The human immune response to saliva of Phlebotomus alexandri, the vector of visceral leishmaniasis in Iraq, and its relationship to sand fly exposure and infection.

BACKGROUND: Sand fly saliva exposure plays an important role in immunity against leishmaniasis where it has mostly been associated with protection. Phlebotomus (Ph.) alexandri transmits Leishmania (L.) infantum, the causative agent of visceral leishmaniasis (VL), in Iraq. Our group recently demonstrated that 20% of Operation Iraqi Freedom (OIF) deployers had asymptomatic VL (AVL) indicative of prior infection by the parasite L. infantum. Little is known about Ph. alexandri saliva, and the human immune response to it has never been investigated. Here, we characterize the humoral and cellular immune response to vector saliva in OIF deployers naturally exposed to bites of Ph. alexandri and characterize their immunological profiles in association to AVL. METHODOLOGY/PRINCIPAL FINDINGS: The humoral response to Ph. alexandri salivary gland homogenate (SGH) showed that 64% of 200 OIF deployers developed an antibody response. To assess the cellular immune response to saliva, we selected a subcohort of subjects based on their post-travel (median 4 months; range 1-22 months) antibody response (SGH Antibody [Ab] positive or negative) as well as their AVL status; ten never-traveled controls were also included. Banked peripheral blood mononuclear cells (PBMC), collected ~10 years after end of deployment, were stimulated with SGH for 96 hours. The levels of IFN- γ, IL-6, IL-10, IL-13 and IL-17 were determined by ELISA. Our findings indicate that OIF deployers mounted a cellular response to SGH where the anti-SGH+ asymptomatic subjects developed the highest cytokine levels. Further, stimulation with SGH produced a mixture of pro-inflammatory and anti-inflammatory cytokines. Contrary to our hypothesis, we observed no correlation between the cellular immune response to Ph. alexandri SGH and prevention from asymptomatic infection with L. infantum. CONCLUSIONS/SIGNIFICANCE: As we found, although all infected deployers demonstrated persistent disease control years after deployment, this did not correlate with anti-saliva systemic cellular response. More exposure to this vector may facilitate transmission of the L. infantum parasite. Since exposure to saliva of Ph. alexandri may alter the human immune response to bites of this vector, this parameter should be taken into consideration when considering the VL risk.

Asymptomatic Visceral Leishmania infantum Infection in US Soldiers Deployed to Iraq.

BACKGROUND: Visceral leishmaniasis (VL), due to Leishmania infantum, is a persistent intracellular parasitic infection transmitted by the bite of infected sand flies. Symptomatic VL has been reported in U.S. soldiers with Iraq deployment. Untreated symptomatic VL can be fatal; asymptomatic VL (AVL) may establish a lifelong risk of reactivation. We report prevalence and AVL risk factors in Operation Iraqi Freedom (OIF) deployers during 2002-11. METHODS: Healthy soldiers exposed to VL endemic areas in Iraq and 50 controls who never traveled to endemic regions were recruited through military healthcare facilities (2015-17). Responses to a risk factor survey and blood samples were obtained. Leishmania research diagnostics utilized included enzyme-linked immunosorbent assay (ELISA), rk39 test strips, quantitative polymerase chain reaction (PCR), and interferon gamma release (IGRA) assays. Statistical analyses included Fisher exact test, Pearson χ2 test, Mann-Whitney U test, and logistic regression. RESULTS: 200 deployed subjects were enrolled, mostly males (84.0%), of white ethnicity (79.0%), and median age 41 (range 24-61) years. 64% were seropositive for Phlebotomus alexandri saliva antibodies. Prevalence of AVL (any positive test result) was 39/200 (19.5%, 95% confidence interval 14.4%-25.8%). Two (1.0%) PCR, 10 (5%) ELISA, and 28 (14%) IGRA samples were positive. Travel to Ninewa governorate increased risk for AVL (P = .01). CONCLUSION: AVL was identified in 19.5% of OIF deployers; travel to northwest Iraq correlated with infection. Further studies are needed to inform risk for reactivation VL in US veterans and to target additional blood safety and surveillance measures.

