James D. Mancuso

Discordance among Commercially Available Diagnostics for Latent Tuberculosis Infection

RATIONALE There is uncertainty regarding how to interpret discordance between tests for latent tuberculosis infection. OBJECTIVES The objective of this study was to assess discordance between commercially available tests for latent tuberculosis in a low-prevalence population, including the impact of nontuberculous mycobacteria. METHODS This was a cross-sectional comparison study among 2,017 military recruits at Fort Jackson, South Carolina, from April to June 2009. Several tests were performed simultaneously with a risk factor questionnaire, including (1) QuantiFERON-TB Gold In-Tube test, (2) T-SPOT.TB test, (3) tuberculin skin test, and (4) Battey skin test using purified protein derivative from the Battey bacillus. MEASUREMENTS AND MAIN RESULTS In this low-prevalence population, the specificities of the three commercially available diagnostic tests were not significantly different. Of the 88 subjects with a positive test, only 10 (11.4%) were positive to all three tests; 20 (22.7%) were positive to at least two tests. Bacille Calmette-Guérin vaccination, tuberculosis prevalence in country of birth, and Battey skin test reaction size were associated with tuberculin skin test-positive, IFN-γ release assay-negative test discordance. Increasing agreement between the three tests was associated with epidemiologic criteria indicating risk of infection and with quantitative test results. CONCLUSIONS For most positive results the three tests identified different people, suggesting that in low-prevalence populations most discordant results are caused by false-positives. False-positive tuberculin skin test reactions associated with reactivity to nontuberculous mycobacteria and bacille Calmette-Guérin vaccination may account for a proportion of test discordance observed.

Chlorhexidine-impregnated cloths to prevent skin and soft-tissue infection in marine recruits: a cluster-randomized, double-blind, controlled effectiveness trial.

BACKGROUND Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) causes skin and soft-tissue infection (SSTI) in military recruits. OBJECTIVE To evaluate the effectiveness of 2% chlorhexidine gluconate (CHG)-impregnated cloths in reducing rates of SSTI and S. aureus colonization among military recruits. DESIGN A cluster-randomized (by platoon), double-blind, controlled effectiveness trial. SETTING Marine Officer Candidate School, Quantico, Virginia, 2007. PARTICIPANTS Military recruits. INTERVENTION Application of CHG-impregnated or control (Comfort Bath; Sage) cloths applied over entire body thrice weekly. MEASUREMENTS Recruits were monitored daily for SSTI. Baseline and serial nasal and/or axillary swabs were collected to assess S. aureus colonization. RESULTS Of 1,562 subjects enrolled, 781 (from 23 platoons) underwent CHG-impregnated cloth application and 781 (from 21 platoons) underwent control cloth application. The rate of compliance (defined as application of 50% or more of wipes) at 2 weeks was similar (CHG group, 63%; control group, 67%) and decreased over the 6-week period. The mean 6-week SSTI rate in the CHG-impregnated cloth group was 0.094, compared with 0.071 in the control group (analysis of variance model rate difference, 0.025  ± 0.016; P = .14). At baseline, 43% of subjects were colonized with methicillin-susceptible S. aureus (MSSA), and 2.1% were colonized with MRSA. The mean incidence of colonization with MSSA was 50% and 61% (P = .026) and with MRSA was 2.6% and 6.0% (P = .034) for the CHG-impregnated and control cloth groups, respectively. CONCLUSIONS CHG-impregnated cloths applied thrice weekly did not reduce rates of SSTI among recruits. S. aureus colonization rates increased in both groups but to a lesser extent in those assigned to the CHG-impregnated cloth intervention. Antecedent S. aureus colonization was not a risk factor for SSTI. Additional studies are needed to identify effective measures for preventing SSTI among military recruits. CLINICAL TRIALS REGISTRATION ClinicalTrials.gov identifier: NCT00475930.

