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.

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.

Deployment-related testing and treatment for latent tuberculosis infection, Part I.

Current Topics in Military Tropical Medicine is a Continuing Medical Education series, which updates military medical personnel on questions related to clinical practice while deployed. This issue is Part I of a two-part series on the approach to decision to test, testing and management of latent tuberculosis infection. A representative case is explored in both parts to highlight how to approach service members and their units with regards to latent tuberculosis infection screening and intervention.

Deployment-related testing and treatment for latent tuberculosis infection, part II.

Current Topics in Military Tropical Medicine is a Continuing Medical Education series, which updates military medical personnel on questions related to clinical practice while deployed. This issue is Part II of a two-part series on the approach to decision to test, testing and management of latent tuberculosis infection. A representative case is explored in both parts to highlight how to approach service members and their units with regard to latent tuberculosis infection screening and intervention.

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.

Species diversity and relative abundance of phlebotomine sand flies (Diptera: Psychodidae) on three Army installations in the southern United States and susceptibility of a domestic sand fly to infection with Old World Leishmania major.

Leishmania infections in American veterans of Iraq and Afghanistan have raised concern that veterans could serve as reservoirs of Old World parasites for domestic vector populations. A survey of sand flies on three U.S. Army facilities in the southern United States was conducted to identify potential vectors. Five species, including two new state records, are reported for Fort Hood, TX. Very few flies were detected in Fort Bragg, NC. Large numbers of a man-biting species, Lutzomyia shannoni, were trapped on Fort Campbell, KY. Weekly activity patterns for dominant species are presented. In addition, an infection experiment was conducted to determine if a domestic sand fly is susceptible to infection with Old World Leishmania major. Lu. shannoni became infected and supported Le. major up to 6 days postprandial. Metacyclogenesis and actual transmission of Le. major to an uninfected mouse did not occur because infected flies did not take subsequent blood meals.

Detection of Mycobacterium tuberculosis infection in United States Navy recruits using the tuberculin skin test or whole-blood interferon-gamma release assays.

BACKGROUND: Military personnel are at risk for acquiring Mycobacterium tuberculosis infection because of activities in close quarters and in regions with a high prevalence of tuberculosis (TB). Accurate tests are needed to avoid unnecessary treatment because of false-positive results and to avoid TB because of false-negative results and failure to diagnose and treat M. tuberculosis infection. We sought to estimate the specificity of the tuberculin skin test (TST) and 2 whole-blood interferon-gamma release assays (QuantiFERON-TB assay [QFT] and QuantiFERON-TB Gold assay [QFT-G]) and to identify factors associated with test discordance. METHODS: A cross-sectional comparison study was performed in which 856 US Navy recruits were tested for M. tuberculosis infection using the TST, QFT, and QFT-G. RESULTS: Among the study subjects, 5.1% of TSTs resulted in an induration > or = 10 mm, and 2.9% of TSTs resulted in an induration > or = 15 mm. Eleven percent of QFT results and 0.6% of QFT-G results were positive. Assuming recruits at low risk for M. tuberculosis exposure were not infected, estimates of TST specificity were 99.1% (95% confidence interval [CI], 98.3%-99.9%) when a 15-mm cutoff value was used and 98.4% (95% CI, 97.3%-99.4%) when a 10-mm cutoff value was used. The estimated QFT specificity was 92.3% (95% CI, 90.0%-94.5%), and the estimated QFT-G specificity was 99.8% (95% CI, 99.5%-100%). Recruits who were born in countries with a high prevalence of TB were 26-40 times more likely to have discordant results involving a positive TST result and a negative QFT-G result than were recruits born in countries with a low prevalence of TB. Nineteen (50%) of 38 recruits with this type of discordant results had a TST induration > or = 15 mm. CONCLUSIONS: The QFT-G and TST are more specific than the QFT. No statistically significant difference in specificity between the QFT-G and TST was found using a 15-mm induration cutoff value. The discordant results observed among recruits with increased risk of M. tuberculosis infection may have been because of lower TST specificity or lower QFT-G sensitivity. Negative QFT-G results for recruits born in countries where TB is highly prevalent and whose TST induration was > or = 15 mm suggest that the QFT-G may be less sensitive than the TST. Additional studies are needed to determine the risk of TB when TST and QFT-G results are discordant.

Outcomes From U.S. Military-Supported Overseas Training Rotations in Tropical Medicine and Global Health, 2006-2015.

BACKGROUND: Since 2006, the Division of Tropical Public Health at the Uniformed Services University (USU) has sponsored the Tropical Medicine Training Program (TMTP). Despite practice guidelines stating that global health education should include the collection and evaluation of data on the impact of the training experiences, no quantitative evaluation of program outcomes had previously occurred. The objective of this report was to evaluate TMTP outcomes to guide program improvement. METHODS: We developed an anonymous, web-based survey to assess program outcomes as part of routine program evaluation. The survey addressed four main areas of potential TMTP impact: (1) career engagement, (2) military service contributions, (3) scholarly activity, and (4) acquisition of knowledge and skills. In February 2016, we sent the survey electronically to 222 program participants between Fiscal Years 2006 and 2015 who had e-mails available in DoD administrative systems. FINDINGS: Ninety-eight (44%) of these responded to the survey. TMTP demonstrated impact in several areas. Increased knowledge and skills were reported by 81% of trainees, and 70% reported increased interest in serving at military overseas medical research laboratories. Subsequent career engagement by trainees included seven assignments to overseas research laboratories, 71 military deployments, and 193 short-term military missions. The ability to achieve many of the desired outcomes was associated with time elapsed since completion of formal medical education, including 24% who were still enrolled in graduate medical education. DISCUSSION/IMPACT/RECOMMENDATIONS: The TMTP has improved the U.S. military's ability to perform surveillance for emerging tropical and infectious diseases and has contributed to force health protection and readiness. Although many of the outcomes, such as service in the overseas research laboratories and military deployments, are dependent on military service requirements, these results remain perhaps the most relevant ways that the TMTP meets global health requirements of the US military and the nation. Additional outcomes from this training are expected to accrue as these participants complete their medical postgraduate training programs.