Predicting Risk of Imported Disease with Demographics: Geospatial Analysis of Imported Malaria in Minnesota, 2010-2014.

Although immigrants who visit friends and relatives (VFRs) account for most of the travel-acquired malaria cases in the United States, there is limited evidence on community-level risk factors and best practices for prevention appropriate for various VFR groups. Using 2010-2014 malaria case reports, sociodemographic census data, and health services data, we explored and mapped community-level characteristics to understand who is at risk and where imported malaria infections occur in Minnesota. We examined associations with malaria incidence using Poisson and negative binomial regression. Overall, mean incidence was 0.4 cases per 1,000 sub-Saharan African (SSA)-born in communities reporting malaria, with cases concentrated in two areas of Minneapolis-St. Paul. We found moderate and positive associations between imported malaria and counts of SSA- and Asian-born populations, respectively. Our findings may inform future studies to understand the knowledge, attitudes, and practices of VFR travelers and facilitate and focus intervention strategies to reduce imported malaria in the United States.

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.

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.

Characterizing the relationship between tick bites and Lyme disease in active component U.S. Armed Forces in the eastern United States.

Lyme disease (LD) is the most commonly diagnosed vector-borne illness in the U.S. Analysis of ticks that are removed from patients (rather than collected from the environment) may inform LD surveillance. In this ecological study, LD rates among active component U.S. Armed Forces in the eastern U.S. were compared with tick data from the U.S. Army Public Health Command Human Tick Test Kit Program (HTTKP) covering the same geographic region. In the population of service members in the study sample, mean annual LD incidence was 52.2 per 100,000 person-years (95% CI±; 7.6 per 100,000) between 1 January 2006 and 31 December 2012. A 10% increase in the rate of ticks submitted to the HTTKP corresponded to an increase in LD incidence of 5.7% (p<0.01). Where Borrelia burgdorferi infection of Ixodes scapularis ticks was high (20% or greater tick infection prevalence), tick removal rates explained 53.7% of the annual variation in LD incidence (p=0.01). These data support using location-specific rates of ticks removed while feeding on active component service members to complement LD surveillance.

An outbreak of Campylobacter enteritis associated with a community water supply on a U.S. military installation.

An outbreak of acute gastroenteritis involving 249 persons, 32% of whom were hospitalized, occurred on a U.S. Army installation in 1990. Campylobacter jejuni was isolated from 81 of 163 (50%) persons cultured. Seventeen isolates of C. jejuni available for serotyping were Lior serotype 5. The outbreak remained restricted to one recruit barracks area and adjacent Junior Reserve Officer Training Corps cadet barracks. Infection of sequential cohorts of recruits over an interval of 3 weeks suggested a continuing or intermittent common source. Contaminated food was not implicated because affected persons ate at separate dining facilities and other facilities with the same food sources had no associated illnesses. There was a strong association between the amount of water consumed by recruits and risk of diarrhea (chi-square test for trend, p<0.001). Samples of drinking water collected in the affected area had no residual chlorine and when cultured yielded greater than 200 colonies of coliform bacteria per 100 mL of water sampled. Although Campylobacter was not isolated from water, living and dead birds were found in an elevated water storage tank providing drinking water to the affected area. This and other similar outbreaks indicate that contamination of water storage tanks can lead to large outbreaks of Campylobacter enteritis.

A retrospective cohort study of military deployment and postdeployment medical encounters for respiratory conditions.

