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3 Evaluation of the Evidence Base and Background of Major Studies and Cohorts This chapter explains how the committee carried out its evaluation of the papers, reports, and other documents that form the foundation of its analyses. It is divided into two primary parts. The chapter begins with a description of the approach and process used by the committee to identify and evaluate the scientific and medical literature on the association between exposure to airborne hazards and respiratory health outcomes among military personnel and veterans who served in Afghanistan and the Southwest Asia Theater of Military Operations1 from 1990 to the present. The majority of the evidence considered by the committee when making its conclusions on the strength of the evidence of an association between exposure to airborne hazards in theater and a specific respiratory health outcome consisted of published epidemiologic studies. The committeeâs literature search criteria as well as its process for screening abstracts, conducting full-text review of studies identified as possibly relevant in the abstract screening, and evaluating the final set of studies identified as relevant are described in detail, including the basic methodologic considerations used for assessment of individual studies. This is followed by the classification system, or categories of association, that the committee used to draw conclusions about the strength of the evidence for each respiratory health outcome it considered. The second part of the chapter provides background descriptions of major cohorts and research initiatives that the committee was tasked with examining. The details of the populations, assessment methods, and outcomes are presented here to minimize repetition when the results of the studies are described in Chapter 4. The section begins with cohorts of post-9/11 operations veterans followed by 1990â1991 Gulf War veterans. Cohorts and large studies of U.S. veterans are presented first, followed by those of foreign coalition forces. IDENTIFICATION AND SCREENING OF LITERATURE The committee was tasked with comprehensively reviewing, evaluating, and summarizing the scientific litera- ture regarding associations between airborne hazards and respiratory health outcomes in theater veterans in order to draw conclusions on the strength of the associations between exposure and outcomes. This section describes 1â The Department of Veterans Affairs defines the Southwest Asia Theater of Military Operations to comprise Iraq, Kuwait, Saudi Arabia, the neutral zone between Iraq and Saudi Arabia, Bahrain, Gulf of Aden, Gulf of Oman, Oman, Qatar, the United Arab Emirates, and the waters of the Persian Gulf, the Arabian Sea, and the Red Sea (VA, 2019). For the sake of brevity, this report refers to this region plus Afghanistan as the âSouthwest Asia theaterâ or simply the âtheater.â 43
44 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES the extensive searches of the published scientific literature that were conducted using major biomedical databases and the process for screening through the identified titles and abstracts. Literature Identification Under the direction of the committee, National Academies staff worked to define and refine searches of the scientific literature. Five databases were examined: Embase, Scopus, Medline, PubMed, and Toxline/Toxnet. These databases index peer-reviewed medical, chemical, biologic, and toxicologic publications. The searches covered the full text of the articles whenever that text was available. If any of the search terms were included in the title or abstract or indexed in the key words or text of the article, the article would be included in the results. The committeeâs search included specific exposure and outcome terms indicated in the Statement of Task as well as terms that were not explicitly mentioned but were implied by the scope of the work. The full set of search terms is shown in Box 3-1. That set included full and abbreviated names, common and scientific names, BOX 3-1 MeSH Search Terms Respiratory Health Outcomes* mortality, bronchitis, asthma, bronchiolitis, chronic bronchitis, chronic obstructive pulmonary disease, bronchiolitis obliterans, cough, dyspnea, emphysema, pulmonary eosinophilia, gastroesophageal reflux, extrinsic allergic alveolitis, idiopathic pulmonary fibrosis, obstructive sleep apnea, pneumonia, pulmonary hypertension, respiratory tract diseases, respiratory tract infections, respiratory signs and symptoms, rhinitis, sarcoidosis, sinusitis, spirometry, vocal cord dysfunction, respiratory sounds, esophageal neoÂ plasms, laryngeal neoplasms, lung neoplasms, nose neoplasms, nasopharyngeal neoplasms, mouth neoplasms, oropharyngeal neoplasms, oropharynx neoplasms Airborne Hazards Exposures Industrial exposure: industrial environment OR occupational air pollutants OR occupational asthma OR occupational diseases OR occupational illnesses OR occupational exposure Environmental exposure: air pollutants OR environmental air pollutants OR air pollution OR environmental illness OR environmental illnesses OR environmental hypersensitivities OR environmental hypersensitivity OR environmental pollutants OR environmental carcinogens Burn pits: incineration OR solid waste incineration OR burn pits OR open burning OR open pits OR open- air burning OR solid waste incineration OR uncontrolled burning OR uncontrolled combustion Fossil fuels: petroleum OR fuel oils OR gasoline OR diesel OR kerosene OR kerosine OR coal Geographic Region Middle East OR Afghanistan OR Bahrain OR Iraq OR Kuwait OR Oman OR Qatar OR Saudi Arabia OR United Arab Emirates OR Djibouti OR Indian Ocean OR Persian Gulf OR Red Sea OR Arabian Sea OR Gulf of Aden OR Gulf of Oman OR SaudiâIraqi neutral zone Military Personnel Air Force OR Armed Forces OR Army OR Navy OR Coast Guard OR Marines OR military OR military deployment OR sailors OR soldiers OR submariners OR veterans * Primary MeSH listings only.
EVALUATION OF THE EVIDENCE BASE 45 and Medical Subject Heading (MeSH) descriptors for each of the exposure and health outcome terms. The search terms for respiratory health outcomes included mortality, cancer, bronchial asthma, chronic bronchitis, sinusitis, constrictive bronchiolitis, and other relevant respiratory health outcomes. The airborne hazards exposure terms included industrial exposures, environmental exposures, and fossil fuels as well as hazards associated with burn pit exposures. Other search terms included geographic regions and military- and veteran-specific nomenclature. The search was limited to articles published in English and was conducted in April 2019. After removing duplicate studies that were identified in multiple databases, 41,646 titles and abstracts were initially identified to be screened. Literature Screening The search strategy was devised to ensure that abstracts of all potentially relevant articles were identified, but it also resulted in the identification of a large number of non-relevant studies. Again under direction of the committee, National Academies staff began screening the results of the literature using a web-based platform to systematically screen and review large volumes of literature. Two reviewers reviewed each title or abstract. When the two primary reviewers were not in agreement, a third reviewer made the determination whether to include an article. Articles that did not have abstracts were generally passed to the full-text review stage unless the informa- tion included in the title clearly excluded it. After a preliminary screening of the first few thousand identified studies, the committee deliberated and deter- mined that the exclusion criteria needed to be strengthened. Studies considered not relevant and excluded from further consideration during the screening phase included studies published before 1991 (approximately 7,500), studies focused solely on respiratory outcomes of children and people under the age of 18, and studies that measured exposures without respiratory health outcomes. Studies that examined conditions or diseases that were not part of the respiratory system (such as cardiovascular system diseases) or that caused secondary effects on the respiratory system (such as amyotrophic lateral sclerosis, which causes breathing problems but which is not a respiratory disease), as well as respiratory health issues caused by physical injuries were all excluded. Animal studies were generally excluded. A complete list of exclusion criteria is found in Box 3-2. The committee focused its review BOX 3-2 Exclusion Criteria â¢ Therapeutic or treatment studies following intentional or unintentional exposure to an agent found in theater â¢ Descriptions of intentional acute exposures or poisoning, including suicide â¢ Narrative or historical accounts of service in theater â¢ Studies that did not relate an exposure of interest to a health outcome of interest â¢ Study populations composed solely of people less than 18 years of age â¢ Exposures that occurred in the Southwest Asia theater prior to 1990 â¢ Respiratory health outcomes resulting from physical injury (e.g., lung injuries due to blast exposure) â¢ Respiratory health conditions or diseases that occur as a result from diseases that do not primarily affect the pulmonary system (e.g., psychogenic dyspnea and cardiovascular disease) â¢ Studies of military populations involved in conflicts outside of the Southwest Asia Theater of Military Operations â¢ Studies of exposures that are not associated with deployment â¢ Non-human studies that do not aim to specifically evaluate the toxic effects from airborne hazards in theater â¢ Populations of non-military or veteran personnel, such as populations of civilians in Southwest Asia countries, firefighters, incinerator workers, or people living near incinerators
46 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES on epidemiologic studies, rather than medical case studies or animal models because epidemiology deals with the frequency, determinants, and distribution of disease in human populations rather than in individuals or in animal models. Epidemiologic studies effectively integrate any results of exposure to a target substance in combination with other substances that may be etiologically relevant. Several types of epidemiologic studies were captured and evaluated, including cohort, caseâcontrol, and cross-sectional designs. Because Southwest Asia theater veterans are the topic of the charge to the committee, the committee chose not to consider studies of respiratory health outcomes in other non-military populations with ostensibly similar exposures. Such populations would include those exposed to the aftermath of the World Trade Center attacks, incinerator workers, and firefighters. While these populations also had or have exposure to smoke or dust associ- ated with the burning of diverse materials, the composition of the chemical agents and particulates present and the duration, intensity, and other circumstances of exposure are materially different from those experienced by deployed service members. In addition, other characteristics associated with deployment, such as living conditions and combat, may also confound the association between airborne exposures and effects. For these reasons, the committee concluded that the differences between these populations and theater veterans were too great to justify their use in evaluations of the health effects of military service in Southwest Asia. Of the more than 41,000 study titles and abstracts screened, only fewer than 200 (n = 196) were found to be relevant. Full text articles of the approximately 200 articles that had passed the screening stage were then retrieved and reviewed. Additional studies were dropped from further consideration after their full text had been read if they met one or more of the exclusion criteria. The committee supplemented the epidemiologic studies identified by the comprehensive literature review with epidemiologic studies found in the reference lists of reviews and relevant studies, book chapters, and government reports as those were presumed to have also undergone some type of review before publication. Additional studiesÂ that were published after the April 2019 literature search were also captured by committee members familiar with the literature in the area and by web alerts set to the topic, although the list of publications identified in this manner may not be exhaustive. Supplemental Evidence Considered Peer-reviewed studies with original data collection and analyses were preferred over studies that were re- analyses of a population (without the incorporation of additional information), pooled analyses or meta-analyses, reviews, and so on. In general, the committee used only published papers that had undergone peer review as the basis for its conclusions. As a supplement to these published epidemiologic studies, a number of identified case studies, conference abstracts and presentations, topic-specific reviews, and commentaries, letters to the editor, and author responses to an included article were used as supportive information for certain topic areas. These supple- mental pieces may be discussed in conjunction with the results from the epidemiologic literature or in synthesis sections on a given exposure or health outcome. Toxicologic studies, which would include studies of laboratory animals and in vitro cultures, focus on mechanisms rather than clinical outcomes, with the latter being the focus of the committeeâs charge. As such, toxicologic studies were included as supplemental sources of information where relevant, but they were not reviewed in the same comprehensive manner as the epidemiologic literature. The supplemental sources, while providing additional information, did not drive the committeeâs conclusions. The committee did not collect original data or perform any secondary data analyses. Invited Presentations As part of fulfilling its Statement of Task, the committee held two open sessions to assist in information gatherÂ ing, which served to inform the discussions throughout this report. During the first open session, on March 27, 2019, representatives from the Department of Veterans Affairs (VA) gave a presentation to formally charge the committee with its Statement of Task and to answer clarifying questions related to the charge. The second open session occurred on October 3â4, 2019, when the committee held a workshop as part of its third in-person meet- ing to assist it in information gathering concerning past and current research efforts that informed discussions
EVALUATION OF THE EVIDENCE BASE 47 throughout this report. The workshop agenda is reproduced in Appendix A. PDF copies of speakersâ presentations are posted to the National Academies website;2 videos of the presentations are also available.3 Highlights of this information are summarized below. During the October 3â4, 2019, workshop, seven of the invited workshop presenters discussed the objectives, methodology, and future efforts of major epidemiologic studies on military and veteransâ health. Rudolph Rull from the Naval Health Research Center presented on topics related to respiratory health research in the Millennium Â Cohort Study (Rull, 2019). This included data regarding the study participantsâ deployment status, combat expo- sure, combat deployment, burn pit exposure, and biomarkers of burn pit exposure. Aaron Â chneiderman from the S VA Post-Deployment Health Services Epidemiology Program spoke about the respiratory conditions and diseases, environmental exposures, and deployment status of study participants in the National Health Study for a New Gen- eration of U.S. Veterans (Schneiderman, 2019). He also presented information on the Comparative Health Assess- ment Interview (CHAI) Study, a national study on the health and well-being of veterans, which was undergoing data cleaning and preliminary analysis in autumn 2019. Drew Helmer from the Michael E. DeBakey VA Medical Center presented work conducted by the VA Airborne Hazards and Burn Pits Center of Excellence (AHBPCE) at the War Related Illness and Injury Study Center (WRIISC) in New Jersey (Helmer, 2019). He discussed the cumulative clinical experience of the WRIISC/AHBPCE post-deployment cardiopulmonary evaluation network, the Airborne Hazards and Open Burn Pit Registry, and other ongoing research at the center. Michael Falvo from WRIISC and the Rutgers New Jersey Medical School discussed the primary outcomes and preliminary data from the Effects of Deployment on Cardiopulmonary and Autonomic Function, a VA pilot study with 50 participants (Falvo, 2019). Michael Morris from the Brooke Army Medical Center presented on the post-deployment respira- tory symptoms of the Study of Active Duty Military for Pulmonary Disease Related to Environmental Deployment Exposures (STAMPEDE) (Morris, 2019a). This included acute eosinophilic pneumonia, chronic obstructive pul- monary disease (COPD), asthma, and sarcoidosis, among others. Eric Garshick from the Harvard Medical School and the VA Boston Healthcare System addressed the Service and Health Among Deployed Veterans (SHADE) study, VA SHADE ancillary study, and burn pitârelated exposures and visibility measurements to predict PM2.5 exposures (Garshick, 2019). Rebekah R. Wu from the Duke University School of Medicine and the Durham VA Cooperative Studies Program Epidemiology Center spoke in depth about the Gulf War Era Cohort Biorepository Project to develop a research cohort of Gulf Warâera veterans and a biorepository to be made available for future research studies (Wu, 2019). This presentation included information on the eligibility of participants, data collected, participant demographics, respiratory exposures, and respiratory symptoms and conditions. Five workshop speakers gave presentations on health issues related to in-theater airborne hazards exposures. Timothy Blackwell from the Vanderbilt University Medical Center presented a detailed overview on lung pathology in patients with post-deployment constrictive bronchiolitis, including an analysis of small airways, blood vessels, and parenchyma in the lungs of service members (Blackwell, 2019). Michael Morris gave a second talk, this one addressing pre- and post-deployment spirometry among military personnel (Morris, 2019b). This included pre- and post-deployment spirometry performed as part of the STAMPEDE series of studies and screening and respiratory health investigations conducted in other populations of military personnel. Joan Reibman from the New York University (NYU) Grossman School of Medicine, NYU Langone Health, NYU/BellevueÂ Asthma Clinic, and the World Trade Center Environmental Health Center, presented on the respiratory health outcomes in community members exposed to environmental toxins from the World Trade Center disaster and its pertinence to Gulf War veterans (Reibman, 2019). Karan Uppal from Emory University explained how the application of high-resolution metabolomics, data science, and integrative omics can be used to evaluate the health effects of environmental exposures (Uppal, 2019). Kimberly Sullivan of the Boston Univer- sity School of Public Health and Nancy Klimas of the Miami VA Medical Center and NOVA Southeastern University spoke about the use of military veteran Â iorepositoriesâparticularly the Gulf War Illness Consortium Biorepository and b the Boston Biorepository, Recruitment and Integrated Network for Gulf War Illnessâin collecting data and conducting research on the respiratory health of military personnel (Klimas, 2019; Sullivan, 2019). 2â See https://www8.nationalacademies.org/pa/projectview.aspx?key=HMD-BPH-18-09; under âEvents,â âOct 3, 2019â (accessed May 15, 2020). 3â See https://www.youtube.com/playlist?list=PLGTMA6QkejfjaqtcHrad0uWZVlMXjB7w3 (accessed May 15, 2020).
