Duration of Exposure Among Close Contacts of Patients With Infectious Tuberculosis and Risk of Latent Tuberculosis Infection.

BACKGROUND: Predictors of latent tuberculosis infection (LTBI) among close contacts of persons with infectious tuberculosis (TB) are incompletely understood, particularly the number of exposure hours. METHODS: We prospectively enrolled adult patients with culture-confirmed pulmonary TB and their close contacts at 9 health departments in the United States and Canada. Patients with TB were interviewed and close contacts were interviewed and screened for TB and LTBI during contact investigations. RESULTS: LTBI was diagnosed in 1390 (46%) of 3040 contacts, including 624 (31%) of 2027 US/Canadian-born and 766 (76%) of 1013 non-US/Canadian-born contacts. In multivariable analysis, age ≥5 years, male sex, non-US/Canadian birth, smear-positive index patient, and shared bedroom with an index patient (P < .001 for each), as well as exposure to >1 index patient (P < .05), were associated with LTBI diagnosis. LTBI prevalence increased with increasing exposure duration, with an incremental prevalence increase of 8.2% per 250 exposure hours (P < .0001). For contacts with <250 exposure hours, no difference in prevalence was observed per 50 exposure hours (P = .63). CONCLUSIONS: Hours of exposure to a patient with infectious TB is an important LTBI predictor, with a possible risk threshold of 250 hours. More exposures, closer exposure proximity, and more extensive index patient disease were additional LTBI predictors.

Risk Factors for Tuberculosis and Effect of Preventive Therapy Among Close Contacts of Persons With Infectious Tuberculosis.

BACKGROUND: Close contacts of persons with pulmonary tuberculosis (TB) have high rates of TB disease. METHODS: We prospectively enrolled TB patients and their close contacts at 9 US/Canadian sites. TB patients and contacts were interviewed to identify index patient, contact, and exposure risk factors for TB. Contacts were evaluated for latent TB infection (LTBI) and TB, and the effectiveness of LTBI treatment for preventing contact TB was examined. RESULTS: Among 4490 close contacts, multivariable risk factors for TB were age ≤5 years, US/Canadian birth, human immunodeficiency virus infection, skin test induration ≥10 mm, shared bedroom with an index patient, exposure to more than 1 index patient, and index patient weight loss (P < .05 for each). Of 1406 skin test-positive contacts, TB developed in 49 (9.8%) of 446 who did not initiate treatment, 8 (1.8%) of 443 who received partial treatment, and 1 (0.2%) of 517 who completed treatment (1951, 290, and 31 cases/100 000 person-years, respectively; P < .001). TB was diagnosed in 4.2% of US/Canadian-born compared with 2.3% of foreign-born contacts (P = .002), and TB rates for US/Canadian-born and foreign-born contacts who did not initiate treatment were 3592 and 811 per 100 000 person-years, respectively (P < .001). CONCLUSIONS: Treatment for LTBI was highly effective in preventing TB among close contacts of infectious TB patients. Several index patient, contact, and exposure characteristics associated with increased risk of contact TB were identified. These findings help inform contact investigation, LTBI treatment, and other public health prevention efforts.

Risk and Timing of Tuberculosis Among Close Contacts of Persons with Infectious Tuberculosis.

Background: The risk and timing of tuberculosis among recently exposed close contacts of patients with infectious tuberculosis are not well established. Methods: We prospectively enrolled patients ≥15 years of age with culture-confirmed pulmonary tuberculosis and their close contacts at 9 health departments in the United States and Canada. Close contacts were screened and cross-matched with tuberculosis registries to identify those who developed tuberculosis. Results: Tuberculosis was diagnosed in 158 of 4490 contacts (4%) of 718 index patients with tuberculosis. Of tuberculosis cases among contacts, cumulative totals of 81 (51%), 119 (75%), 128 (81%), and 145 (92%) were diagnosed by 1, 3, 6, and 12 months, respectively, after the index patients' diagnosis. Tuberculosis rates among contacts were 2644, 115, 46, 69, and 25 cases per 100000 persons, respectively, in the 5 consecutive years after the index patients' diagnosis. Of the tuberculosis cases among contacts, 121 (77%) were identified by contact investigation and 37 (23%) by tuberculosis registry cross-match. Conclusions: Close contacts to infectious patients with tuberculosis had high rates of tuberculosis, with most disease diagnosed before or within 3 months after the index patient' diagnosis. Contact investigations need to be prompt to detect tuberculosis and maximize the opportunity to identify and treat latent infection, to prevent disease.

