Magnitude of Mycobacterium tuberculosis transmission among household and non-household contacts of TB patients.

The household and non-household contacts of patients with tuberculosis (TB) face varying degrees of risk of infection by Mycobacterium tuberculosis. To quantify new infection and to determine the risk factors associated with new infection among named contacts in San Francisco, CA, USA. We performed a cohort study in patients with culture-positive pulmonary TB. We analyzed patient, contact, environmental and bacterial characteristics. Of the 2422 contacts named by 256 patients, 149 (6.2%) had new infection due to recent transmission from 79 (30.9%) patients. Of the 149 new infections, 87 (58.4%) occurred among household contacts and 62 (41.6%) among non-household contacts. Numerous acid-fast bacilli in sputum (odds ratio [OR] 2.64, 95%CI 1.32-5.25) and contacts being named by more than one patient (OR 2.90, 95%CI 1.23-6.85) were associated with new infection among household contacts. Being older than 50 years (OR 1.93, 95%CI 1.09-3.41) and an Asian/Pacific Islander (OR 3.09, 95%CI 1.50-6.37) were associated with new infection among non-household contacts. Fewer than one third of patients caused new infection to his/her contacts. A substantial proportion of transmission resulting in new infection occurred outside of the household. The risk factors for infection among household and non-household contacts are different and should be considered when prioritizing control interventions. .

Specificity of QuantiFERON-TB Plus, a New-Generation Interferon Gamma Release Assay.

Interferon gamma release assays (IGRAs) are important tools in identifying prior tuberculosis exposure. The new-generation QuantiFERON-TB Gold Plus (QFT-Plus) assay, recently approved for use in the United States, differs from the current-generation QFT Gold-In-Tube (QFT-GIT) assay with the addition of a second antigen tube that also contains novel CD8+ T-cell-stimulating peptides. The QFT-Plus assay has increased sensitivity in immunocompromised populations, and we sought to assess the specificity of QFT-Plus compared to that of QFT-GIT in low-risk individuals. We enrolled adults without tuberculosis risk factors, including a subgroup with pulmonary nontuberculous mycobacterial (NTM) disease due to Mycobacterium avium complex (MAC) or Mycobacterium abscessus. The primary outcome measures included specificity, interassay concordance, and agreement between the QFT-Plus and QFT-GIT assays. Of 262 participants enrolled, 51 had pulmonary NTM. The median age was 39 years (age range, 18 to 78 years); 73% were female. Among the 262 individuals who were enrolled, 5 (1.9%) individuals had positive QFT-Plus results, and 3 of these individuals also had positive QFT-GIT results. The two individuals with discordant results (QFT-Plus positive/QFT-GIT negative) had only one tube positive in the QFT-Plus assay. The overall specificity of QFT-Plus and QFT-GIT was 98.1% (95% confidence interval [CI], 95.6, 99.4%) and 98.9% (95% CI, 96.7, 99.8%), respectively. The QFT-Plus specificity was similar in both the NTM (98.0% [95% CI, 89.4, 99.9%]) and non-NTM (98.1% [95% CI, 95.2, 99.5%]) groups. QFT-Plus has a high specificity, similar to that of the QFT-GIT assay, including in patients with pulmonary MAC or M. abscessus disease.

Treatment for LTBI in contacts of MDR-TB patients, Federated States of Micronesia, 2009-2012.

SETTING: Few studies have shown the operational feasibility, safety, tolerability, or outcomes of multidrug-resistant latent tuberculous infection (MDR LTBI) treatment. After two simultaneous multidrug-resistant tuberculosis (MDR-TB) outbreaks in Chuuk, Federated States of Micronesia, infected contacts were offered a 12-month fluoroquinolone (FQ) based MDR LTBI treatment regimen. DESIGN: Between January 2009 and February 2012, 119 contacts of MDR-TB patients were followed using a prospective observational study design. After MDR-TB disease was excluded, 12 months of daily FQ-based preventive treatment of MDR LTBI was provided by directly observed therapy. RESULTS: Among the 119 infected contacts, 15 refused, while 104 began treatment for MDR LTBI. Of the 104 who initiated treatment, 93 (89%) completed treatment, while 4 contacts discontinued due to adverse effects. None of the 104 contacts who undertook MDR LTBI treatment of any duration developed MDR-TB disease; however, 3 of 15 contacts who refused and 15 unidentified contacts developed MDR-TB disease. CONCLUSION: Providing treatment for MDR LTBI can be accomplished in a resource-limited setting, and contributed to preventing MDR-TB disease. The Chuuk TB program implemented treatment of MDR LTBI with an 89% completion rate. The MDR LTBI regimens were safe and well tolerated, and no TB cases occurred among persons treated for MDR LTBI.