48 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES Six of the invited workshop presenters expanded on the use of exposure assessment and diagnostic-related innovations to measure in-theater exposures. Steven Patterson and Jennifer Therkorn from the Johns Hopkins Uni- versity Applied Physics Laboratory gave an overview of exposure assessment in a military environment, covering topics such as burn pits, toxic mixtures, fuel vapor exposures, silicone wristbands, and particulate matter (PM) sensors (Patterson, 2019; Therkorn, 2019). William Funk from Northwestern University talked about emerging biomarker approaches and technologies for exposure assessment (Funk, 2019). This included targeted versus untar- geted biomarker approaches and dried blood spot sampling. Eric Hoffman from the University of Iowa explained how computed tomography (CT) and magnetic resonance imaging can serve to provide lung structureâfunction relationships for the phenotyping of lung disease (Hoffman, 2019). He addressed multi-scale imaging, xenon imag- ing, and dual energy CT. Camilla Mauzy from the Air Force Research Laboratory gave a presentation on toxicity evaluation and biomarker identification in rats exposed to burn pit emissions and respirable sand from Afghanistan (Mauzy, 2019). She explained how molecular analyses using epigenomics, blood proteomics, urine metabolomics, and lung microbiome can aid with identifying biomarkers. Katrina Waters from the Pacific Northwest National Laboratory also discussed various biomarker strategies for exposure and response outcomes (Waters, 2019). The workshop open session also included comments from the public. These included presentations made by representatives from two veterans advocacy organizations. Anthony Hardie from the Veterans for Common Sense gave a brief introduction about his organization and spoke about the impact of respiratory health research on vet- erans like himself (Hardie, 2019). Ronald Brown from the Vietnam Veterans of America gave a presentation on exposure to oil-well fires, chemical weapons, and sandstorms from the perspective of service members (Brown, 2019). He concluded that Gulf War veterans have higher rates of respiratory illnesses after returning from service in the Gulf War. Information Requests Additional requests for information on the details of past and planned research and on reports of respiratory health problems in veterans were made to VA and to experts who were consulted or cited in the course of the committeeâs work. Those requests and the received responses are part of the committeeâs public access file. This information was integrated with the other evidence and used to form the basis of the reportâs findings, conclusions, and recommendations. EVALUATION PROCESS This section details the methods used by the committee for evaluating and synthesizing the identified studies included in the post-full-text review. As part of its evaluation, the committee first outlined the components of an ideal epidemiologic study so that when individual studies were assessed, these aspects were given the most weight. The categories of association used for making conclusions about the strength of the relationship between exposure to airborne hazards and respiratory health outcomes among Southwest Asia theater veterans are presented as the final topic of this section. The quantitative and qualitative procedures underlying the committeeâs evaluation of the literature have been made as explicit as possible, but ultimately the conclusions regarding the associations expressed in this report are based on the committeeâs collective judgment. The committee has strived to express its judgments as clearly and precisely as the data allow. The full-text articles that met the inclusion criteria were distributed among the committee members based on their areas of expertise, with at least one committee member reviewing each paper. The committee began its assessment of the literature by assuming neither the presence nor the absence of an association between exposure and any particular health outcome. Each study was reviewed and objectively evaluated for each health outcome it presented. If a study examined more than one health outcome, it was considered separately as part of the evidence base for each of those outcomes. All studies were grouped by outcome (e.g., all studies that addressed asthma). For each outcome, the committee members responsible read and evaluated each study and presented the information to the entire committee. Such information included the design; methods used for selecting the study populations, conducting exposure and outcome assessment, and analyzing the association; relevant results; and an assessment
EVALUATION OF THE EVIDENCE BASE 49 of the overall strengths, limitations, and potential biases of the study. Following the discussion of each individual study, the lead committee member for the outcome reviewed and summarized the epidemiologic evidence for the outcome. Using the assessments of the individual studies and supplemental evidence where available, the com- mittee discussed the evidence until it came to a consensus regarding the conclusion and assigned a category of association based on the strength of the evidence of a link between exposure to airborne hazards in the Southwest Asia theater and the respiratory health outcome under scrutiny. The committee did not use a formulaic approach to determining the number of studies that would be necessary to assign a specific category of association. Rather, the committeeâs review required expert judgment and a nuanced consideration of all the studies. The committee reviewed all identified studies of U.S. and international Southwest Asia theater veterans published since 1991. In general, few studies included objective measures of the composition and concentrations of airborne hazards. Instead, presence in the Southwest Asia theater was used as a proxy for all military-related and general environmental airborne (and other hazardous) exposures encountered by service members. In some circumstances, a specific potentially harmful exposure was distinguished for analysis, such as proximity to burn pits. Consequently, it is difficult to quantify the risk of a specific respiratory health outcome or the risk of expo- sure to a specific agent or environmental contaminant. Furthermore, it is reasonable to assume that there were variations in exposures across the populations that were studied. In the absence of actual measures of exposure, comparisons between deployed and nondeployed theater-era veterans are considered a more relevant comparison since this implicitly factors in at least some common military exposures. In many studies of in-theater veterans, not all health outcomes of interest were reported, or multiple outcomes were grouped (e.g., studies that examined emphysema, bronchitis, and COPD together). For others, there were too few cases to perform an analysis of certain outcomes, and only the number of outcomes observed was reported. Methodologic Considerations for Assessment Randomized double-blind controlled studies (also called experimental studies) are often considered the âgold standardâ for evaluating the association between an exposure and a health outcome. However, such a design is either not possible or unethical in many circumstances. For example, it is not possible to randomize which ser- vice members are deployed for the purpose of later evaluating health outcomes in the population. Observational study designs (cohort or caseâcontrol, among others) are thus important epidemiologic tools that can complement randomÂzed controlled studies or be used when the former is not possible. i The basic components of any well-designed and methodologically rigorous study of respiratory health out- comes include â¢ designing the study to specifically collect data relevant to respiratory health outcomes rather than using a design or sources that collected information on many health outcomes; â¢ identifying an appropriate comparison group, which should consist of individuals who are similar in both their eligibility for exposure and their baseline risk of developing the outcomes of interest; â¢ using adequate sample size and power to detect a true effect if one does exist (because statistical power depends on several factors, including how common an outcome of interest is, larger sample sizes are needed to study rarer outcomes, such as constrictive bronchiolitis); â¢ performing suitable exposure assessment, a task that is especially critical if one is to attribute adverse health outcomes to specific airborne hazards, such as burn pit exposures, rather than to exposures common to combat and desert environments (the assessment should be based on objective measures when possible rather than self-report of specific exposures); â¢ conducting rigorous outcome assessment based on objective measures and tests, allowing for adequate follow-up time (which could be many years to assess latent effects), and carrying out assessments at multiple time points in order to measure changes in incidence and severity over time; â¢ factoring information on known and potential confounders, which include demographic characteristics, military characteristics, deployment locations, lifestyle and behavioral factors (such as smoking), and other potential exposures to airborne hazards throughout the life course, such as living in areas with high
50 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES air pollution and nonmilitary jobs or hobbies that can entail high airborne exposures (woodworking for asthmatics, for example); and â¢ using appropriate statistical analysis techniques. As part of its charge, the committee that authored Long-Term Health Consequences of Exposure to Burn Pits in Iraq and Afghanistan assessed the feasibility of designing a prospective longitudinal epidemiologic study to answer the question of whether there are long-term health effects from exposure to burn pits in military p Â ersonnelâat Joint Base Balad, specifically (IOM, 2011). Although that committee focused on a single base, many of the elements are the same as those needed to design an ideal epidemiologic study of respiratory health outcomes. That committee recommended that pilot studies be conducted to address issues of statistical power and to develop design features for specific health outcomes; it stated that once a prospective cohort infrastructure has been established, multiple health outcomes could be studied in the cohort over time. Intermediate outcomes on the pathway to the development of chronic diseases could also be assessed. That committee also recommended taking a tiered approach to characterizing exposures to the complex mixture of burn pit emissions and separating them from the other sources of air pollutants in the ambient environment. The three tiers of the study recom- mended by that committee are characterized by decreasing specificity of exposure and would answer different research questions. As with any literature base, the studies of Southwest Asia theater veterans that have been conducted are quite diverse in both their methods and their quality. To assess their contribution to the overall weight of evidenceâgiven that most did not perform objective exposure assessmentâit is essential to consider the quality of the particular methods used to investigate the association because of the substantial unevenness in the rigor and informativeness of specific studies. As already noted, many studies make the implicit assumption that all deployed veterans have the same exposures to airborne hazards. This assumption likely leads to biasing the effect estimate toward the null due to non-differential exposure misclassification. The committee sought to weigh the evidence in the most objective manner possible using methodologic principles. The summaries of the studies that met the committeeâs inclusion criteria include the study methodology, the reported results, the implications of the methods (especially when there are shortcomings) on the results and inferences that can be made, and an assessment of the contribution that the study makes individually and in the aggregate to the evidence base. As has been the case with several other National Academies reports, the author- ing committee of this report recognizes the challenges in traditional hypothesis testing and in an over-reliance on âstatistically significantâ p-values that rely on arbitrary cutoffs. In drawing its conclusions, the committee weighted the consistency of direction of associations over specific statistically significant findings, and the body of evidence was considered as a whole. In its examination and assessment of the available evidence, the committee was looking for signals of associations, so even isolated findings that may well reflect random error from making multiple comparisons or findings that have not been corroborated are reported. Ultimately, replications of results were considered indications of stronger evidence for an association that the committee considered in its weighing. The committee notes that most of the studies reported the results of two-sided tests, which formally assess only whether there is a difference between two groups (which could be either a positive or a negative association). For simplicity and readability, the committee generally discusses the results as âincreasedâ or âdecreasedâ based on the magnitude and precision of the point estimate; in doing so, it does not mean to imply that a formal one-sided hypothesis test was done (which was rarely the case). Categories of Association To rate the strength of the scientific evidence for respiratory health outcomes following exposure to airborne hazards in Southwest Asia, the committee used a system of four categories of association. These categories were adapted from the categories used by the International Agency for Research on Cancer, which have gained wide acceptance by Congress, VA, researchers, and veterans groups and have been used in report series, including Veterans and Agent Orange and Gulf War and Health (both of them being 11-volume series), as well as in several stand-alone reports on topics such as adverse health outcomes of antimalarial drugs when used for prophylaxis
EVALUATION OF THE EVIDENCE BASE 51 (NASEM, 2020). The criteria for each of the four categories of association express a degree of confidence based on the extent to which bias and other sources of error can be reduced and thus on the quality of the evidence. The coherence of the full body of epidemiologic information, including supplemental evidence, was considered when the committee reached a judgment about association for a given outcome. As was the case with several commit- tees that chose to use these categories of association, criteria identified by Hill were used to frame their evaluation of whether an observed association might be causal (Hill, 1965). These criteria, in brief, consist of nine considerations: strength of association, consistency, specificity, temporality, biologic gradient, plausibility, coherence, experiment, and analogy.4 These considerations were not applied, however, as a checklist for strength-of-association assess- ments because they are not a definitive set of elements for assessing causality, and they vary in the importance or weight that might be assigned to each. Instead, the committee discussed the evidence and reached a consensus on the categorization of the evidence for each respiratory outcome of interest. Their collective judgment is presented Â in the Conclusions section for each outcome in Chapter 4. Evidence on each respiratory condition was reviewed in detail, but the committeeâs conclusions are based on the accumulated evidence of published articles, not just on recently published studies. When drafting language for a conclusion, the committee considered the nature of the exposures, the nature of the specific condition, the population exposed, and the quality of the evidence examined. Implicit in these categories is that âthe absence of evidence is not evidence of absence.â That is, based on the cur- rently available literature that met the committeeâs criteria for inclusion, a lack of informative data does not mean that there is no increased risk of a specific adverse event, only that the available evidence does not support claims of an increased risk. When the literature base allows, separate conclusions are made for 1990â1991 Gulf War veterans and post-9/11 veterans. The four categories of association and the criteria for each are described below. Sufficient Evidence of an Association For effects to be classified as having âsufficient evidence of an association,â a positive association between one or more in-theater airborne exposures and a respiratory health outcome in humans must have been observed in studies in which chance, bias, and confounding can be ruled out with reasonable confidence. For example, the committee might regard evidence from several small studies that have no known bias or confounding and that show an association that is consistent in magnitude and direction to be sufficient evidence of an association. ExperiÂ mental animal and in vitro data supporting the biologic plausibility of an association strengthen the likelihood of an association but they are not a prerequisite and are not enough to establish an association without corresponding epidemiologic ï¬ndings. Limited or Suggestive Evidence of an Association For health outcomes in the category of âlimited or suggestive evidence of an association,â the evidence must suggest an association between an in-theater exposure and a respiratory outcome in studies of humans, but it can be limited by an inability to confidently rule out chance, bias, or confounding. Typically, at least one high-quality study indicates a positive association, but the results of other studies could be inconsistent. Because there are a number of agents of concern whose toxicity proï¬les are not expected to be uniformâspeciï¬cally, the many airborne hazards that may be encountered in theaterâapparent inconsistencies can be expected among study populations that have experienced different exposures. Even for a single exposure, a spectrum of results would be expected, depending on the power of the studies, the inherent biologic relationships, and other study design factors. Inadequate or Insufficient Evidence to Determine an Association By default, any health outcome is placed in the category of âinadequate or insufï¬cient evidence to determine an associationâ unless enough reliable scientiï¬c data have accumulated to place it in another of the categories. 4â A more complete discussion of these criteria and the application of the criteria is contained in Gulf War and Health: Volume 8, in a discus- sion titled âInferring Causalityâ (IOM, 2010, pp. 27â28).
