Lisa W. Keep

Detection of Mycobacterium tuberculosis Infection in United States Navy Recruits Using the Tuberculin Skin Test or Whole-Blood Interferon-γ 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.

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.

Non-battle injury casualties during the Persian Gulf War and other deployments.

OBJECTIVE To review injury occurrence and to evaluate various injury surveillance systems used on recent deployments of U.S. military personnel. BACKGROUND Injuries that occur in a deployed military force are more likely to have an immediate and detrimental effect on the military mission than those in garrison or training. These injuries have a direct impact on deployed personnel and unit readiness and consume limited field medical resources. METHODS Data collected during four recent deployments were evaluated. Administrative databases established for the routine collection of death and hospital admissions were used to characterize mortality and morbidity in the Persian Gulf War. Surveillance teams deployed to Haiti, Somalia, and Egypt provided inpatient and outpatient data for those missions. RESULTS Data collected by these surveillance systems are presented. Unintentional trauma accounted for 81% of deaths during the Persian Gulf War and 25% of hospital admissions. During operations in Somalia and Haiti, 2.5% to 3.5% of about 20,000 troops in each deployment sought medical treatment for an injury or orthopedic problem each week. In Egypt, injuries accounted for about 25% of all outpatient visits to medical treatment facilities. CONCLUSIONS Injuries were the leading cause of death and a leading cause of morbidity during recent deployments of U.S. troops. Comprehensive injury surveillance systems are needed during deployments to provide complete and accurate information to commanders responsible for the safety of the force. Recommendations for establishing such systems are made in this article.

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.

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.

Habitat analysis of North American sand flies near veterans returning from leishmania-endemic war zones

BackgroundNearly 1300 cases of leishmaniasis have been identified in American military personnel deployed to Iraq and Afghanistan. The symptoms of this disease can range from a mild, self-limiting cutaneous infection to a deadly visceral infection and are not prevented by chemoprophylaxis or immunization. Effective treatments, however, are available. The disease-causing parasite is spread through the bite of the female sand fly. Although the disease occurs in both the Old World and the New World, the parasite species differ between the hemispheres. The large number of cases in military veterans has caused some concern that Old World, temperate-adapted parasite species could be introduced into the native sand fly populations of American military facilities where veterans of the current conflicts return following their deployments. This paper reports part of a larger study to analyze the risk of such an accidental importation. Four potential habitats on two large Army facilities in the Southeast United States were surveyed to determine relative sand fly density. The National Land Cover Map was used to provide sand fly density prediction maps by habitat.ResultsSand fly density was significantly higher in deciduous forest and even higher at the interface between forest and open grassland. The evergreen forest and agricultural fields supported very low densities. On Fort Campbell, KY, the percentage of land covered by suitable habitat was very high. A sand fly density prediction map identified large tracts of land where infected individuals would be at higher risk of exposure to sand fly bites, resulting in an increased risk of introducing the parasite to a native insect population. On Fort Bragg, NC, however, commercial farming of long leaf pine reduced the percentage of the land covered in vegetation suitable for the support of sand flies. The risk of introducing an exotic Leishmania spp. on Fort Bragg, therefore, is considered to be much lower than on Fort Campbell.ConclusionA readily available land cover product can be used at the regional level to identify areas of sand fly habitat where human populations may be at higher risk of exposure. The sand fly density prediction maps can be used to direct further surveillance, insect control, or additional patient monitoring of potentially infected soldiers.

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.

Morphometric and molecular analyses of the sand fly species Lutzomyia shannoni (Diptera: Psychodidae: Phlebotominae) collected from seven different geographical areas in the southeastern United States.

ABSTRACT A morphometric and molecular study of adult male and female Lutzomyia shannoni (Dyar 1929) collected at seven different locations within the southeastern United States was conducted to assess the degree of divergence between the grouped specimens from each location. The collection locations were as follows: Fort Bragg, NC; Fort Campbell, KY; Fort Rucker, AL; Ossabaw Island, GA; Patuxent National Wildlife Research Refuge, MD; Suwannee National Wildlife Refuge, FL; and Baton Rouge, LA. Forty males and forty females from each location were analyzed morphometrically from 54 and 49 character measurements, respectively. In addition, the molecular markers consisting of the partial cytochrome c oxidase subunit I (from 105 sand flies: 15 specimens/collection site) and the partial internal transcribed spacer 2 (from 42 sand flies: six specimens/collection site) were compared. Multivariate analyses indicate that the low degree of variation between the grouped specimens from each collection site prevents the separation of any collection site into an entity that could be interpreted as a distinct population. The molecular analyses were in concordance with the morphometric study as no collection location grouped into a separate population based on the two partial markers. The grouped specimens from each collection site appear to be within the normal variance of the species, indicating a single population in the southeast United States. It is recommended that additional character analyses of L. shannoni based on more molecular markers, behavioral, ecological, and physiological characteristics, be conducted before ruling out the possibility of populations or a cryptic species complex within the southeastern United States.

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