Changes in characteristics of inmates with latent tuberculosis infection.

OBJECTIVES: Health and social characteristics place prisoners at high risk for progression from latent tuberculosis infection (LTBI) to tuberculosis (TB), but completion of LTBI therapy is low with many patients lost to follow-up after release. Despite decreases in active TB, demographic characteristics of active cases have remained relatively unchanged. This study investigated whether characteristics have changed in inmates diagnosed with LTBI in San Francisco, CA, USA. STUDY DESIGN: Cross-sectional. METHODS: Data from baseline interviews of randomized trials conducted in 1998-1999 and 2004-2007 were compared. RESULTS: In both time periods, most subjects with LTBI (>60%) were Latinos, while the proportion in both the jail and San Francisco remained at 15-20%. Overall, the prisoners interviewed in 2004-2007 were less likely to have been on medication for LTBI previously, and expressed more likelihood of finishing their medication compared with those interviewed in 1998-1999. In 2004-2007, the foreign-born subjects were more likely to prefer English to Spanish, to have been in stable housing and to have been employed before jail compared with 1998-1999, while no such changes were seen between the two time periods for US-born subjects. CONCLUSIONS: The pool of TB-infected individuals coming from a jail is not static, and understanding the changes over time is of importance for targeted programmes. Given the high infection rate and the predominance of foreign-born individuals who may have received bacillus Calmette-Guérin vaccination, screening with interferon-gamma release assay may be beneficial to identify those with true infection.

Programmatic impact of using QuantiFERON®-TB Gold in routine contact investigation activities.

OBJECTIVES: To retrospectively assess the proportion of contacts tested with QuantiFERON ® -TB Gold (QFT-G) compared to the tuberculin skin test (TST) who were successfully evaluated and treated for latent tuberculosis infection (LTBI), and to assess the correlation of positive test results with measures of TB exposure. METHODS: Contacts of culture-confirmed pulmonary TB cases reported to the San Francisco Department of Public Health between 1 March 2005 and 31 December 2007 were included. RESULTS: Of 1291 contacts meeting the eligibility criteria, 641 (50%) were tested with QFT-G and 650 (50%) with TST. Contacts tested with QFT-G were more likely to complete evaluation (64% vs. 56%, OR(adj ) = 1.52, 95%CI 1.12-2.06). Infected contacts started (89% vs. 72%, OR(adj) = 5.18, 95%CI 2.10-14.18) and completed (70% vs. 53%, OR(adj) = 3.37, 95%CI 1.78-6.56) LTBI treatment more often in the group tested with QFT-G. Positive QFT-G results, but not positive TST results, correlated with the intensity, proximity and duration of TB exposure in foreign-born subjects. CONCLUSION: More contacts were successfully evaluated and treated for LTBI when screened with QFT-G compared to TST. Measures of exposure correlated better with QFT-G-positive results and, therefore, appropriately identified high-risk contacts for TB prevention.

Improving tuberculosis therapy completion after jail: translation of research to practice.

Inmates have high rates of latent tuberculosis infection (LTBI), but inmates are often released early and do not complete therapy in the community. This study evaluated the translation of results from a randomized trial to improve therapy completion to usual care in a county jail using Rogers' Diffusion of Innovation theory. Inmates who received a single education in the randomized trial in 1998-1999 (study group) were compared to inmates educated by Jail Discharge Planners in 2002-2003 (usual care group). Outcomes were rates of completion of a visit to the TB clinic and completion of therapy. Subjects in the usual care group were significantly less likely to go to clinic in the 30-day period after release (relative risk 0.84, 95% confidence interval 0.75-0.95). The transfer of an educational protocol did not achieve results seen under study conditions, mostly because of implementation fidelity. The educational session in the usual care period for 81.0% of inmates took 5 min, as compared to 10-15 min during the randomized trial. Differences in personnel administering the protocol, training, high turnover and time available may also account for lower rates seen. Practical clinical trials should focus on the context of care as well as the intervention and should have participation by those who will be implementing results.