52 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES In this category, the available human studies of exposure to airborne hazards in the Southwest Asia theater and respiratory conditions may have inconsistent ï¬ndings or be of insufï¬cient quality, validity, consistency, or statistical power to support a conclusion regarding the presence of an association. Such studies might have failed to control for confounding factors (such as smoking) or might have had an inadequate assessment of exposure. In some cases, the body of evidence is too small to permit firm conclusions, such as when there are no available studies to validate or corroborate the findings of a single study. In other cases, some evidence from human studies exists, but the heterogeneity of exposures, outcomes, and methods leads to inconsistent findings that preclude a more definitive conclusion. Evidence in experimental animal studies may provide insight regarding the biologic plausibility of these associations but, in the absence of human data, is not enough to establish an association. Because the committee could not possibly address every rare condition or disease, it does not draw explicit conclusions about outcomes that are not discussed; thus, this category is the default or starting point for any health outcome. If a respiratory condition or outcome is not addressed specifically in this report, then it can be considered to be in this category. Limited or Suggestive Evidence of No Association The category of âlimited or suggestive evidence of no associationâ is used for health outcomes for which several adequate studies covering the full range of human exposure were consistent in showing no association or a reduced risk with an exposure to airborne hazards encountered in the Southwest Asia theater at any concentra- tion, with the studies having relatively narrow conï¬dence intervals. A conclusion of âno associationâ is inevitably limited to the conditions, exposures, and observation periods covered by the available studies, and the possibility of a small increase in risk related to the magnitude of exposure studied can never be excluded. However, a change in classiï¬cation from inadequate or insufï¬cient evidence of an association to limited or suggestive evidence of no association would require new studies that correct for the methodologic problems of previous studies and that have samples large enough to limit the possible study results attributable to chance. BACKGROUND ON EPIDEMIOLOGIC STUDIES AND POPULATIONS A number of epidemiologic studies have been conducted on the health status of U.S. and other veterans who served in Southwest Asia. The primary objectives of some of the studies have been to determine the nature of the diseases and symptoms experienced by deployed persons, to discern whether symptom clusters represent any new or unique syndromes, and to explore what types of exposures might have produced the health outcomes. The epidemiologic studies of these veterans have contributed to our understanding of veteransâ health, although many are beset by the limitations commonly encountered in all epidemiologic studies. In many cases, the studies used deployment as a surrogate of exposure and made comparisons using veterans of the same era who were not deployed to Southwest Asia (they either remained in the United States or deployed to places outside of Southwest Asia such as Bosnia or Korea). This has led to limitations of representativeness. Studies that group veterans according to their deployed or nondeployed status are limited because this has the effect of assuming that all in-theater veterans have the same exposures with respect to their military duties, locations, status during and after deployment (active duty, reserves, or National Guard or separated), and time in theater (days in theater and number of deployments). Many of the studied populations are chosen based on the ease of recruitment or ease of ascertaining data. This section describes the major studies of service members and veterans as set forth in the Statement of Task as well as others that were identified and are referenced several times in Chapter 4, such as the National Health Survey of Gulf War Era Veterans and Their Families. The accompanying information includes the primary objec- tives; methods and sources of data collection and timeframes of investigation; populations studied; comparison groups; exposure assessment; the respiratory outcomes of interest and how they were identified, such as by self- reported questions, checklists of outcomes, or clinical examinations; relevant demographic, military, behavioral, and lifestyle information collected; and notable strengths and limitations. Some of this information was previ- ously addressed in Gulf War and Health Volumes 4, 8, and 10 (IOM, 2006, 2010; NASEM, 2016) and in the 2017 National Academies report Assessment of the Department of Veterans Affairs Airborne Hazards and Open Burn Pit Registry. New studies on established cohorts are also considered, and the committee has included descriptions
EVALUATION OF THE EVIDENCE BASE 53 of additional cohorts that were not discussed in the previous National Academies reports. However, respiratory health findings from the studies described in this section are presented in Chapter 4. The cohorts were assembled at different times and with different primary intents, but each is important for increasing the understanding of the health of service members and veterans who served in the Southwest Asia theater. Major studies that collected new data (reference studies) or used previously collected data (derivative Â tudies) s to analyze the associations between exposure to airborne hazards in Southwest Asia and respiratory outcomes are listed in this chapter,5 but the details of the individual analyses and the corresponding results are presented in Chapter 4. Some cohorts, once established, led to numerous studies or multiple publications that examined more detailed questions about specific health outcomes; these derivative studiesâwhich may be publications reporting additional results, subcohort analyses, or nested caseâcontrol studies based on the population described by the reference studyâare presented under the same heading as the reference cohort from which the study population was drawn. This organization helped the committee identify populations that have been studied and understand which studies were independent of one another. Establishing which studies rely on the same population sample was important because it helped the committee assess the literature base as a whole when weighing the evidence. Some research efforts resulted in only one or a very small number of papers; these are not addressed here but are summarized in Chapter 4. The Statement of Task directs the committee to pay particular attention to â¦ emerging evidence on respiratory health outcomes in service members from research such as the Millennium Cohort Study, Study of Active Duty Military for Pulmonary Disease Related to Environ- mental Deployment Exposures (STAMPEDE), National Health Study for a New Generation of U.S. Veterans, Com- parative Health Assessment Interview (CHAI) Study, Pulmonary Health and Deployment to Iraq and Afghanistan Objective Study, Effects of Deployment Exposures on Cardiopulmonary and Autonomic Function Study. Additionally, research conducted by WRIISCâs Airborne Hazards Center of Excellence in New Jersey was to be considered. Information on these research efforts is thus presented in this section. Studies of Post-9/11 Operations Veterans The post-9/11 U.S. military operations in the Southwest Asia theater have been Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), Operation New Dawn (OND), Combined Joint Task ForceâOperation Inherent Resolve, and Operation Freedomâs Sentinel. These operations, details of which are provided in Chapter 1, first began in October 2001 (the start of OEF; an operation that has since concluded) and Combined Joint Task ForceâOperation Inherent Resolve and Operation Freedomâs Sentinel are still ongoing as of early 2020. Millennium Cohort Study The Millennium Cohort Study is an ongoing population-based longitudinal study that was initiated to exam- ine long-term health outcomes among U.S. military members. In response to concerns about the health effects of deployments following the 1990â1991 Gulf War, the Institute of Medicine6 recommended that the Department of Defense (DoD) conduct prospective epidemiologic research to evaluate the impact of military exposures, includ- ing deployment, on long-term health outcomes (IOM, 1999). DoD subsequently launched a large epidemiologic study in 2001 through the Naval Health Research Center. Service members from all branches (Army, Navy, Air Force, Marine Corps, and Coast Guard) and all service components (active duty, reserve, National Guard) of the military were randomly selected to participate (Chesbrough et al., 2002; Porter et al., 2020; Smith et al., 2008). Women, reserve and National Guard service members, along with personnel with past deployment experience, 5â Additional publications of outcomes not related to respiratory health outcomes may have been conducted, but only those specific to r Â espiratory health outcomes are listed. 6â As of March 2016, the Health and Medicine Division of the National Academies of Sciences, Engineering, and Medicine continues the consensus studies and convening activities previously undertaken by the Institute of Medicine.