Deployed military personnel are exposed to inhalational hazards that may increase their risk of chronic lung conditions. This evaluation assessed associations between Operation Iraqi Freedom (OIF) deployment and postdeployment medical encounters for respiratory symptoms and medical conditions. This retrospective cohort study was conducted among military personnel who, between January 2005 and June 2007, were deployed to either of two locations with burn pits in Iraq, or to either of two locations without burn pits in Kuwait. Incidence rate ratios (IRRs) were estimated using two nondeployed reference groups. Rates among personnel deployed to burn pit locations were also compared directly to those among personnel deployed to locations without burn pits. Significantly elevated rates of encounters for respiratory symptoms (IRR = 1.25; 95% confidence interval [CI]: 1.20-1.30) and asthma (IRR = 1.54; 95% CI: 1.33-1.78) were observed among the formerly deployed personnel relative to U.S.-stationed personnel. Personnel deployed to burn pit locations did not have significantly elevated rates for any of the outcomes relative to personnel deployed to locations without burn pits. These results are consistent with the hypothesis that OIF deployment is associated with subsequent risk of respiratory conditions. Elevated medical encounter rates were not uniquely associated with burn pits.

Public health practice is not research.

Scientific and clinical activities undertaken by public health agencies may be misconstrued as medical research. Most discussions of regulatory and legal oversight of medical research focus on activities involving either patients in clinical practice or volunteers in clinical trials. These discussions often exclude similar activities that constitute or support core functions of public health practice. As a result, public health agencies and practitioners may be held to inappropriate regulatory standards regarding research. Through the lens of the Departments of Defense and Veterans Affairs, and using several case studies from these departments, we offer a framework for the adjudication of activities common to research and public health practice that could assist public health practitioners, research oversight authorities, and scientific journals in determining whether such activities require regulatory review and approval as research.

Assessing potentially hazardous environmental exposures among military populations: 2010 symposium and workshop summary and conclusions.

From May 19 to May 21, 2010, the Armed Forced Health Surveillance Center and the Uniformed Services University cosponsored an educational symposium and workshop on the assessment of potentially hazardous environmental exposures among military populations. Symposium participants reviewed and analyzed historical exposure events, from herbicides in Vietnam to the 1991 Gulf War oil well fires and World Trade Center dust exposure in 2001, using the framework that the Institute of Medicine developed for addressing environmental exposures and their possible impact on military populations. Historical exposures were critically assessed in terms of methods used to identify and define harmful exposures, to prevent or limit exposures, and to define the health risks to exposed people. The lessons learned were then used during small group discussions to deliberate on the current scientific approach for dealing with hazardous environmental exposures. This article summarizes the major conclusions and proceedings of the symposium and provides suggestions to improve the U.S. military's current strategy on identifying and assessing potentially hazardous environmental exposures.

The Armed Forces Health Surveillance Center: enhancing the Military Health System's public health capabilities.

Since its establishment in February 2008, the Armed Forces Health Surveillance Center (AFHSC) has embarked on a number of initiatives and projects in collaboration with a variety of agencies in the Department of Defense (DoD), other organizations within the federal government, and non-governmental partners. In 2009, the outbreak of pandemic H1N1 influenza attracted the major focus of the center, although notable advances were accomplished in other areas of interest, such as deployment health, mental health and traumatic brain injury surveillance.

Malaria and other vector-borne infection surveillance in the U.S. Department of Defense Armed Forces Health Surveillance Center-Global Emerging Infections Surveillance program: review of 2009 accomplishments.

Vector-borne infections (VBI) are defined as infectious diseases transmitted by the bite or mechanical transfer of arthropod vectors. They constitute a significant proportion of the global infectious disease burden. United States (U.S.) Department of Defense (DoD) personnel are especially vulnerable to VBIs due to occupational contact with arthropod vectors, immunological naiveté to previously unencountered pathogens, and limited diagnostic and treatment options available in the austere and unstable environments sometimes associated with military operations. In addition to the risk uniquely encountered by military populations, other factors have driven the worldwide emergence of VBIs. Unprecedented levels of global travel, tourism and trade, and blurred lines of demarcation between zoonotic VBI reservoirs and human populations increase vector exposure. Urban growth in previously undeveloped regions and perturbations in global weather patterns also contribute to the rise of VBIs. The Armed Forces Health Surveillance Center-Global Emerging Infections Surveillance and Response System (AFHSC-GEIS) and its partners at DoD overseas laboratories form a network to better characterize the nature, emergence and growth of VBIs globally. In 2009 the network tested 19,730 specimens from 25 sites for Plasmodium species and malaria drug resistance phenotypes and nearly another 10,000 samples to determine the etiologies of non-Plasmodium species VBIs from regions spanning from Oceania to Africa, South America, and northeast, south and Southeast Asia. This review describes recent VBI-related epidemiological studies conducted by AFHSC-GEIS partner laboratories within the OCONUS DoD laboratory network emphasizing their impact on human populations.

