional methods.

QuantiFERON TB Gold test (QFT-G)

Dec. 22, 2005 —The QuantiFERON TB Gold test (QFT-G) essentially can be used in all cases in which the tuberculosis skin test is currently used, according to new guidelines released by the US Centers for Disease Control and Prevention (CDC) and published in the Dec. 16 issue of the Morbidity and Mortality Weekly Report: Recommendations and Reports. These guidelines are intended for public health officials, healthcare providers, and laboratory workers with responsibility for TB control activities in the United States.

"On May 2, 2005, a new in vitro test, QuantiFERON-TB Gold (QFT-G, Cellestis Limited, Carnegie, Victoria, Australia), received final approval from the U.S. Food and Drug Administration (FDA) as an aid for diagnosing Mycobacterium tuberculosis infection," write Gerald H. Mazurek, MD, and colleagues from the Division of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention. "This test detects the release of interferon-gamma (IFN-γ) in fresh heparinized whole blood from sensitized persons when it is incubated with mixtures of synthetic peptides representing two proteins present in M. tuberculosis: early secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10). These antigens impart greater specificity than is possible with tests using purified protein derivative [PPD] as the tuberculosis (TB) antigen."

Direct comparisons have shown that the sensitivity of QFT-G was not statistically different from that of the tuberculin skin test (TST) for detecting infection in people with untreated culture-confirmed TB. Currently, the diagnostic value of QFT-G for finding latent TB infection (LTBI) is being evaluated in certain populations targeted by TB control programs in the United States. To date, the ability of this test to predict who will eventually have TB disease is unknown, and years of observational research in large cohorts would be needed to determine this.

In July 2005, the CDC organized a meeting of experts to review scientific evidence and clinical experience with QFT-G. This group concluded that QFT-G may be used in all circumstances in which the TST is now used, including contact investigations, evaluation of recent immigrants, and sequential-testing surveillance programs for infection control, such as those for healthcare workers. The CDC guidelines also list specific cautions for interpreting negative QFT-G results in selected subgroups populations and provide interim guidance for use and interpretation of QFT-G.

"Confirming or excluding TB disease and assessing the probability of LTBI require a combination of epidemiologic, historic, physical, and diagnostic findings that should be considered when interpreting QFT-G results," the authors write. "This report is intended to assist public health officials, clinicians, and laboratorians in their efforts to understand the use of QFT-G for TB control."

The FDA approved QFT-G as an in vitro laboratory test to assist in the diagnosis of both TB disease and LTBI, both in clinical and in public health settings, ideally in concert with the local or regional public health TB control program. Instructions for the QFT-G assay are in the package insert, and QFT-G test results can be calculated by using software provided by the manufacturer. The guidelines also include a table for interpreting test results. Laboratory reports should include interpretation of QFT-G test results and indicate the concentration of IFN-γ in each plasma sample.

Although some limitations of QFT-G appear to be similar to those of the TST, they have not been studied extensively to date. In persons with untreated, culture-confirmed TB, the sensitivity of QFT-G for detecting M. tuberculosisinfection is approximately 80% in published studies, but the sensitivity in specific subgroups of TB patients, such as young children and immunocompromised patients, is still unknown. For LTBI, QFT-G sensitivity might be less than that of the TST, but the lack of a confirmatory test makes this difficult to evaluate. Estimating the sensitivity of any indirect test for LTBI by testing patients with TB disease might be inaccurate because of differences between these conditions, and the ability of QFT-G to predict risk for LTBI progressing to TB disease is still undetermined.

Like the TST, QFT-G cannot distinguish infection associated with TB disease from LTBI. For definitive diagnosis of LTBI, TB disease must be ruled out by medical evaluation, which should include ascertaining history of suggestive symptoms and signs, chest x-ray, and examination of sputum or other clinical samples for M. tuberculosis when indicated. As for other diagnostic tests, the prevalence of M. tuberculosis infection in the population being tested affects the predictive value of QFT-G results.