54 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES were oversampled to ensure adequate power for statistical analysis purposes (Smith et al., 2009). The Millennium Cohort Study was designed to have multiple groups (termed panels) of participants who were enrolled every 3â4 years and followed up at multiple time pointsâon average, every 3 years at the same time that the baseline assessment was conducted for the next panel. The first panel consists of 77,047 enrolled participants who were randomly selected from DoD rosters in October 2000. Four additional panels have been recruited since then, and, in total, more than 200,000 service members and veterans have taken part in the study to date. The studyâs self-administered questionnaire consists of more than 450 questions and can be completed online or via hardcopy and returned by mail. Questions include information on potential occupational exposures, health behaviors, health conditions, health care use, military life, and other health and well-being concerns at each 3-year interval. Some questionnaire data are linked to administrative records and military databases to collect or verify information on topics such as mortality, demographics, cancer diagnoses (through cancer registries), medical histories, health care use, and deployment status. This allows for investigators to study additional associations or to factor additional covariates into their analyses of health outcomes. The two most notable advantages of the Millennium Cohort Study are its time period and the size of the sample. Data have been collected in various waves of the study since 2001. The large sample size allows for a more accurate representation of the population of interest. The follow-up surveys allow for the identification of changes in health data over time. As a prospective cohort study, this study reduces the amount of recall bias commonly seen in retrospective studies. Consistent follow-up surveys and the linking of medical databases and deployment records with the responses on the questionnaire further minimizes any significant recall or reporting biases seen in self-reported survey data studies. The study also allows for an examination of multiple outcomes from one or more exposures. Smith et al. (2008) assert that â[p]revious analyses have demonstrated that Millennium Cohort participants well represent the U.S. military, prior health did not influence response rates, and questionnaire data are reliableâ (p. 580). The Millennium Cohort Study, however, does have some limitations. As previously noted, although the amount of recall or reporting bias is designed to be low, it is impossible to completely eliminate bias. Digital military medical records were available only for active-duty military personnel, making it harder to link survey data with military databases for separated military personnel (Rivera et al., 2018). Because data are collected every 3 years, it is often not possible to know the exact timeframe between exposure to a hazard and the onset of a symptom or illness. Additionally, because hazardous exposures are self-reported and validated by deployment status or proxim- ity to a burn pit, the study does not possess accurate information regarding the duration or quantity of exposure to a health hazard. Like all prospective studies, this study is also susceptible to bias resulting from the loss of study participants (illness, death, or refusal to participate) as well as bias between panels and in the overall study. To date, more than 100 papers using data from the Millennium Cohort Study have been published, but few of these examine respiratory health outcomes or airborne hazards exposures among Southwest Asia theater military personnel. Salient publications are described below, and their results summarized in Chapter 4. Smith et al. (2008) conducted an assessment to compare the agreement of 38 medical conditions obtained via self-reported, clinician-diagnosed information with that in electronic medical records of regular, active-duty par- ticipants from the first panel (2001â2003) of the Millennium Cohort Study (n = 37,798). Reservists and National Guard members were excluded because their electronic medical records are not fully available within the DoD medical record system; cohort members who failed to respond to any of the questionnaire items related to the medical conditions of interest or who had missing covariate data were also excluded. Demographic and military covariates included sex, date of birth, education, marital status, race/ethnicity, previous deployment experience (from January 1, 1998, to September 1, 2000), pay grade, service component, service branch (Army, Navy/Coast Guard, Air Force, and Marine Corps), and occupation. Self-reported medical conditions were based on yes/no responses to a list of conditions. Individual, electronic hospitalization and ambulatory data included diagnoses using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes that were obtained from three sources: the Standard Inpatient Data Record, the Standard Ambulatory Data Record, and the Health Care Service Record. For each participant, all electronic data were scanned for ICD-9-CM codes corresponding to medical conditions from the time that the earliest records were available (1988 for the Standard Inpatient Data Record) up to and including the date of survey submission. ICD-9-CM codes were selected to best
EVALUATION OF THE EVIDENCE BASE 55 represent the 38 medical conditions included in the questionnaire (of interest are sinusitis, sleep apnea, asthma, chronic bronchitis, and emphysema). Annual changes in ICD-9-CM coding up to 2003 (the last year of survey submission) were accounted for in the final list of codes. Electronic medical records were scanned in chronological order, and diagnostic fields were scanned in numerical order for the selected diagnostic codes. Any diagnostic code in any portion of the medical record indicated agreement with a self-reported medical condition. Both positive and negative agreement were used to compare self-reported data with those from electronic medical records. One limita- tion with the use of ICD-9-CM codes for assessing concordance is that ICD-9-CM codes are not uniquely related to only one condition. Furthermore, the medical conditions of interest in this study are not mutually exclusive of each other or sometimes have symptoms that overlap (such as chronic bronchitis and emphysema). Conditions diagnosed prior to the time of the medical records search or prior to military service may not be identified from DoD records, which may lead to disagreement between self-reported and medical record conditions. The strengths of this study include its large population and its use of a relatively complete information source to examine a wide range of health conditions. Smith et al. (2009) used responses from 46,077 participants of the Millennium Cohort Study who completed baseline (July 2001âJune 2003) and follow-up (June 2004âFebruary 2006) questionnaires to investigate the occur- rence of respiratory symptoms, asthma, chronic bronchitis, and emphysema. Respiratory outcome assessments were analyzed by deployment status (deployed versus nondeployed) and by cumulative time deployed, while stratifying by service branch and controlling for military and demographic characteristics and smoking behavior. The length of deployment was calculated in days for each participant and based on the cumulative number of deployments from the first deployment occurring after completion of the baseline questionnaire through the last deployment prior to completion of the follow-up questionnaire, after which it was categorized into quartiles ranging from 0 days (nondeployed, referent group) to greater than 270 days. Multivariable logistic regression adjusted for sex, birth year, marital status, race/ethnicity, education, smoking status, service component, military pay grade, and occupational code was used to compare the adjusted odds of the newly reported respiratory outcomes for deployed versus nondeployed participants. Additional models were used to assess associations between the respiratory health outcomes and cumulative deployment length, adjusted for the same covariates. This study is somewhat limited by its use of self-reported data without validation from clinical exams or medical records. However, the strengths of this analysis include its population-based design; its use of prospectively collected data on the same individuals; its inclusion of personnel from all service branches and components, including those no longer in military service; its use of large sample sizes that allow for adequate statistical power to assess the outcomes of interest; and the use of statistical methods to control for multiple demographic, military, and lifestyle confounders. Smith et al. (2012) investigated the effects of exposure to documented open-air burn pits within 2, 3, or 5 miles on self-reported respiratory outcomes of symptoms of persistent or recurring cough or shortness of breath, asthma, and chronic bronchitis or emphysema among 22,844 Millennium Cohort Study Army and Air Force participants who were deployed to Iraq or Afghanistan after January 1, 2003, and who completed the baseline questionnaire and one of the follow-up assessment cycles through 2008. This analysis built on those performed by the Naval Health Research Center (AFHSC, 2010), which used a 5-mile radius of burn pit exposure and is detailed later in this chapter under the heading Armed Forces Health Surveillance Center Studies. Three proxy measurements were used to assess exposure: deployments near any of three documented, open-air burn pit sites (Joint Base Balad, Camp Taji, or Camp Speicher) were compared with deployments to other locations that had no known burn pits; cumulative days exposed within the vicinity of any of the burn pits (categorized into quartiles) were compared with no days deployed to the burn pit locations; and to measure whether a specific burn pit site was associated with risk, deployment to one of the three sites was compared with deployments to other locations with no burn pits, where specific burn pit sites were modeled separately and individually. Separate models compared the odds of associa- tion between each respiratory outcome and each of the three proxy measures assessing open-air burn pit exposure while adjusting for all demographic (sex, birth year, marital status, race/ethnicity, education), behavioral (smok- ing status: nonsmoker, past smoker, consistent smoker, or resumed or new smoker; aerobic activity), and military (service branch, military rank, pay grade, occupation, and date of military separation, if applicable) covariates. The demographic and military characteristics for the study participants were provided by the Defense Manpower Data Center (DMDC), and the respiratory outcomes, smoking status, and aerobic activity were collected using the
56 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES Millennium Cohort Study questionnaire. Most of the results that were presented focused on analyses using burn pit exposures within 3 miles; the 2-mile analysis was restricted to newly reported respiratory outcomes among Air Force members. The primary purpose of the study was to examine each respiratory outcome by service branch for those with and without exposure to burn pits. This study is limited by its use of self-reported outcomes, which were not confirmed by clinical examinations or a review of medical records. The average follow-up period was 2.9 years, which may not adequately capture the development of more chronic conditions or changes in symptoms (cough or shortness of breath) that may change over time. The exposure assessment was broad and non-specific, and the characteristics of burned materials were not considered. The use of the number of days of exposure and individual camps with documented burn pits and consideration of distance from the burn pit locations strength- ened the analysis since individual levels of exposure were not possible; this and the ability to control for multiple confounders, including smoking status, were considered strengths of the study. In addition to the studies summarized above, other analyses also used data from the Millennium Cohort Study. Rivera et al. (2018) examined risk factors for new-onset asthma, specifically combat deployment, among 75,770 cohort study participants who were deployed to Southwest Asia and participated in the study from 2001 to 2013 (panels 1, 2, and 3). In its analysis of the association between deployment to areas near burn pits and respira- tory health outcomes, the Armed Forces Health Surveillance Center (AFHSC, 2010) used merged data from the M Â illennium Cohort Study as part of their analyses. Abraham et al. (2014) and Sharkey et al. (2015), described later in this chapter under Armed Forces Health Surveillance Center Studies, also built on these analyses. Study of Active-Duty Military for Pulmonary Disease Related to Environmental Deployment Exposures STAMPEDE is a series of prospective studies that examine deployment-related respiratory symptoms and pulmonary disease among U.S. service members returning from the Southwest Asia theaterâspecifically, Iraq, Afghanistan, Kuwait, and Qatar (Morris et al., 2013, 2014, 2019, 2020). Though the three studies in the series have overlapping information, the questionnaires and overall methods used for each differ from one another. In brief, STAMPEDE I participants were asked to complete a deployment questionnaire, STAMPEDE II participants were administered one pre-deployment and one post-deployment questionnaire, and STAMPEDE III participants were asked to submit a deployment questionnaire and answer additional questions related to their potential expo- sure to burn pits. Three STAMPEDE papers that address outcomes of interest in this report are summarized below. The STAMPEDE I study (Morris et al., 2014) was a preliminary prospective evaluation of new-onset respiratory symptoms in 50 military personnel deployed to Iraq or Afghanistan whose goal was to determine potential etiologies for symptoms. All study participants were active-duty military personnel who were recruited after deployment to Southwest Asia starting in July 2010. Participants were evaluated for deployment-related pulmonary symptoms after reporting respiratory symptoms within 6 months of returning to their duty station. This relatively small study consisted of multiple study components, such as medical examinations and diag- nostic procedures, designed to provide a comprehensive evaluation of pulmonary symptoms. The components included a detailed deployment questionnaire (which included questions concerning deployment history; air- borne exposures; smoking; pulmonary symptoms experienced before, during, and post-deployment; and medical treatment data) that was completed by 42 of the participants, a laboratory examination, radiographic imaging, pulmonary function testing, impulse oscillometry, methacholine challenge testing, fiberoptic bronchoscopy with bronchoalveolar lavage, and chest tomography. Lung biopsies were performed if clinically indicated. The major- ity of participants were male (80%), identified as white (58%), and had deployed to Iraq (64%). The mean age was 31.9 Â± 8.4 years, and the mean deployment period was 11.7 Â± 3.6 months. Most participants (58%) never smoked, while 26% were previous smokers, and 16% were current smokers, who averaged 0.5 packs per day. The reported airborne hazards exposures included sandstorms and blowing dust (97%), burn pit smoke (92%), smoke/vehicle exhaust (86%), and various chemicals (52%). The differences in lung measures were calculated using t-tests. This primarily descriptive study was limited by its small sample size, which was drawn from a single referral center, which leads to concerns regarding generalizability and statistical power. Although recall bias is another potential concern, diagnostic tests and clinical examinations performed as part of the study help to temper some of the recall bias effects on questionnaire responses. No modeling was performed, and analyses