The role of molecular epidemiology in contact investigations: a US perspective.

Preventing tuberculosis (TB) transmission through treatment of active cases and contact investigation is the highest priority of TB control programs in the United States. The role of contact investigation is becoming increasingly important as the number of TB cases declines nationally. However, the effectiveness of contact investigation has been difficult to assess because, prior to the availability of molecular genotyping techniques, levels of transmission were crudely measurable. Epidemiological links within and outside the traditional concentric circle approach are limited by the quality of the contact investigation, the skill and knowledge of the investigator and the information provided by the patient. Molecular epidemiology has added a new dimension by enabling the recognition of unsuspected transmission, likely locations of transmission, and quantification of the extent of transmission that is occurring within a given population. In the future, as real-time genotyping becomes more available, the role of molecular epidemiology is likely to expand.

CTL response to Mycobacterium tuberculosis: identification of an immunogenic epitope in the 19-kDa lipoprotein.

The successful resolution of infection with Mycobacterium tuberculosis (M.tb) is believed to involve the induction of CTLs that are capable of killing cells harboring this pathogen, although little information is known about the MHC restriction or fine specificity of such CTLs. In this study, we used knowledge of the HLA-A*0201-binding motif and an immunofluorescence-based peptide-binding assay to screen for potential HLA-A*0201-binding epitopes contained in the 19-kDa lipoprotein of M.tb (M.tb19). CD8+ T cells derived from HLA-A*0201+ patients with active tuberculosis (TB) as well as tuberculin skin test-positive individuals who had no history of TB were used as effector cells to determine whether these epitopes are recognized by in vivo-primed CTLs. An in vitro vaccination system using HLA-A*0201+ dendritic cells (DCs) as APCs was used to determine whether these epitopes can sensitize naive CD8+ T cells in vitro, leading to the generation of Ag-specific CTLs. The results show that an HLA-A*0201-binding peptide comprised of residues 88 to 97 of M.tb19 (P88-97) is recognized by circulating CD8+ CTLs from both healthy tuberculin skin test-positive individuals and patients with active TB but not by tuberculin skin test-negative subjects. Moreover, dendritic cells pulsed with this peptide induced class I MHC-restricted CTLs from the T cells of healthy unsensitized persons. Finally, CTL lines that were specific for P88-97 were shown to lyse autologous monocytes that had been infected acutely with the H37Ra strain of M.tb. These results demonstrate that M.tb19 elicits HLA class I-restricted CTLs in vitro and in vivo that recognize endogenously processed Ag. Epitopes of the type identified here may prove useful in the design of an M.tb vaccine.

Predictive value of contact investigation for identifying recent transmission of Mycobacterium tuberculosis.

Contact tracing, the evaluation of persons who have been in contact with patients having tuberculosis, is an important component of tuberculosis control. We used DNA fingerprinting to test the assumption that tuberculosis in contacts to active cases represents transmission from that person. Cases of tuberculosis in San Francisco between 1991 and 1996 with positive cultures who had been previously identified as contacts ("contact cases") to active cases ("index cases") were studied. Of 11,211 contacts evaluated, there were 66 pairs of culture-positive index and contact cases. DNA fingerprints were available for both members of these pairs in 54 instances (82%). The index and contact cases were infected with the same strain of Mycobacterium tuberculosis in 38 instances (70%; 95% CI: 56 to 82%); 16 pairs (30%) were infected with unrelated strains. Unrelated infections were more common among foreign-born (risk ratio [RR] = 5.22, p < 0.001), particularly Asian (RR = 3.89, p = 0.002) contacts. Contact investigation is an imperfect method for detecting transmission of M. tuberculosis, particularly in foreign-born persons. However, because such investigations target a group with a high prevalence of tuberculosis and tuberculous infection, these efforts remain an important activity in the control of tuberculosis.