Pseudoepidemics of Tuberculin Skin Test Conversions in the U.S. Army after Recent Deployments

RATIONALE The tuberculin skin test (TST) has many sources of error. These can lead to predominantly false-positive reactions when used in low-risk populations. The U.S. Army deploys to areas considered at high risk for tuberculosis (TB) infection, but often has limited contact with the local population. OBJECTIVES We describe the investigation of eight pseudoepidemics of TST conversions in U.S. Army populations, five of which were associated with overseas deployments. METHODS Outbreak investigations of these pseudoepidemics consisted of several components: evaluation of active and latent TB surveillance data, review of medical records, investigation and interviews of active TB cases and their contacts, evaluation of materials and personnel screening procedures, and placement and reading of repeat skin testing. MEASUREMENTS AND MAIN RESULTS Initially reported risk of conversion in the outbreaks ranged from 1.3 to 15%. Repeat testing of converters (positives) found that 30 to 100% were negative on retesting. Several sources of false-positive results were identified in these pseudoepidemics, including variability in reading and administration, product variability, and cross-reactions to nontuberculous mycobacteria. CONCLUSIONS Pseudoepidemics of TST conversions are a common occurrence after U.S. Army deployments and in U.S. Army populations. U.S. Army forces generally have a low risk of TB infection resulting from deployments due to limited exposure to local nationals with active TB, and universal testing in this population has a low positive-predictive value.

The Prevalence of Latent Tuberculosis Infection in the United States

RATIONALE Individuals with latent tuberculosis infection (LTBI) represent a reservoir of infection, many of whom will progress to tuberculosis (TB) disease. A central pillar of TB control in the United States is reducing this reservoir through targeted testing and treatment. OBJECTIVES To estimate the prevalence of LTBI in the United States using the tuberculin skin test (TST) and an IFN-γ release assay. METHODS We used nationally representative data from the 2011-2012 National Health and Nutrition Examination Survey (n = 6,083 aged ≥6 yr). LTBI was measured by both the TST and QuantiFERON-TB Gold In-Tube test (QFT-GIT). Weighted population, prevalence, and multiple logistic regression were used. MEASUREMENTS AND MAIN RESULTS The estimated prevalence of LTBI in 2011-2012 was 4.4% as measured by the TST and 4.8% by QFT-GIT, corresponding to 12,398,000 and 13,628,000 individuals, respectively. Prevalence declined slightly since 2000 among the U.S. born but remained constant among the foreign born. Earlier birth cohorts consistently had higher prevalence than more recent ones. Higher risk groups included the foreign born, close contact with a case of TB disease, and certain racial/ethnic groups. CONCLUSIONS After years of decline, the prevalence of LTBI remained relatively constant between 2000 and 2011. A large reservoir of 12.4 million still exists, with foreign-born persons representing an increasingly larger proportion of this reservoir (73%). Estimates and risk factors for LTBI were generally similar between the TST and QFT-GIT. The updated estimates of LTBI and associated risk groups can help improve targeted testing and treatment in the United States.

Systematic Review and Meta-Analysis of TST Conversion Risk in Deployed Military and Long-Term Civilian Travelers

BACKGROUND Transmission of tuberculosis (TB) during travel is a significant potential infectious disease threat to travelers. However, there is uncertainty in the travel medicine community regarding the evidence base for both estimates of risk for latent TB infection (LTBI) in long-term travelers and for information regarding which travelers may benefit from pre- or post-travel TB screening. The purpose of this study was to determine the risk for tuberculin skin test (TST) conversion, used as a surrogate for LTBI, in long-term travelers from low- to high-risk countries. METHODS We performed a systematic review to acquire all published and unpublished data on TST conversion in long-term civilian and military travelers from 1990 to June 2008. Point estimates and confidence intervals (CIs) of the incidence of TST conversion were combined in a random effects model and assessed for heterogeneity. RESULTS The cumulative risk with CI for LTBI as measured by TST conversion was 2.0% (99% CI: 1.6%-2.4%). There was a marked heterogeneity (chi(2) heterogeneity statistic, p < 0.0001) which could not be explained by evaluable study characteristics. When stratifying by military and civilian studies, the cumulative risk estimate was 2.0% (99% CI: 1.6-2.4) for military and 2.3% (99% CI: 2.1-2.5) for civilian studies. CONCLUSION The overall cumulative incidence of 2.0% is what could be expected to occur among the local population in many developing-country settings, though TST conversion likely overestimates the risk of TB infection because of the low positive predictive value (PPV) of the TST in low-prevalence populations such as travelers. To maximize the PPV of a screening test for LTBI, a targeted testing strategy for long-term military and civilian travelers is recommended, based on exposures known to increase the risk of TB. Studies to better define higher risk groups, activities, and locations are needed.