EVALUATION OF THE EVIDENCE BASE 57 were not adjusted for potential confounders. The study is further limited by the lack of a comparison group. The extensive examinations, procedures, and diagnostic tests performed are an important strength of this study as they provide for more accurate diagnoses of symptoms. In STAMPEDE II, Morris et al. (2019) conducted a prospective study of pre- and post- deployment lung func- tion among Army personnel deployed to Iraq, Afghanistan, Kuwait, or Qatar. Active-duty soldiers were recruited from the Soldier Readiness Processing Center at Fort Hood, Texas, from 2011 to 2014. Any soldier with a pending deployment to Southwest Asia was eligible to participate. A total of 1,693 participants completed a pre-deployment questionnaire that collected data on demographics, smoking status, and respiratory health and underwent baseline chest radiography, spirometry, and impulse oscillometry. The post-deployment evaluation was conducted within 2 weeks of return from deployment for those individuals who returned to the Fort Hood processing center and included the same questions as on the pre-deployment questionnaire but also included additional questions on current medica- tions; medical history including respiratory illnesses; respiratory symptoms before, during, and after deployment; run time performance on the physical fitness test; and airborne exposures experienced during deployment (dust and/ or sand, vehicle exhaust, burning trash, and industrial fumes). Repeated chest radiography, spirometry, and impulse Â oscillometry were also conducted as part of the post-deployment exam. Only half (n = 843) of the soldiers who completed the baseline examinations also completed the post-deployment testing. The majority of the participants who completed the post-deployment questionnaire and exam were male (83.4%), white (58.4%), never smokers (70.1%), and overweight or obese (76.2%). Soldiers were nearly equally split by component: active duty (29.1%), National Guard (35.1%), and reserve (35.1%). Although only half of the participants who completed the baseline questionnaire and exam also completed them post-deployment, no differences in demographics were found between those who completed the post-deployment questionnaire and exam and those who did not. The mean values Â± standard deviation were used as summary statistics for continuous variables, such as spirometry data, and student t-tests were used when appropriate. Odds ratios were calculated using multivariable logistic regression models, which included potential risk factors (smoking, presence of obstruction, increased body mass index [BMI], or self- reported asthma) for spirometric obstruction during deployment and post-deployment symptoms (dyspnea, cough, wheezing, sputum production, and decreased exercise tolerance). STAMPEDE II has the advantages of having a prospective design that assessed respiratory health pre- and post-deployment and using a much larger sample size than STAMPEDE I. Although recall bias is a concern, diagnostic tests and clinical examinations performed as part of the study help to temper some of the possible recall bias effects on questionnaire responses and are a strength of this study as they provide for more accurate diagnoses of symptoms. Because participants were limited to soldiers who were passing through a single processing center, the generalizability of the findings is limited. The purpose of STAMPEDE III was to enroll active duty and retired military personnel who had deployed to Southwest Asia for a minimum of 6 months with onset of chronic respiratory symptoms (primarily exertional dyspnea or decreased exercise tolerance) temporally related to deployment and to perform a comprehensive clinical cardiopulmonary evaluation on them (Morris et al., 2020). A total of 380 military personnel were recruited from the Brooke Army Medical Center or the Walter Reed National Military Medical Center. Participants completed a deployment questionnaire (deployment history, airborne exposures, smoking status, and pulmonary symptoms before, during, and after deployment), answered questions taken from the VA Airborne Hazards and Open Burn Pit Registry questionnaire, and underwent a history and physical examination. The pulmonary function testing consisted of spirometry, lung volume, diffusing capacity, impulse oscillometry, and bronchodilator testing. Other tests included methacholine challenge, exercise laryngoscopy, high-resolution CT scan, electrocardiography, and transthoracic echocardiography. The deployment questionnaire was completed by 86% of participants. Of the 380 participants, the majority were male (88%), white (70%), and never smokers (64%). The average age of participants who completed testing was 38.5 Â± 8.4 years. One-third of the participants were obese. Most participants served in Iraq or Afghanistan, with total deployments of 1.7 Â± 2.0 per individual. The reported results were primarily descriptive, with comparisons of the diagnostic categories based on means and standard deviations. Continuous variables were analyzed using the Wilcoxon test with a Steel-Dwass adjustment for pairwise comparisons. The use of several objective pulmonary function tests and the large sample size are strengths of the analysis. However, as in STAMPEDE I, this study is limited by recall bias for reporting the presence and severity of symptoms pre- deployment and is also limited by the fact that the study population was limited to service members with chronic
58 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES respiratory symptoms who were seen at one of two medical centers, thereby limiting the generalizability of the findings. National Health Study for a New Generation of U.S. Veterans The population-based cohort study National Health Study for a New Generation of U.S. Veterans, known as NewGen, was initiated by VA to examine the overall health of a randomly selected sample of 60,000 veterans who served in the military between October 2001 and June 2008 (Eber et al., 2013). All participants were sampled from DoD records. This included 30,000 veterans deployed to OEF or OIF and 30,000 veterans who were not deployed to these conflicts. Service members from each branch and component of the military were included in the study. Female veterans were oversampled by 20%. All veterans participated in the study by completing the 72-item, self-administered questionnaire, which collected a variety of information, including environmental exposures, respiratory conditions, health behaviors, physical parameters, and VA health care use. In addition, the medical records of 2,000 participants were reviewed for certain health conditions. The overall study had a response rate of approximately 34%, or 20,563 participants, and was conducted between August 2009 and January 2011 (Eber et al., 2013). NewGen has multiple strengths as well as limitations. Although the response rate was just 34.3%, the overall number of survey participants was still more than 20,500, with representation from all branches and components of the military. As with any cohort study that uses self-reported surveys to collect data, this study was likely subject to recall bias in its survey responses, leading to both overreporting and underreporting. Though the study takes into account the number of deployments among OEF and OIF service members, it does not contain data on the total time spent in service or the start date of the participantâs entry into the military, leading to inaccurate measurement of exposure to respiratory hazards (Barth et al., 2014, 2016). Two NewGen studies that report on respiratory health outcomesâBarth et al. (2014), which examined the prevalence of asthma, bronchitis, and sinusitis, and Barth et al. (2016), which determined the lifetime prevalence of respiratory exposures and the, relationship between exposures and respiratory healthâare summarized below. The results of their analyses are presented in Chapter 4, along with information from a third NewGen study (DÃaz Santana et al., 2017). Barth et al. (2014) investigated the population prevalence of asthma, bronchitis, and sinusitis using the data from 20,563 veterans who participated in NewGen. The researchers compared veterans deployed to post-9/11 con- flicts (n = 13,162) with nondeployed veterans (n = 7,401). Birth year, unit component, and branch of service were all gathered from the administrative records used to design the NewGen survey; all other variables were assessed based on participant self-report on the study questionnaire. Conditions were identified by asking, âHas a doctor ever told you that you have any of the following conditions?â with a follow-up question, âYear first told?â Condi- tions reported before 2001 were classified as before service. Statistical weights were used to adjust the stratified sampling design for non-response and to improve the precision and accuracy of the population prevalence. Logistic regression was used to produce unadjusted and adjusted odds ratios (adjusted for birth year, sex, service branch, unit component, race/ethnicity, education, and smoking status). Separate models were used to examine diagnoses before 2001 and during or after 2001 because the impact of deployment should differ based on whether the respiratory disease was diagnosed before or after deployment. This study has several strengths. Its weighted effect estimates ensure that the prevalence estimates are a robust representation of the burden of respiratory illnesses. Investigators controlled for confounders during data analysis, although it is unclear if the investigators used causal diagrams to choose the appropriate confounders, which can be important to ensure that model adjustments do not introduce biases (Shrier and Platt, 2008). The study also had a highly relevant comparison group of nondeployed veterans, which was appropriate, although the nondeployed comparison group was much smaller than the deployed group. Furthermore, the data used in this study were not restricted to medical encounter data from within the VA health system. The use of self-reported data has limitations, including the potential for recall bias. The study investiga- tors also did not account for the impact of multiple deployments or deployment during the 1990â1991 Gulf War, which may have affected the studyâs findings. Finally, the authors did not address whether the deployment occurred during the etiologically relevant time period for the development of the disease. Additionally, although NewGen
EVALUATION OF THE EVIDENCE BASE 59 could be used to evaluate disease changes over time through the collection of repeated measures, this paper is a baseline assessment and cannot calculate those more complex rates. Barth et al. (2016) expanded on the analysis of NewGen data by Barth et al. (2014) to examine the preva- lence of respiratory diseases (asthma, bronchitis, sinusitis) and added a category of âany respiratory diseaseâ and their association with self-reported respiratory exposures during military service for OEF/OIF deployed and nonÂ eployed veterans. Respiratory exposures were collected by self-report responses (yes/no) to five options that d were specified to have occurred during military service: dust and sand; burning trash/feces; diesel, kerosene, and/or other petrochemical fumes; smoke from oil fires; and industrial pollution. âAny respiratory exposureâ was defined by at least one affirmative response to any of the five exposures. The five respiratory exposures were summed for each individual to create a variable for the number of different exposures, where low exposure was defined as one to two different exposures, and high exposure was defined by three to five different exposures. Of the deployed veterans, approximately 32% were considered to have low exposure, 55% were considered to have high exposure, and 13% had no exposure. Weights were created to improve accuracy of the population prevalence estimates by adjusting for the sample design, non-response, and misclassification in the sampling frame. Logistic regression analyses were used to calculate weighted, adjusted odds of respiratory disease stratified by deployment status and controlled for sex, birth year, race/ethnicity, education, smoking status, unit component, service branch, and number of OEF/OIF deployments. Similar to the other analyses of NewGen data, the population-based sample of veterans included those who accessed VA health care and those who did not, which is more generalizable to the total OEF/ OIF and OEF/OIF-era veteran populations than is the group of those who use only VA health care services. As with this groupâs prior work (Barth et al., 2014), the data were based only on self-report, so recall bias is a factor, especially for individuals who deployed many years before the survey. Other limitations included unknown dates of respondentsâ entry into the military and not adjusting for respiratory conditions that occurred before or after joining the military or before or after deployments. The survey questions regarding respiratory exposures inquired about exposures during military service, not specifically during OEF/OIF deployment. Comparative Health Assessment Interview Study The CHAI Study is a health survey conducted on veterans who served after September 11, 2001, whose goal is to help VA better understand the effects of military service, deployment, and combat on the health and well-being of veterans who served in OEF, OIF, and OND. The study consists of two components: an online or telephone survey and an in-person interview to test neurocognitive function for a subsample of veterans. Out of 38,633 veterans who were invited to participate in the study, 15,166 veterans completed the survey. This 39% response rate included 6,591 veterans who were deployed to Southwest Asia, 4,195 veterans who were not deployed to Southwest Asia, and 4,380 veterans who were never deployed. Of 16,483 civilian controls who were invited to participate in the study as the comparison group, 4,654 (response rate 28%) completed the survey. Women were oversampled by 30%. The investigators have also completed 300 neurocognitive assessments from a subsample of veterans. The study questionnaire collects data on physical health, mental health, social relationships, and occupational well- being. Both the veteran and civilian versions of the survey were framed in a way that provides a direct comparison of health and experiences between the two groups. The latest update on the study suggests that the researchers have completed the survey data collection and the neurocognitive assessments. As of early 2020, the study was in the analysis stage, and no publications related to respiratory health outcomes were available for the committeeâs review (Schneiderman, 2019; Schneiderman et al., 2020). Effects of Deployment Exposures on Cardiopulmonary and Autonomic Function Study The cross-sectional study Effects of Deployment Exposures on Cardiopulmonary and Autonomic Function Study (AirHzds) was conducted by VAâs Office of Research and Development to evaluate cardiorespiratory and autonomic function in 32 OEF, OIF, and OND veterans exposed to high levels of PM compared with 18 veter- ans who were deployed to regions other than Southwest Asia. Cardiopulmonary function was evaluated using a standardized exercise challenge and bronchodilator spirometry, while autonomic nervous system function was
60 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES evaluated by examining the indices of heart rate variability and cardiovascular reflex regulation during different tasks (Falvo, 2017, 2019). No AirHzds study publications related to respiratory health outcomes were available for the committeeâs review at the time its work was completed in early 2020. War Related Illness and Injury Study Center WRIISC was established in 2001 as part of VAâs Post Deployment Health Services as a national research program that focuses on the post-deployment health concerns and health care needs of veterans. Research gener- ated from WRIISC is used to identify new areas of concern and to provide post-deployment health care solutions to âveterans and their health care providers through environmental exposure assessments, medical evaluations, clinical care, education and risk communicationâ (VA, 2020). WRIISC also provides post-deployment health educa- tion to families of veterans who were deployed. The topics of research studies conducted by WRIISC include the long-term health effects of combat; neurological diseases, traumatic brain injuries, and other deployment-related disabilities; the environmental exposures of deployment; and womenâs health. The Airborne Hazards Center of Excellence (AHCE), which was designated the Airborne Hazards and Burn Pits Center of Excellence in 2019, is a part of WRIISC. The center works to improve the health of veterans through gaining a better understanding of the potential health effects of exposure to airborne hazards. Its inves- tigators study the impact of exposure to airborne hazards on a variety of health outcomes, including respiratory health. Studies conducted by AHCE involve many of the same tests used in specialty care, such as assessment of cardiopulmonary function and exercise ability. These assessments aid the center in making recommendations regarding the management of symptoms and follow-up care needed to improve the quality of life among veterans exposed to airborne hazards. Research on respiratory health issues conducted by WRIISC and center investigators is summarized in Chapter 4 (Butzko et al., 2019; Falvo et al., 2016a,b; Garshick et al., 2019; Jani et al., 2017; Lindheimer et al., 2019). Studies of Burn Pit Exposures Exposure to emissions from burn pits has been of particular concern among those interested in respiratory health. The effects of such emissions have been examined in several publications, including a 2017 National Academies report and an analysis from the Armed Forces Health Surveillance Center (AFHSC, 2010), the latter of which was then used as the basis for additional work. These publications are described next. Airborne Hazards and Open Burn Pit Registryâ The committee responsible for the 2017 National Academies report Assessment of the Department of Veterans Affairs Airborne Hazards and Open Burn Pit Registry carried out an analysis of the initial months of data gathered from respondents to the registry questionnaire as part of its Statement of Task (NASEM, 2017). The registry, which was created by Public Law (PL) 112-260, is open to service members who were deployed to the Southwest Asia theater and Djibouti, Africa; participation is voluntary. The data analyzed by the committee were derived from the first 13 months (June 2014âJuly 2015) of completed questionnaires (n = 46,404), accounting for approximately 1.0% of the 1990â1991 Gulf War veterans and 1.7% of post-9/11 veterans who met the registryâs eligibility criteria. As this is a registry, there was no comparison group. Health outcomes were characterized by self-reports of health care providerâdiagnosed conditions, by exposures to burn pits and other airborne hazards based on self-report, and by DoD data on the number and location of deployments. The committee also synthesized exposure metrics by combining the responses to questions regarding specific exposures. For that committeeâs multivariate analysis of airborne hazards exposure potentials and selected respiratory and cardiovascular health outcomes, the population was limited to post-9/11 conflict respondents. Several metrics of exposure were considered. First, the committee examined exposure to burn pits using three measures that combine the duration and presumed intensity of exposure based on self- reported responses to the questionnaire: (1) cumulative days deployed near a burn pit, derived by summing the number of days of each deployment for which a respondent indicated that he or she was near a burn pit; (2) cumulative days of burn pit duty; and (3) cumulative hours of exposure to smoke from burn pits, created