Assessment of the QuantiFERON-TB Gold In-Tube test for the detection of Mycobacterium tuberculosis infection in United States Navy recruits.

BACKGROUND: Immunologic tests such as the tuberculin skin test (TST) and QuantiFERON®-TB Gold In-Tube test (QFT-GIT) are designed to detect Mycobacterium tuberculosis infection, both latent M. tuberculosis infection (LTBI) and infection manifesting as active tuberculosis disease (TB). These tests need high specificity to minimize unnecessary treatment and high sensitivity to allow maximum detection and prevention of TB. METHODS: Estimate QFT-GIT specificity, compare QFT-GIT and TST results, and assess factor associations with test discordance among U.S. Navy recruits. RESULTS: Among 792 subjects with completed TST and QFT-GIT, 42(5.3%) had TST indurations ≥10mm, 23(2.9%) had indurations ≥15mm, 14(1.8%) had positive QFT-GIT results, and 5(0.6%) had indeterminate QFT-GITs. Of 787 subjects with completed TST and determinate QFT-GIT, 510(64.8%) were at low-risk for infection, 277(35.2%) were at increased risk, and none had TB. Among 510 subjects at low-risk (presumed not infected), estimated TST specificity using a 15mm cutoff, 99.0% (95%CI: 98.2-99.9%), and QFT-GIT specificity, 98.8% (95%CI: 97.9-99.8%), were not significantly different (p>0.99). Most discordance was among recruits at increased risk of infection, and most was TST-positive but QFT-GIT-negative discordance. Of 18 recruits with TST ≥15mm but QFT-GIT negative discordance, 14(78%) were at increased risk. TB prevalence in country of birth was the strongest predictor of positive TST results, positive QFT-GIT results, and TST-positive but QFT-GIT-negative discordance. Reactivity to M. avium purified protein derivative (PPD) was associated with positive TST results and with TST-positive but QFT-GIT-negative discordance using a 10 mm cutoff, but not using a 15 mm cutoff or with QFT-GIT results. CONCLUSIONS: M. tuberculosis infection prevalence was low, with the vast majority of infection occurring in recruits with recognizable risks. QFT-GIT and TST specificities were high and not significantly different. Negative QFT-GIT results among subjects with TST induration ≥15 mm who were born in countries with high TB prevalence, raise concerns.

DoD-Supported Overseas Training Rotations in Tropical Medicine and Global Health, 2000-2015.

In 1999, the Department of Defense developed a tropical medicine training program (TMTP) to train military physicians, medical students, and scientists in performing surveillance activities in an overseas environment. This review describes the competencies, educational approach, program participants, institutional collaborations, and process outcomes of the TMTP from 2000 to 2015. TMTP-sponsored rotations addressed a wide variety of interdisciplinary competencies, many of which have military-unique applications. Rotations consisted of both didactic and experiential (overseas) components. The program provided 282 rotations for 260 trainees between 2006 and 2015, the years for which data were available. The Department of Defense accrues benefits from this training program in three main ways: (1) building a cadre of health care professionals who will go on to work at the overseas research laboratories, (2) supporting force health protection and readiness through experiential tropical medicine training, and (3) engaging in global health collaborations and partnerships. The primary challenges include funding, health and security, trainee and site heterogeneity, supervision, trainee engagement, and burden on the host institution. The program will continue to focus on improvement in these areas, with special attention to trainee preparation, communication with both trainees and host sites, and increasing reciprocity with host sites and their faculty.

Randomized, controlled, double-blind trial of daily oral azithromycin in adults for the prophylaxis of Plasmodium vivax malaria in Western Thailand.

We assessed the prophylactic efficacy of azithromycin (250 mg/day) against malaria in 276 adults in western Thailand in a randomized, double-blind, placebo-controlled trial. After antimalarial suppressive treatment, volunteers were randomized in a 2:1 ratio to either the azithromycin or placebo, respectively. Study medication was given for an average of 74 days. The azithromycin group (n = 179) had five endpoint parasitemias (1 Plasmodium vivax and 4 P. falciparum), and the placebo group (n = 97) had 28 endpoint parasitemias (21 P. vivax, 5 P. falciparum, and 2 mixed infections). Adverse events and compliance and withdrawal rates were similar in both groups. The protective efficacy (PE) of azithromycin was 98% for P. vivax (95% confidence interval [CI] = 88-100%). There were too few cases to reliably estimate the efficacy of azithromycin for P. falciparum (PE =71%, 95% C =-14-94%). We conclude that daily azithromycin was safe, well-tolerated, and had a high efficacy for the prevention of P. vivax malaria.

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.

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.