Profiling T cell activation using single-molecule fluorescence in situ hybridization and flow cytometry.

Flow cytometric characterization of Ag-specific T cells typically relies on detection of protein analytes. Shifting the analysis to detection of RNA would provide several significant advantages, which we illustrate by developing a new host immunity-based platform for detection of infections. Cytokine mRNAs synthesized in response to ex vivo stimulation with pathogen-specific Ags are detected in T cells with single-molecule fluorescence in situ hybridization followed by flow cytometry. Background from pre-existing in vivo analytes is lower for RNAs than for proteins, allowing greater sensitivity for detection of low-frequency cells. Moreover, mRNA analysis reveals kinetic differences in cytokine expression that are not apparent at the protein level but provide novel insights into gene expression programs expected to define different T cell subsets. The utility of probing immunological memory of infections is demonstrated by detecting T cells that recognize mycobacterial and viral Ags in donors exposed to the respective pathogens.

Acquired rifamycin resistance with twice-weekly treatment of HIV-related tuberculosis.

RATIONALE: Rifabutin was recommended in place of rifampin during treatment of HIV-related tuberculosis (TB) to facilitate concomitant potent antiretroviral therapy, but this approach has not been evaluated in a prospective study. OBJECTIVE: To evaluate the activity of intermittent rifabutin-based therapy. METHODS: Patients with culture-confirmed TB were treated under direct supervision with 2 mo of rifabutin, isoniazid, pyrazinamide, and ethambutol (given daily, thrice-weekly, or twice-weekly per the local tuberculosis control program), followed by 4 mo of twice-weekly rifabutin plus isoniazid. MEASUREMENTS: Culture-positive treatment failure or relapse. MAIN RESULTS: A total of 169 eligible patients were enrolled. Most had advanced HIV disease; the median CD4 cell count and HIV-RNA level were 90 cells/mm3 (interquartile range, 35-175) and 5.3 log10 copies/ml (interquartile range, 4.8-5.7), respectively. Nine (5.3%) patients had culture-positive treatment failure (n = 3) or relapse (n = 6). Eight of these nine (89%) cases had isolates with acquired rifamycin resistance. Treatment failure or relapse was associated with baseline CD4 lymphocyte count, being 12.3% (9/73; 95% confidence interval, 6.5-22.0%) among patients with CD4 < 100 cells/mm3 versus 0% (0/65; 95% confidence interval, 0.0-4.5%) among those with higher CD4 lymphocyte counts (p < 0.01). One hundred thirty-seven (81%) patients received antiretroviral therapy during TB treatment. Adverse events were common, but only two patients (1%) permanently discontinued study drugs. CONCLUSIONS: Intermittent rifabutin-based therapy for HIV-related TB was well tolerated, but there was a high risk of treatment failure or relapse with acquired rifamycin resistance among patients with low CD4 lymphocyte counts.

Rethinking the socioeconomics and geography of tuberculosis among foreign-born residents of New Jersey, 1994-1999.

OBJECTIVES: This study investigated the socioeconomic profile of foreign-born tuberculosis patients in New Jersey. METHODS: Foreign- and US-born tuberculosis patients in 1994-1999 were compared using various measures of socioeconomic status. RESULTS: Out of 4295 tuberculosis patients, 2005 (47%) were foreign-born. Foreign-born patients resided in more affluent, more educated, and less crowded areas than did US-born patients (P <.005). They were also more likely to have been employed during the 2 years before diagnosis (62% vs 41%, P <.001). Private physicians treated the majority of South Asian-born patients. CONCLUSIONS: Substantial numbers of employed foreign-born tuberculosis patients now reside in affluent New Jersey locations. Changes in tuberculosis control programs may be required when the socioeconomic status and place of residence of foreign-born populations diverge from traditional assumptions linking poverty with tuberculosis.

Evaluation of investigations conducted to detect and prevent transmission of tuberculosis.