EVALUATION OF THE EVIDENCE BASE 61 by multiplying the average number of hours each day that smoke or fumes from burn pits entered the worksite or housing by the number of days of deployment. Those measures were presented as quartiles, with the first (lowest exposure) quartile serving as the reference group. Other exposures contribute pollutants that may lead to respiratory distress, and therefore dust, diesel/exhaust/fuel, combat, and construction exposure potential scores were considered in the analysis and were presented as categories ranging from 0 to 6, where 0 was the lowest level of exposure potential and also served as the reference group for comparisons. The committee also used a composite exposure potential measure, which was calculated based on the levels of exposure to the six individual exposure categories (burn pits, dust, diesel, combat, construction, soot) to examine the association between the totality of airborne exposures of concern and each health outcome; those results were presented as quartiles, with the first quartile again serving as the reference. The respiratory outcomes that were examined included asthma; emphysema, chronic bronchitis, or COPD as a composite variable; any functional limitation due to a lung or breathing problem; and respiratory symptoms as a composite variable. The models excluded respondents who had been diagnosed with a respiratory disease before deployment. Respondents with missing exposure or disease were excluded from the analysis. Sample sizes differed across models and ranged from 32,178 for construction exposure and emphysema, chronic bronchitis, or COPD to 39,271 for each of the three burn pit metrics and any respiratory symptoms. All models were adjusted for sex; age at questionnaire completion in approximate quartiles (19â30, 31â37, 38â44, or â¥45 years); education level (less than college or âsome college or moreâ); race/ethnicity (white or âotherâ); BMI (underweight/normal [<25 kg/m2], overweight [25â30 kg/m2], or obese [>30 kg/m2]); smoking status (current smoker, former smoker, or never smoker); unit component (active duty, National Guard, or reserve); rank (enlisted, warrant officer, or commissioned officer); service branch (Army, Navy, Marine Corps, Air Force, or Coast Guard); and primary duty occupational specialty (10 broad groups based on the groups used in the Millennium Cohort Study). For covariates with less than 5% missing data, the missing data were imputed with the modal category. For covariates with greater than 5% missing data, a separate âmissingâ category was included in the analysis. The report detailed a number of issues with the quality and limitations of the registryâs information, which led the committee to conclude that the results of the analyses could not be taken at face value and that any identified associations (or lack thereof) might be an artifact of the populationâs selection and the limitations of the voluntary participation and self-reported exposure and disease data. Specific respiratory health results are discussed in Chapter 4. Armed Forces Health Surveillance Center Studiesâ An analysis conducted by the Armed Forces Health Surveil- lance Center (AFHSC, 2010) examined medical encounters at military facilities by Army and Air Force personnel within 36 months of April 2006, after deployment to Joint Base Balad, Camp Taji, or Contingency Operating Base Speicher (which were located in Iraq and which had burn pits), Camp Buehring or Camp Arifjan (which were located in Kuwait and did not have burn pits), or the Republic of Korea (where there was exposure to urban air pollution and other airborne PM) from 2005 to 2007. Personnel who served within 3 miles of burn pits were considered to have been exposed (15,908 at Joint Base Balad and 2,522 at Camp Taji) and were compared with 51,299 personnel at bases without burn pits and 237,714 personnel in the United States who had not deployed as of April 2006. Respiratory outcomes were limited to all diseases of the respiratory system (ICD-9 460â519) and, specifically, acute respiratory infections (ICD-9 460â466), COPD and allied conditions (ICD-9 490â492, 494â496), and asthma (ICD-9 493). Incidence rate ratios were calculated using Poisson regression models and adjusted for age at the start of follow-up, sex, race, military pay grade at the start of follow-up, and service branch to compare the deployed populations to the U.S.-based population. Only the overall results were presented because, as the authors state, service-stratified and time-stratified analyses were similar to the overall cohort. Additional analyses of respiratory health outcomes were conducted using data merged with those collected as part of the Millennium Cohort Study (described earlier in this chapter). Information from the Millennium Cohort Study included data on smoking status (nonsmoker, past smoker, current smoker, or resumed or new smoker), mental and physical health, and physical activity, among other demographic, behavioral, and military c Â haracteristics. Specific questions on respiratory health included self-reported provider-diagnosed asthma, chronic b Â ronchitis, emphysema, and persistent or recurrent cough and shortness of breath. Data on demographic and military characteristics, deployment in support of the operations in Iraq and Afghanistan, and deployment within
62 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES a 5-mile radius of a documented burn pit from the three camp sites were obtained from DoD. For the respiratory outcomes analysis, the population included deployed personnel who completed the baseline questionnaire (admin- istered June 2004âFebruary 2006) and the first follow-up questionnaire cycle (administered June 2007âDecember 2008) of the Millennium Cohort Study. Newly reported outcomes were defined as the presence of the condition at follow-up without an indication of the condition at baseline, while the prevalence of self-reported respiratory symptoms was measured at both time points. Separate models were developed for each respiratory outcome. MultiÂ variable logistic regression analyses were performed to compare the adjusted odds of association for respiratory outcomes relative to three metrics of exposure within a 5-mile radius of the documented burn pits: dichotomous deployment near the documented burn pits, cumulative days exposed to the burn pits, and exposure to the burn pits at three different base camp sites (Balad, Taji, or Speicher). Cumulative days exposed within a 5-mile radius of the documented burn pits were summed and categorized into quartiles, and persons in each quartile were com- pared with those with no documented exposure to these burn pit sites. The analyses were adjusted for sex, birth year, marital status, race/ethnicity, education, smoking status, physical activity, service branch, military rank, pay grade, and occupation. All covariates were measured at baseline, but smoking status was prospectively assessed using the 2004 and 2007 survey instruments, and physical activity was measured using the 2007 survey instrument. Both Abraham et al. (2014) and Sharkey et al. (2015) used the same population as the AFHSC study (2010) but reported on analyses with an additional 12 months of follow-up (48 months total, starting April 2006) for respiratory outcomes. While both studies used the same cohort and data sources, there were slight methodologic differences between them, including the size of the nondeployed referent group (112,091 in Abraham et al.  and 237,714 in Sharkey et al. ) and the covariates used. None of the analyses were able to control for smok- ing or other important exposures related to respiratory disease, and both were limited by their exclusive use of military medical records (medical encounters outside of the military system were not included). Sharkey et al. (2016) extended the analyses of this cohort by considering data from three additional sites, two of them located in the Southwest Asia theater. Study participants were U.S. Army or Air Force personnel who were deployed to Kabul (n = 5,670) and Bagram (n = 34,239) Air Force bases in Afghanistanâsites with similar, poor air qualityâand Manas Air Force Base in Kyrgyzstan (n = 15,851)âa site with relatively better air quality. Any active-duty service member who spent 30 days or more deployed to one of these locations between January 1, 2002, and December 31, 2011, was eligible for inclusion in those exposure groups. These deployed personnel were compared with 40,470 stationed in Korea (a site with poor air quality) and with 122,687 service members who remained in the United States but who were fit to deploy. Demographic and location data from DoDâs DMDC were extracted and combined with inpatient and outpatient medical encounter records maintained in the Defense Medical Surveillance System for use in the analyses. Deployed personnel were followed for up to 12 years from when they returned to the United States until the end of the study (December 31, 2013), while nondeployed service members were followed from entry into the study (April 15, 2006) through its end. Deployment location was used as a proxy for exposure as individual environmental exposures were not available. As is true with nearly all other studies that use deployment or base-specific location as a proxy of exposure, deployment duties, job classifica- tion, and specific individual behaviors would likely have a major impact on individual environmental exposures. Other Studies of Post-9/11 Operations Veterans Eight other epidemiologic studies of military personnel involved in post-9/11 operations in the Southwest Asia theater have addressed multiple respiratory health outcomes. Their study parameters are summarized below, while the results of these studies are presented where applicable in the outcomes sections of Chapter 4. Abraham and Baird (2012) sought to evaluate the impact of ambient PMâspecifically, PM2.5 and PM107âon acute cardiorespiratory morbidity among U.S. military personnel deployed to Southwest Asia. The researchers conducted a case-crossover study, a type of case-only study in which each case serves as its own matched control, by linking ambient PM data collected by DoD between December 2005 and June 2007 with personnel, medical, 7â PM 2.5 and PM10 refer to, respectively, particulate matter with a diameter less than 2.5 microns and particulate matter of size less than 10 microns.
EVALUATION OF THE EVIDENCE BASE 63 and meteorological data (Engelbrecht and McDonald, 2009; Engelbrecht et al., 2008). They estimated base-specific associations and pooled those estimates using meta-analytic methods. The study population consisted of a case series of military personnel who had a medical encounter for a qualifying cardiovascular or respiratory event recorded in either Joint Medical Workstation or Transportation Command Regulating and Command and Control Evacuation System during the time period of environmental sampling and for whom deployment data at the time of the health event were known. The case status was defined as having any one of the qualifying outcomes in the medical record (ICD-9 390â459 âdiseases of the circulatory systemâ or ICD-9 460â519 âdiseases of the respiratory systemâ). Outcomes occurring within 7 days of the initial record were excluded from the analysis. Most qualifying encounters were for acute respiratory symptoms, but of the 343 encounters for COPD and allied conditions (ICD-9 490â496), 327 (95%) were for asthma (ICD-9 493). Standard stratified data analysis methods were used to analyze the case-crossover data. The stratifying (matching) variable was the individual subject experiencing an outcome event. Each risk set consisted of one individual as that individual âcrossed overâ between exposure levels in the referent and hazard time periods (and back again). The hazard period corresponding to each observed outcome event was matched with referent time periods within a 28-day time window centered on the event day. To minimize the influence of autocorrelation between hazard and referent periods, referent PM exposures were selected only from sampling days greater than 7 days on either side of the hazard day. Logistic regression was used to calculate the effects of PM exposure on respiratory diseases, and adjustments were made for meteorological parameters. The authors also conducted several sensitivity analyses, such as running models incorporating 2-day lagged exposures and running the models with PM data imputed for missing days using observed PM levels and meteorological data. These sensitivity analyses yielded qualitatively similar results to the primary analysesâ results. This study benefits from a well-matched comparison group and from a primary sampling of the exposures of interest. As mentioned in Chapter 2, the sampling used in the DoD PM surveillance program has been criticized in previous reports (NRC, 2010) for using an inappropriate sampler, which may lead to exposure misclassification. Although there were flaws with the exposure measurement method, this is one of the few studies that objectively measured exposure. The authors did not adjust for confounders, but the case-crossover study design is less subject to bias from confounders that do not vary over short time periods. Residual confounding by time-varying factors is a potential source of bias in this study. The main source of bias is likely that the study was underpowered, given the small expected magnitude of the effect of PM exposure on the risk of respiratory disease in this population over such a short time period (2 years). Abraham et al. (2012) linked deployment and medical history data of active-duty U.S. military personnel from DoD administrative databases to evaluate the association between post-deployment respiratory conditions and deployment to Iraq or Afghanistan. Using the number of deployments to categorize service members into single and multiple deployment groups, a 10% random sample of each group was selected, resulting in a cohort population of 44,919 single deployers and 14,695 multiple deployers to OEF/OIF through June 30, 2005. Medial encounters were based on primary ICD-9-CM diagnostic codes and classified into six categories: acute respiratory infections (ICD-9-CM 460â466), other diseases of the upper respiratory tract (ICD-9-CM 470â478), pneumonia and influenza (ICD-9-CM 480â487), asthma/COPD and allied conditions (ICD-9-CM 490â496), pneumoconiosis and other lung diseases due to external agents (ICD-9-CM 500â508), and other diseases of the respiratory system (ICD-9-CM 510â519). Primary diagnoses of âsymptoms involving respiratory system and other chest symptomsâ (ICD-9-CM 786) were also considered. All service members had at least 6 months of visits before and after deploy- ment. Incidence rates of encounters were calculated and compared between single and multiple deployers in the pre- and post-deployment periods. To examine the independent effects of deployment status and cumulative time in theater on incident post-deployment obstructive pulmonary disease onset, they also conducted a nested caseâcontrol study. Cases (n = 532) of ICD-9-CM codes 490â496 post-deployment diagnosis of obstructive pulmonary disease and controls (n = 2,128) were selected from those who were free of respiratory diagnoses within 6 months before their deployment. Controls were matched on the year of case definition and the year of the last encounter during the study period as well as the total number of post-deployment medical encounters. In the nested caseâcontrol study, two proxy variables were created for exposure: number of deployments and cumulative time in theater, using the start and end dates of deployment records. Cumulative time in theater was calculated by summing the time for all the deployments before an obstructive pulmonary disease encounter for cases and before the last medical
64 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES encounter for controls, and subsequently categorized into five levels (0â3, 4â6, 7â9, 10â12, and â¥13 months). Rates of encounters within selected primary diagnoses by deployment status for the pre- and post-deployment periods and by order of deployment were calculated. Conditional logistic regression analyses were used to exam- ine the independent effects of number of deployments at diagnosis and cumulative time in theater up to diagnosis on post-deployment obstructive pulmonary disease encounter, controlling for potential confounders (gender, age, grade, occupation, time in theater, number of deployments, service branch, and tobacco-related diagnoses) in the model. This study had several limitations. Primary among them is a lack of smoking pattern data for the cohort. Because of the deployment and redeployment cycle, the follow-up period between deployments was likely too short for longer-term chronic obstructive disease conditions, such as emphysema, to develop. Finally, the study was further limited by a lack of specific deployment-related exposure assessments. Baird et al. (2012) studied a unique exposure source: a fire at the Al-Mishraq sulfur plant near Mosul, Iraq, in 2003 that burned for nearly a month and that released dense clouds of sulfur dioxide into the atmosphere. The primary aim of this retrospective cohort study was to characterize the post-deployment respiratory health status of the U.S. Army personnel potentially exposed to emissions from that event and to compare the risk of plausible adverse health outcomes among this group with the risks in unexposed personnel. Health questionnaire data were based on completion of DoD mandatory standardized pre-deployment and 3-month post-deployment health assessments and documented medical encounters up to 4 years after the presumed exposure period. During the year before and the time after the index deployment, the authors used ICD-9-CM codes to identify clinical encounters related to diseases of the respiratory system overall (ICD-9-CM 460â519); diseases of the circulatory system (ICD-9-CM 390â459); and symptoms, signs, and ill-defined conditions (ICD-9-CM 780â799). Specific respiratory outcomes assessed included COPD, asthma, other chronic bronchitis, pneumoconiosis and other lung disease due to external agents, and symptoms involving the respiratory system (ICD-9-CM 786). Two were groups potentially exposed to the sulfur fire smoke plumeâpersonnel involved in fighting the fire (n = 191) and personnel presumably downwind during the time of the fires (n = 6,341). These were compared with two unexposed groups: those that deployed to the area after the fire was extinguished (n = 2,284) and those deployed to other Southwest Asia locations contemporaneously with the time of the fire (n = 1,869). Two-thirds of the exposed groups were less than 29 years of age at the time of exposure, compared with 56% of the unexposed groups. The impact of exposure was assessed by calculating and comparing standardized morbidity ratios that were standardized for age, and by calculating incidence rates per 1,000 person-years within each exposure and comparison group in both the pre- and post-deployment time periods. This study has the advantage of evaluating a specific event with two exposure groups and two comparison groups. The study has several limitations, however. There was a lack of direct exposure assessment, so an inherent assumption made in all analyses is that the exposures were the same across each exposure group, which may lead to information bias. A threat of information bias is also inherent with self-reported symptoms and health concerns using pre- and post-deployment health assessments because responses may be influenced by different motivations for reporting or not reporting certain exposures and health concerns. Confounding is a major threat to validity in this study, as incidence rates were unadjusted, and the morbidity ratios were only standardized for age. Other uncharacterized differences in risk factors for adverse health outcomes, such as smoking behavior and other environmental or occupational exposures, may exist between the sulfur-fire- exposed and unexposed groups. The relatively short follow-up time (up to 4 years) does not permit the evaluation of associations between sulfur fire plume exposures and diseases with long latencies. Krefft et al. (2017) conducted a pilot study to examine the role of lung clearance index as an early marker of lung injury in a sample of 24 healthy volunteers and 28 symptomatic veterans who had deployed to Southwest Asia in support of post-9/11. The symptomatic deployers had cough, chest tightness, wheezing, shortness of breath, or decreased exercise tolerance during or following OEF/OIF/OND deployment. Individuals who were found to have other explanations for their respiratory symptoms were excluded. Healthy controls who were at least 18 years of age, had no history of pre-existing lung disease, and reported no respiratory illness in the 4 weeks preceding enrollment and testing were also recruited. Both groups underwent lung clearance index testing to identify whether abnormalities were present in the peripheral airways of the lung. As part of their clinical evaluation, the veteran group completed body plethysmographic pulmonary function testing with pre- and post-bronchodilator spirometry, lung volumes, and diffusion capacity; cardiopulmonary exercise tolerance testing; and chest CT scans. Surgical