"Each QFT-G result and its interpretation should be considered in conjunction with other epidemiologic, historic, physical, and diagnostic findings," the guidelines note. "As with a negative TST result, negative QFT-G results should not be used alone to exclude M. tuberculosis infection in persons with symptoms or signs suggestive of TB disease. The presence of symptoms or signs suggestive of TB disease increases the likelihood that M. tuberculosis infection is present, and these circumstances decrease the predictive value of a negative QFT-G or TST result."

Symptomatic individuals should have a medical evaluation including history and physical examination, chest x-ray, bacteriologic studies, serology for HIV, and other tests as indicated.

The sensitivity and rate of indeterminate results using QFT-G has not been determined in immunocompromised persons with HIV infection, AIDS, current treatment with immunosuppressive drugs, selected hematologic disorders, and certain malignancies. These conditions or treatments are known or suspected to decrease responsiveness to the TST, and they might also decrease production of IFN-γ in the QFT-G assay. As with a negative TST result, negative QFT-G results alone might be insufficient to exclude M. tuberculosis infection in these persons.

Practical limitations of the QFT-G include the need for venipuncture and for transporting the 5-mL blood sample to a qualified laboratory in time for testing.

"QFT-G can be used in all circumstances in which the TST is used, including contact investigations, evaluation of recent immigrants who have had BCG [Bacille Calmette-Guérin] vaccination, and TB screening of health-care workers and others undergoing serial evaluation for M. tuberculosis infection," the authors write. "QFT-G usually can be used in place of (and not in addition to) the TST. A positive QFT-G result should prompt the same public health and medical interventions as a positive TST result."

The guidelines note that there is no reason to follow a positive QFT-G result with a TST; instead, those with a positive QFT-G result, regardless of their symptoms or findings, should be evaluated for TB disease before LTBI is diagnosed. HIV counseling, testing, and referral is also recommended because HIV infection increases the suspicion for TB and the urgency for treating LTBI. Once TB has been ruled out, treatment of LTBI should be considered.

"For persons with recent contact with persons who have infectious TB, negative QFT-G results should be confirmed with a repeat test performed 8 - 10 weeks after the end of exposure, as is recommended for a negative TST result," the authors conclude. "Studies to determine the best time to retest contacts with negative QFT-G results have not been reported. Until more information is available, the timing of QFT-G testing should be the same as that used for the TST."

MMWR Morb Mortal Wkly Rep. 2005;54(RR- 15):49-55

Tx:

    • Hospitalization to initiate Tx provides an opportunity for intensive patient education. Tx does not have to be in a hospital setting.

    • If hospitalized, proper isolation in a negative-pressure room is essential.

    • The local health dept. should be notified of all cases of TB so that contacts can be identified and adherence to the regimen can all be ensured by directly observed therapy.

    • At least two drugs to which the organism is susceptible must be used because of the high frequency with which primary drug resistance to a single drug develops. Extended therapy is necessary because of the prolonged generation time of mycobacteria.

    • DOT should be used for all patients, to avoid noncompliance.

    • Initial Tx of uncomplicated pulmonary TB should usually include 4 drugs:

    • INH (5 mg/kg; max, 300 mg PO daily), rifampin (RIF, 10 mg/kg; max, 600 mg PO daily), pyrazinamide (PZA, 15-30 mg/kg; max, 2 g PO daily), and either ethambutol (EMB, 15-25 mg/kg PO daily) or streptomycin (15 mg/kg; max, 1.5 g IM daily). Pyridoxine (Vit B6), 25-50 mg PO daily, should be used with INH to prevent neuropathy.

    • If the isolate proves to be fully susceptible to INH and RIF, then EMB (or streptomycin) can be dropped and INH, RIF, and PZA continued to finish 8 wks, followed by 16 wks of INH and RIF. Pts with high risk of relapse (cavitary pulmonary TB or positive TB cultures after 2 months of therapy) should be treated for 9 months. After at least 2 wks of daily therapy, the drugs can be administered two or three times per week at adjusted doses.

    • When INH resistance is documented, the INH should be discontinued, and the remaining three drugs should be continued for the duration of therapy. Organisms resistant only to INH can be effectively treated with a 6 month regimen if a standard 4 drug regimen consisting of INH, RIF, PZA, and EMB or streptomycin was started initially. Therapy for MDR TB has been less well studied, and consultation with an expert in the treatment of TB should be considered.