Seasonal influenza vaccine and protection against pandemic (H1N1) 2009-associated illness among US military personnel.

INTRODUCTION: A novel A/H1N1 virus is the cause of the present influenza pandemic; vaccination is a key countermeasure, however, few data assessing prior seasonal vaccine effectiveness (VE) against the pandemic strain of H1N1 (pH1N1) virus are available. MATERIALS AND METHODS: Surveillance of influenza-related medical encounter data of active duty military service members stationed in the United States during the period of April-October 2009 with comparison of pH1N1-confirmed cases and location and date-matched controls. Crude odds ratios (OR) and VE estimates for immunized versus non-immunized were calculated as well as adjusted OR (AOR) controlling for sex, age group, and history of prior influenza vaccination. Separate stratified VE analyses by vaccine type (trivalent inactivated [TIV] or live attenuated [LAIV]), age groups and hospitalization status were also performed. For the period of April 20 to October 15, 2009, a total of 1,205 cases of pH1N1-confirmed cases were reported, 966 (80%) among males and over one-half (58%) under 25 years of age. Overall VE for service members was found to be 45% (95% CI, 33 to 55%). Immunization with prior season's TIV (VE = 44%, 95% CI, 32 to 54%) as well as LAIV (VE = 24%, 95% CI, 6 to 38%) were both found to be associated with protection. Of significance, VE against a severe disease outcome was higher (VE = 62%, 95% CI, 14 to 84%) than against milder outcomes (VE = 42%, 95% CI, 29 to 53%). CONCLUSION: A moderate association with protection against clinically apparent, laboratory-confirmed Pandemic (H1N1) 2009-associated illness was found for immunization with either TIV or LAIV 2008-09 seasonal influenza vaccines. This association with protection was found to be especially apparent for severe disease as compared to milder outcome, as well as in the youngest and older populations. Prior vaccination with seasonal influenza vaccines in 2004-08 was also independently associated with protection.

Preparing military installations for pandemic influenza through tabletop exercises.

Effective Department of Defense (DoD) response to pandemic influenza requires robust and well-exercised plans at the installation level. This article describes proceedings and key findings from a half-day "train-the-trainer" pandemic influenza tabletop exercise for Tri-Service installation public health emergency officers (PHEOs) at the August 2008 Force Health Protection conference. Exercise participants were expected to facilitate the execution of a pandemic influenza exercise at their respective installations within 6 months of attendance. On a 6-month follow-up survey (N= 50), 68% indicated their installations had since created a new pandemic influenza plan or revised an existing one, whereas 44% indicated that their installation had since conducted a pandemic influenza exercise. Chief reported barriers to conducting installation-level pandemic influenza exercises included competing priorities, followed by time, personnel, and budget limitations. Relevant policy implications for installation-level pandemic influenza readiness include access to higher level plans, strategic utilization of assets to optimize surge capacity, and cross-training of personnel.

Gaining experience with military medical situational awareness and geographic information systems in a simulated influenza epidemic.

The purpose of medical situational awareness is to provide useful and actionable information for preparing and employing medical assets in support of a wide variety of operational missions around the world, and monitoring and protecting the health of the force in the face of rapidly changing health threats. Since 2005, the Medical Situational Awareness in the Theater Advanced Concept Technology Demonstration has exploited advances in information technology, geographic information systems, and open systems architecture to produce a functioning prototype of a medical situational enhancement capability. In May 2006, this prototype supported the medical staff of a combined/joint task force in a realistic command postexercise featuring a simulated outbreak of influenza during Exercise COBRA GOLD in Thailand. The proliferation and maturation of geographic information systems present many opportunities for the military medical community to improve the health of the populations for which it is responsible.