EVALUATION OF THE EVIDENCE BASE 65 lung biopsies were performed on 17 of the 28 veterans. Descriptive analyses were conducted, and the Fisher exact test was used to compare the demographic data between the deployers and the controls. Multiple linear regression models that adjusted for smoking, age, and BMI were used to compare differences in lung clearance index score between the deployers and healthy controls. This study aimed to describe the utility of lung clearance index to diagnose small airway abnormalities before they are readily apparent in clinical testing and without an invasive biopsy. This study is limited most by its small sample size, nonmatched controls, and absence of spirometry data in the healthy control group. The small sample of veterans is highly selective as they were all symptomatic and were seen at a single occupational lung disease clinic. Given that all of the members of the deployed group in this study were symptomatic and that they were compared with healthy controls, the study provides rather limited evidence to the committeeâs charge to understand the impact of deployment to Southwest Asia on the health of veterans. Additionally, the study was not designed to evaluate the impacts of deployment to theater on the health of veterans, and no adjustments were made for confounders such as smoking, obesity, or age in the assessments that were made. Krefft et al. (2020) sought to describe deployment-related respiratory disease and the diagnostic utility of resting and exercise pulmonary function testing with a retrospective study of 127 military personnel, veterans, and civilian contractors who supported military operations in Southwest Asia who presented with new-onset respiratory symptoms between 2009 and 2017. The cohort was made up of patients who deployed to Southwest Asia between 2001 and 2019 and were self-referred or referred by treating physicians to a single occupational lung disease clinic for an evaluation of persistent respiratory symptoms that limited their ability to meet military physical fitness requirements. A comprehensive standardized questionnaire was used to collect detailed medical, occupational, and smoking histories and was completed by 107 of the 127 patients. For the other 20 patients, medical, occupational, and smoking histories were abstracted from the patientsâ electronic medical records. Of the 127 patients, 113 under- went pulmonary function testing, including pre- and post-bronchodilator spirometry, lung volumes determined by plethysmography, and carbon monoxide diffusion capacity measurement following American Thoracic Society standards. Chest CT scans were available for 118 of 127 symptomatic patients. Lung biopsies were performed in 52 patients (51 video-assisted thoracoscopic surgery, 1 transbronchial cryobiopsy). Deployment-related respira- tory diseases were classified as proximal or distal or both. Distal lung disease was diagnosed when at least one of the following was present: emphysema under low- or high-power magnification, histopathologic findings of hyperinflation/emphysema, bronchiolitis, non-necrotizing granulomatous inflammation, small airways inflamma- tion, peribronchiolar fibrosis, or granulomatous pneumonitis on surgical lung biopsy. Descriptive statistics and logistic regression were used to analyze lung function parameters associated with deployment-related distal lung disease. The biopsy reports were reviewed for several diagnoses. Descriptive statistical tests were conducted to analyze demographic factors, deployment, pulmonary function, and exercise testing. The researchers carried out Fisherâs exact test for class variables, two-sample t-tests for continuous variables, and the Wilcoxon rank sum test for count or right-skewed continuous variables. This study provides a characterization of deployment-related lung disease in a cohort of veterans and military contractors with a history of deployment to Southwest Asia. The study is limited by having included only cases with respiratory disease and by not having included a control group. Madar et al. (2017) retrospectively reviewed a series of biopsies of non-neoplastic lung disease that were evalu- ated at the Armed Forces Institute of Pathology or Joint Pathology Center from January 2005 through December 2012. Service members were grouped by the timing of the biopsy, before or after deployment to Southwest Asia. Of 391 individuals examined, 137 (35.0%) had deployed to Southwest Asia prior to the biopsy (termed the deployed group). Those under age 40 represented nearly 60% of the deployed personnel and 28.7% of the nondeployed per- sonnel. Nondeployed personnel who underwent lung biopsy were more likely to be age 50 years or older. Accord- ing to electronic medical records, 41% of the deployed and 56% of the nondeployed subjects were prior smokers; whether the individuals were smoking in theater or at the time of biopsy is not documented, and the records may underreport the service membersâ smoking history. Among the surgical biopsies, 79 occurred post-deployment and 137 occurred before deployment, and among the non-surgical biopsies 58 occurred post-deployment and 117 occurred before deployment. Histologic diagnoses were sorted into 38 categories, and the categories were collapsed into 10 major histologic groups: no specific pathologic diagnosis, smoking-related lung disease, idiopathic inter- stitial pneumonia, small airways disease, chronic inflammation (not otherwise specified), granulomatous disease,
66 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES infection, eosinophilic pneumonia, pneumoconiosis, and other (which included, for example, pulmonary alveolar proteinosis and pleuritis). Multivariable binary logistic regressions were conducted to estimate the independent effect of deployment in predicting the probabilities of histologic diagnoses when the prevalence was amenable to statistical analysis. Logistic regression models controlled for age, gender, ethnicity, and tobacco use history. A separate series of multivariate binary logistic regressions also controlled for time in theater. All regressions included only those people for whom a single diagnosis was made. Pulmonary function testing data (available from associated medical records) were compared using a series of independent means t-tests. The specific results of this study are presented in the following respiratory outcomes sections of Chapter 4: Pulmonary Function Test- ing, Constrictive Bronchiolitis, Interstitial Lung Diseases (Sarcoidosis, Idiopathic Interstitial Pneumonias, Acute Eosinophilic Pneumonia, and Pulmonary Alveolar Proteinosis). Not all lung biopsies in the military are reviewed at the Joint Pathology Center, so there may be some degree of referral bias. The demographic characteristics of the deployed and nondeployed groups were statistically different with respect to age and tobacco use. Incomplete clinical data limited the ability to make associations with the presenting symptoms that prompted the biopsy. The inclusion of non-surgical samples may have enhanced the studyâs ability to diagnose some conditions, such as sarcoidosis, but it would have resulted in underestimates of other diagnoses, such as bronchiolitis and idiopathic interstitial lung diseases, that require surgical lung biopsy for diagnostic confirmation. Other conditions, such as eosinophilic pneumonia, do not typically require biopsy for diagnosis, and therefore this study design would not be expected to identify many such cases if they were present. Pugh et al. (2016) conducted a retrospective cohort study to examine the prevalence of chronic lung disease and its relationship with military deployment using health care system data from 760,621 U.S. veterans deployed to combat operations in Iraq or Afghanistan who received care from VA between October 1, 2002, and September 30, 2011. Study investigators reviewed ICD-9-CM codes of inpatient and outpatient encounters for diseases of the respiratory system, which included asthma, COPD, and interstitial lung diseases. Smoking status was determined based on one of several indicators in the medical record, including ICD-9-CM codes for tobacco use/nicotine dependence, prescriptions for medications for the treatment of nicotine dependence, and individuals who received VA care in a smoking cessation clinic. Diagnoses of traumatic brain injury were collected and used in the analyses, as was whether an individual had two or more deployments. For each condition, the prevalence was calculated by year, with the number of unique OEF/OIF veterans who received VA care in that year being used as the denomina- tor. Generalized estimating equations were used to determine if the log-odds of having a diagnosis of any of the respiratory outcomes increased from fiscal year 2003 to fiscal year 2011. Models were adjusted for demographic characteristics, multiple deployments, tobacco use, and traumatic brain injury to determine if the log-odds of diagnosis increased from 2003 to 2011. A total of 33,962 individuals had at least one diagnosis of the respiratory conditions of interest over the study period. The strengths of this study included the use of ICD-9-CM-coded diag- noses and a large study population. Although study investigators were able to assess the number of deployments, they were not able to assess the lengths of the deployments (to calculate total potential exposure time). Finally, temporal relationships between exposures and respiratory health outcomes could not be established, and the study population was limited to individuals who had received care within the VA health system. Rohrbeck et al. (2016) conducted a small cohort study to look for associations between various health outcomes, which were based on ICD-9 codes assigned from post-deployment medical encounters, and known exposures to burn pits, which were based on deployment location. Using data from the Defense Medical Surveil- lance System, 200 service members were selected based on their participation in a previous environmental health assessment and known exposure to burn pits; of these 163 were Army personnel who had been assigned to Joint Base Balad, Iraq, and 37 were Air Force personnel who had been assigned to Bagram Airfield, Afghanistan. Each participant provided pre- and post-deployment serum specimens. Controlsâ200 randomly selected nondeployed service members from all branches from the Defense Medical Surveillance Systemâwere matched to cases by time in service on the date on which the pre-deployment serum sample was collected. Data from medical encounters in military treatment facilities, both hospitalizations and outpatient visits, were used to capture information on signs, symptoms, and ill-defined conditions involving the respiratory system and other chest symptoms (ICD-9 786) regardless of diagnostic position. Chi-square statistics were used to compare the nondeployed with the deployed cohort as well as to compare service members who served at Balad with the Bagram cohort. Incident rate ratios
EVALUATION OF THE EVIDENCE BASE 67 were calculated to assess the risk for the various health outcomes among the nondeployed and deployed cohorts. Stratified survival analysis was used to examine deployment effect by location. In the multivariate regression analysis, models were adjusted for age, sex, race/ethnicity, occupation, deployment history, and history of illness prior to deployment, and the Bonferroni correction was used for multiple comparisons to reduce the chances of obtaining false-positive results; the significance level was set at Î± = 0.025. This analysis had limited power for detecting differences in outcomes. Although burn pit exposure was documented, there is still individual variation in exposure that was not accounted for (deployment duties, job classification, and specific individual behaviors). Information on smoking was not available. The combined cohort of deployed service members was an odd choice because the two cohorts deployed 5 years apart, service members belonged to different branches, and the theaters were uniquely different. As with other studies that rely on the use of ICD-9 codes in medical encounter data, these are limited for most respiratory outcomes because most individuals are unlikely to seek medical attention unless the condition worsens or persists. This analysis was also limited by its representativeness, power for detecting differences in outcomes, and inability to control for smoking. 1990â1991 Gulf War Veterans As noted in Chapter 1, the 1990â1991 Gulf War comprised two U.S. military operationsâOperation Desert Shield and Operation Desert Stormâwhich took place between August 1990 and April 1991. In this section, descriptions of studies of U.S. veterans are presented first, followed by descriptions of epidemiologic studies conducted in cohorts of Australian, Canadian, and UK Gulf War veterans. U.S. Gulf War Veterans National Health Survey of Gulf War Era Veterans and Their Families and Follow-Up Studiesâ PL 103-446 mandated that VA conduct a population-based study of U.S. Gulf War veterans. In response, VA has conducted a set of studies of health outcomes in Gulf Warâera veterans that began with a longitudinal survey of 30,000 veterans known as the National Health Survey of Gulf War Veterans and Their Families (NHS).8 Thus far, three survey waves have been conducted: wave 1 in 1993â1995 (Kang et al., 2000), with physical examinations in 1999â2001 (Eisen et al., 2005); wave 2 in 2003â2005 (Kang et al., 2009); and wave 3 in 2012â2013 (Dursa et al., 2016). Participants for waves 2 and 3 were recruited using participants selected for the wave 1 (baseline) population. Several derivative studies of the NHS and its successor research efforts are reviewed in Volumes 4 (IOM, 2006), 8 (IOM, 2010), and 10 (NASEM, 2016) of the Gulf War and Health series of National Academies reports. Four of theseâthe first paper to describe this effort and three other papers that address respiratory health outcomesâare summarized below. Chapter 4 also cites some additional NHS-related studies. VA designed the NHSâoriginally described in Kang et al. (2000)âto be representative of the nearly 700,000 U.S. veterans sent to the Persian Gulf and 800,680 veterans who were not deployed but who were in the military between September 1990 and May 1991. In wave 1 of the survey, VA mailed questionnaires to a stratified random sample of 15,000 deployed and 15,000 nondeployed Gulf War veterans identified by DoDâs DMDC. Women and those serving in the National Guard and reserves were oversampled, resulting in a study population that was approximately 20% women, 25% National Guard, and 33% reservists. The controls were stratified by gender, unit component, and branch of service to mirror the population of deployed veterans. The self-administered structured health questionnaire contained a 48-symptom inventory (somatic and psychological symptoms) and questions about chronic medical conditions, functional limitations, the use of medical services, and environmental exposures. Wave 1 also used telephone interview software in an attempt to capture those who did not respond to the mailed questionnaire. A total of 11,441 (75%) deployed and 9,476 (64%) nondeployed veterans participated in the study; 15,817 veterans responded to the questionnaire, and 5,100 responded to the telephone interview. Characteristics 8â The National Health Survey of Gulf War Veterans and Their Families is also referred to as the Longitudinal Health Study of Gulf War Era Veterans in some VA publications (https://www.publichealth.va.gov/epidemiology/studies/gulf-war-longitudinal-study.asp [accessed June 8, 2020]).