    • Extrapulmonary disease in adults is Tx in the same manner as pulmonary disease, with 6-9 month regimens. TB meningitis should be treated for 9-12 months.

    • Glucocorticoid administration. In TB, the administration of glucocorticoids is controversial. Prednisone, 1 mg/kg PO daily initially, has been used in combination with antituberculous drugs for life-threatening complications such as meningitis and pericarditis.

    • Monitoring response to therapy. Pt. with pulmonary TB whose sputum AFB smears are positive before treatment should submit sputum for AFB smear and culture q1-2 weeks until AFB smears become negative. Sputum should then be obtained qmo until two consecutive negative cultures are documented. Conversion of cultures from positive to negative is the most reliable indicator of a response to treatment. It patient continues to have sx or persistently positive AFB smears or cultures after 3 months of tx, suspect drug resistance, or nonadherence, or poor absorption. Promptly refer such patients to a TB expert.

    • Monitoring for adverse reactions. Obtain a baseline lab evaluation at the start of therapy: LFTs, CBC, and Sr. Cr. Routine lab monitoring for Pts with normal baseline values is probably unnecessary except with HIV, concerns for alcohol consumption, chronic liver disease, and in pregnant women. Monthly clinical evaluation and specific queries about sx of drug toxicity is important. Pts. taking EMB should be tested monthly for visual acuity and red-green color perception.

    • Pregnant Pts should not get PZA or streptomycin, and thus a 9-month course of therapy is recommended. Pregnancy-related TB should be Tx with INH, RIF, EMB, and pyridoxine for the first 2 months, after which the EMB can be stopped if the isolate proves to be drug sensitive.

  • Latent TB infection

      • LTBI is when someone has been exposed to TB, as demonstrated by a positive TST or QuantiFERON-TB blood test, but has no signs or symptoms of current active disease. Criteria for a positive TST are based on the maximum diameter of induration (not erythema).

        • A 5-mm induration is considered positive in patients with HIV inf or other defect in CMI, close contacts of know case of TB Pts with CXR typical for healed TB, and individuals with organ transplantation or other immunosuppression.

        • A 10-mm induration is considered positive in immigrants from high-prevalence areas (Asia, Africa, Latin America; Eastern Europe), prisoners, the homeless, IDU, NH residents, low-income populations, patients with chronic medical illnesses or health and economic disparities, and those people who have frequent contact with these groups (e.g., HCW, prison guards).

        • A 15-mm induration is a positive TST for otherwise healthy individuals who are not in a high-prevalence group.

      • Untreated, approximately 5% of persons with LTBI develop active TB disease within 2 years of infection. TB disease develops in an additional 5% of persons over the life span. Adequate prophylactic treatment can substantially reduce the risk of disease.

Chemoprophylaxis for LTBI

    • Chemoprophylaxis for LTBI should be administered only after active disease has been ruled out by a proper evaluation (CXR, sputum collection, or both). INH, 300 mg PO daily for 9 months, should be administered to persons with LTBI who have risk factors for progression to active TB disease, regardless of age.

      • Risk factors for progression include a TST conversion within 2 years of a previously negative TST; a history of untreated TB or CXR evidence of previous disease; HIV infection, DM, ESRD, hematologic or lymphoreticular malignancy, conditions associated with rapid wt. loss, chronic malnutrition, silicosis, or Pts who are receiving immunosuppressive therapy; household members and other close contacts of patients with active disease who have a reactive TST.

      • Persons with HIV inf wo have a known contact with a patient with active TB should be treated for LTBI regardless of tuberculin status.

      • Contacts with a non-reactive TST should undergo a repeat TST 3 months after the last exposure to the infectious person.

      • A 9-month course of INH is adequate for all Pts with LTBI even among those with HIV infection. Alternative regimens of shorter duration but higher toxicity can be considered in continuation with a TB expert. Referral to the health dept. for chemoprophylaxis is recommended to ensure adherence and to monitor for medication-related complications.