Impact of Targeted Testing for Latent Tuberculosis Infection Using Commercially Available Diagnostics

BACKGROUND The interferon-γ release assays (IGRAs) are increasingly being used as an alternative to the tuberculin skin test (TST). Although IGRAs may have better specificity and certain logistic advantages to the TST, their use may contribute to overtesting of low-prevalence populations if testing is not targeted. The objective of this study was to evaluate the accuracy of a risk factor questionnaire in predicting a positive test result for latent tuberculosis infection using the 3 commercially available diagnostics. METHODS A cross-sectional comparison study was performed among recruits undergoing Army basic training at Fort Jackson, South Carolina, from April through June 2009. The tests performed included: (1) a risk factor questionnaire; (2) the QuantiFERON Gold In-Tube test (Cellestis Limited, Carnegie, Victoria, Australia); (3) the T-SPOT.TB test (Oxford Immunotec Limited, Abingdon, United Kingdom); and (4) the TST (Sanofi Pasteur Ltd., Toronto, Ontario, Canada). Prediction models used logistic regression to identify factors associated with positive test results. RFQ prediction models were developed independently for each test. RESULTS Use of a 4-variable model resulted in 79% sensitivity, 92% specificity, and a c statistic of 0.871 in predicting a positive TST result. Targeted testing using these risk factors would reduce testing by >90%. Models predicting IGRA outcomes had similar specificities as the skin test but had lower sensitivities and c statistics. CONCLUSIONS As with the TST, testing with IGRAs will result in false-positive results if the IGRAs are used in low-prevalence populations. Regardless of the test used, targeted testing is critical in reducing unnecessary testing and treatment. CLINICAL TRIAL REGISTRATION NCT00804713.

Active Tuberculosis and Recent Overseas Deployment in the U.S. Military

BACKGROUND The risk of active TB resulting from military deployment to endemic areas is unknown. It has typically been assumed that the risk of TB approximates the risk among local nationals in that country. PURPOSE This nested case-control study assesses the putative association of overseas deployment with active tuberculosis among active-component U.S. military service members. METHODS Deployment histories and other exposures among 578 active TB cases and 2312 controls matched on year of entry into service and length of service between 1990 and 2006 were compared in 2009 using multivariate conditional logistic regression. Multiple imputation methods were used to account for missing data. RESULTS The matched OR of active TB for military deployers as compared to nondeployers was 1.18 (95% CI=0.91, 1.52). A significant association of deployments of 90-179 days was found, but this was inconsistent with the overall negative result. Significant associations were seen with foreign birth and nonwhite racial or ethnic groups. Overseas stationing in Korea was also found to be associated with active TB. CONCLUSIONS No strong or consistent association was found between active TB and deployment, but an association was seen with long-term residence in TB-endemic countries (Korea). The strongest risk factors for active TB in the U.S. military population were found to exist prior to accession into military service. These conclusions were robust in sensitivity analysis.

The Challenge of Controlling Lead and Silica Exposures from Firing Ranges in a Special Operations Force

In 2000, soldiers from a Special Operations Force had airborne lead exposures 20 to 38 times the permissible exposure limit. Their average blood lead level was 13.9 microg/dL. Immediate implementation of pertinent Occupational Safety and Health Administration regulations was recommended. In 2003, investigators learned that the unit also used an outdoor firing range with exposures exceeding the permissible exposure limit. Attempts to conduct more detailed evaluations and control measures were hindered by frequent deployments in the unit and a strong commitment to realistic training. Despite these challenges, the controls implemented resulted in limited success. The average blood lead level in the unit was 6.8 microg/dL in 2005, a reduction of 51%. Proper initial range construction is essential to controlling lead exposures at firing ranges. Occupational health specialists caring for these soldiers must identify, assess, and mitigate exposures from firing ranges while respecting the importance of realistic training.

Cost-effectiveness analysis of targeted and sequential screening strategies for latent tuberculosis.

SETTING No cost-effectiveness studies of testing for latent tuberculosis infection have incorporated both targeted testing and the use of interferon-gamma release assays (IGRAs) in heterogeneous populations. OBJECTIVE To examine the cost-effectiveness of universal vs. targeted and sequential testing strategies and the use of tuberculin skin testing (TST) vs. IGRAs. DESIGN Using a decision-analytic model, incremental cost-effectiveness ratios were calculated in 2009 among nine potential strategies for screening recruits. A societal perspective was taken over a 20-year analytic horizon, discounting future costs at 3% annually. Sensitivity analyses were conducted to determine how changes in assumptions affected the estimates. RESULTS Targeted strategies cost over US

ELISA underestimates measles antibody seroprevalence in US military recruits

250 000 per case prevented, whereas universal testing strategies cost over US