CONTEXT: Contact investigations are routinely conducted by health departments throughout the United States for all cases of active pulmonary tuberculosis (TB) to identify secondary cases of active TB and latent TB infection and to initiate therapy as needed in these contacts. Little is known about the actual procedures followed, or the results. OBJECTIVES: To evaluate contact investigations conducted by US health departments and the outcomes of these investigations. DESIGN, SETTING, AND SUBJECTS: Review of health department records for all contacts of 349 patients with culture-positive pulmonary TB aged 15 years or older reported from 5 study areas in the United States during 1996. MAIN OUTCOME MEASURES: Number of contacts identified, fully screened, and infected per TB patient; rates of TB infection and disease among contacts of TB patients; and type and completeness of data collected during contact investigations. RESULTS: A total of 3824 contacts were identified for 349 patients with active pulmonary TB. Of the TB patients, 45 (13%) had no contacts identified. Of the contacts, 55% completed screening, 27% had an initial but no postexposure tuberculin skin test, 12% were not screened, and 6% had a history of prior TB or prior positive tuberculin skin test. Of 2095 contacts who completed screening, 68% had negative skin test results, 24% had initial positive results with no prior test result available, 7% had documented skin test conversions, and 1% had active TB at the time of investigation. Close contacts younger than 15 years (76% screened vs 65% for older age groups; P<.001) or exposed to a TB patient with a positive smear (74% screened vs 59% for those with a negative smear; P<.001) were more likely to be fully screened. Close contacts exposed to TB patients with both a positive smear and a cavitary chest radiograph were more likely to have TB infection or disease (62% vs 33% for positive smear only vs 44% for cavitary radiograph only vs 37% for neither characteristic; P<.001). A number of factors associated with TB patient infectiousness, contact susceptibility to infection, contact risk of progression to active TB, and amount of contact exposure to the TB patient were not routinely recorded in health department records. CONCLUSIONS: Improvement is needed in the complex, multistep process of contact investigations to ensure that contacts of patients with active pulmonary TB are identified and appropriately screened.

Treatment of latent tuberculosis infection in contacts of new tuberculosis cases in the United States.

BACKGROUND: Few data are available describing treatment completion rates among recently infected contacts of tuberculosis (TB) cases, a group at high risk for development of active TB. METHODS: Health department records were reviewed for all contacts of 360 culture-positive pulmonary TB cases reported from five health departments in the United States in 1996. RESULTS: Of 2,267 contacts who completed screening, 630 (28%) had newly documented positive skin tests (121 with skin test conversion). Treatment of latent TB infection was documented to have been recommended for 447 (71%). Among these, treatment was documented to be initiated for 398 (89%). Of these, 203 (51%) were documented to have completed a 6-month course of treatment, and 78 (20%) received directly observed treatment. Treatment was recommended more often for contacts < 15 years of age, skin test converters, close contacts, and contacts of smear-positive cases. Treatment completion rates were higher for skin test converters. CONCLUSIONS: In this study, fewer than one third of all persons with newly documented positive skin tests detected during contact investigations were proven to have completed treatment. Achieving high rates of completion of therapy for latent TB infection in recently infected contacts of active cases of pulmonary TB is essential to maximize public health prevention efforts aimed at eliminating TB.

Identification and evolution of an IS6110 low-copy-number Mycobacterium tuberculosis cluster.

A cohort of 56 patients infected with related strains of Mycobacterium tuberculosis, the S75 group, was identified in a New Jersey population-based study of all isolates with a low number of copies of the insertion element IS6110. Genotyping was combined with surveillance data to identify the S75 group and to elucidate its recent evolution. The S75 group had similar demographic and geographic characteristics. Seventeen persons (30%) were linked epidemiologically. The S75 group was segregated from other low-copy-number isolates on the basis of several independent molecular methods. This group included 3 IS6110 genotype variants: BE, H6, and C28, containing 1, 2, and 3 IS6110 insertions, respectively. IS6110 insertion site mapping and comparative sequence analysis strongly suggest a stepwise acquisition of IS6110 elements from BE to H6 to C28. S75 represents a locally produced strain cluster that has recently evolved. The combination of multiple molecular tools with traditional epidemiology provides novel insights into dissemination, local transmission, and evolution of M. tuberculosis.

Brief guide on tuberculosis control for primary health care providers: for countries in the WHO European Region with a high and intermediate burden of tuberculosis

Tuberculosis is an increasingly serious problem in the WHO European region, particularly in the countries of eastern Europe, the Baltic States, and the Commonwealth of Independent States (CIS).Primary health care providers can play an important role in tuberculosis control through early detection of the disease, referral for treatment, and involvement in directly observed treatment. This guide has been written with the aim of developing the knowledge, awareness and skills of primary health care providers regarding tuberculosis and its prevention and control. The guide is not intended as a complete source of information on tuberculosis, but rather a summary of general principles regarding prevention, detection and treatment. The guide does not reflect specific national guidelines on TB control, and is intended to be used in conjunction with the appropriate national regulations. A reference card containing key information is included with this guide.