68 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES of those who did not respond to the mailed survey were also examined. In addition, as part of wave 1, medical records were obtained for a random sample of 4,200 respondents to validate self-reports of clinic visits or hospi- talizations within the previous year. Of the 2,233 veterans with at least one clinic visit, 43.2% provided medical record release consent; of the 310 with at least one hospitalization, 45.2% provided medical record release con- sent. Medical record reviews verified more than 90% of self-reported reasons for clinic visits or hospitalizations. The third phase was a comprehensive medical examination and laboratory testing of a random sample of 2,000 veterans drawn from the deployed and era groups. Three studies analyzed and reported on respiratory symptoms collected from wave 1 (Eisen et al., 2005; Kang et al., 2000; Karlinsky et al., 2004), and they are described below. Kang et al. (2000)Â did not assess exposureâsymptom relationships but rather noted the percentage of veterans who reported each of 23 environmental exposures and 9 vaccine or prophylactic exposures (such as to Âpyridostigmine bromide). The five most common environmental exposuresâreported by more than 60% of survey participantsâ were diesel, kerosene, or other petrochemical fumes; local food other than that provided by the armed forces; chemical protective gear; smoke from oil-well fires; and burning trash or feces. Karlinsky et al. (2004)Â examined pulmonary function and self-reported respiratory symptoms in 1,036 deployed and 1,103 nondeployed veterans who completed the clinical examination component of the NHS. The results of pulmonary function tests were classified into five categories: normal pulmonary function, nonreversible airway obstruction, reversible airway obstruction, restrictive lung physiology, and small-airway obstruction. The authors also reported on the pattern of pulmonary function test results in those exposed (n = 159) and those not exposed (n = 877) (according to DoD exposure estimates developed in 2002) to nerve agents resulting from the destruction of a munitions storage site at Khamisiyah, Iraq, in 1991. Eisen et al. (2005) performed a cross-sectional analysis on health outcomes collected in a subset of 1,061 deployed and 1,128 nondeployed Gulf War veterans who completed the clinical examination component of the third phase of wave 1 of the NHS. The study population consisted of a stratified random sample of the 11,441 deployed and 9,476 nondeployed veterans who had responded to the mailed questionnaire or telephone interview described above. This study included a comprehensive medical examination and laboratory testing. Of the 1,996 eligible deployed veterans, 1,061 (53.1%) were examined, 680 (34.1%) declined, and 255 (12.8%) were not located. Of the 2,883 eligible nondeployed veterans, 1,128 (39.1%) were examined, 1,316 (45.7%) declined, and 439 (15.2%) were not located. Despite extensive recruitment efforts, the participation rate for this study was lowâ60.9% of deployed veterans and 46.2% of the nondeployed. Study participants were assigned a medical center closest to their residence where medical providers took histories and performed examinations; laboratory and pulmonary function tests were also performed. Twelve primary health outcome measures and physical functioning were exam- ined using the 36-Item Short Form Health Survey.Â Outcome measures were chosen by the authors to cover the most common symptoms reported by veterans. Analyses adjusted for age, sex, race, years of education, cigarette smoking history, duty type (active versus reserves or National Guard), service branch (Army or Marines versus Navy or Air Force), and rank (enlisted versus officer). The two main limitations of this study were the fact that it was carried out 10 years after the 1990â1991 Gulf War, which precluded diagnoses that had already resolved, and its low participation rates, which introduced the possibility of participation bias. Results of the third survey wave of the NHS were reported by Dursa et al. (2016). This survey consisted of the same 30,000 Gulf Warâdeployed and Gulf Warâera veterans and the same administration methods as the two prior surveysâthat is, via mail, website, or a computer-assisted telephone interview. A total of 14,252 veterans responded (8,104 deployed and 6,148 era veterans), for a response rate of 50% (57% deployed, 43% nondeployed). Respondents were more likely to have served in the Army compared with other branches, to have been deployed, to have been an officer, to have been older, and to have identified as white than were non-respondents. The wave 3 questionnaire was modified from the earlier versions, but it again collected information about the presence of various symptoms, including respiratory problems, functional status, activity limitations, health perceptions, chronic medical conditions (self-report of provider diagnoses), health care use, and potential confounders, such as the use of alcohol and cigarettes. Other Studies of U.S. Gulf War Veteransâ Several other studies of Gulf War veterans have examined respira- tory outcomes. Some of these examined cohorts that were selected based on their military occupation, such as
EVALUATION OF THE EVIDENCE BASE 69 the Seabees9 (Gray et al., 2002), or state of home of record (Iowa Persian Gulf Study Group, 1997; Steele, 2000). Smith et al. (2006) conducted a large study of post-deployment hospitalization events of active-duty service members to examine respiratory conditions, including asthma, for service members deployed to Southwest Asia for peacekeeping missions post-Gulf War (n = 254,080) and service members deployed to Bosnia (1995â1998, n = 46,911) compared with Gulf Warâdeployed service members (n = 458,727). Bullman et al. (2005) explored the relationship between estimated exposure to chemical munitions destruction (including sarin gas) at Khamisiyah, Iraq, in 1991, with cause-specific mortality of Gulf War veterans through December 31, 2000. In addition to these studies, five other epidemiologic studies of 1990â1991 Gulf War veterans are referenced in multiple locations in Chapter 4 (Hines et al., 2013; Hooper et al., 2008; Khalil et al., 2018; Maule et al., 2018; Zundel et al., 2019). Summaries of these follow. Estimating inhalational exposures has been one of the more challenging aspects of health studies of those deployed to Southwest Asia. Hines et al. (2013) examined 37 1990â1991 Gulf War veterans who were enrolled in the VA Depleted Uranium Surveillance Program and had attended a biennial follow-up between April and June 2011 (the total cohort consisted of 80 veterans with known exposure to depleted uranium [DU]). Each veteran had sustained inhalational exposure to DU during friendly fire incidents in 1991. The purpose of this publication was to compare the likelihood of pulmonary health abnormalities in those with high body burdens of uranium (n = 12; >0.1 Âµg/g creatinine) versus those with low body burdens of uranium (n = 25; â¤0.1 Âµg/g creatinine). The authors hypothesized that service members with embedded DU fragments were more likely to have been closer Â to a blast source and to have undergone greater inhalational exposures to DU and blast particulate than those who had not had injuries from embedded DU. Service members with higher urine uranium concentrations were hypothesized to have reported greater frequencies of chest symptoms, have had more abnormal pulmonary func- tion, and have had more abnormalities on chest CT than those with low urinary uranium concentrations. Study participants attended a 3-day, inpatient clinical assessment that included a detailed medical and exposure history, physical examination, laboratory studies, and a comprehensive assessment of pulmonary health and function via a respiratory symptom questionnaire and full pulmonary function tests, CT chest-imaging studies, and impulse oscillometry. Participants were also questioned regarding physician-prescribed steroids and smoking status. Par- ticipants with embedded uranium fragments underwent positron emission tomography accompanied by low-dose CT. Total uranium concentrations and the 235U/238U isotopic ratio in 24-hour urine samples were measured for all. While the use of an objective biomarker as a measure of exposure is a strength of this study, the findings are of limited relevance to the majority of those deployed, given that exposure to DU was and continues to be uncom- mon. Additionally, given the small sample size, there are concerns the study may be underpowered. Hooper et al. (2008) examined the long-term hospitalization experience of regular active-duty U.S. Gulf War veterans (n = 211,642) still on active duty between 1994 and 2004 (presented at 3-year intervals) compared with veterans who had separated from military service (n = 321,806). Service rosters, demographic and military service characteristics, selected Gulf War exposure variables, and hospitalization data were collected from DMDC data- bases. Environmental exposure data, which included information on potential exposure to the Khamisiyah muni- tions depot demolition (March 10â12, 1991) and smoke from oil-well fires, came from the Naval Health Research Center and the U.S. Army Center for Health Promotion and Preventive Medicine. For multivariate modeling, a three-level Khamisiyah exposure variable (presumed not at risk, at risk of exposure but not exposed, and exposed) was applied. Other war-related exposures or experiences, including anthrax or botulinum immunization, in-theater hospitalization, and presence in theater during ground combat operations, were included and treated as dichotomous variables. To reduce possible effects of other deployments, service members who deployed between the end of the Gulf War and October 1, 1994 (the beginning of the period of observation) were excluded. Hospitalization data consisted of inpatient encounter records from military treatment facilities (including those that occurred in theater) and civilian facilities when costs were reimbursed by DoD that were coded using ICD-9-CM codes. Both primary and secondary diagnoses were included. Individuals could be counted in multiple diagnostic categories (presented by system or injury), but only once per category. Cox proportional hazard modeling was used to evaluate the independent predictors of all-cause hospitalization among those still on active duty and to estimate the cumulative 9â The Seabees are service members who served with the U.S. Naval Mobile Construction Battalions.
70 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES probability of hospitalization, 1994â2004, by service branch. For the 10-year combined observation period, there were 43,346 hospitalizations for those who remained on active duty after 1994. Of those hospitalizations, 12.2% (n = 2,872) were coded as respiratory system. The most frequent categories were diseases of the musculoskeletal system (32.7%); diseases of the digestive system (23.4%); injury and poisoning (21.0%); and symptoms, signs, and ill-defined conditions (18.7%). For each diagnostic category, the top five primary diagnoses over the entire follow-up period were presented. Of the 4,031 hospitalizations for ill-defined conditions, 46.6% had respiratory system and other chest symptoms. Comparisons with the separated veteran group were not presented, nor were category hospitalizations by Gulf War exposures, which limited the informativeness of this study. Khalil et al. (2018) was a descriptive analysis of the study design for the Gulf War Era Cohort and Bioreposi- tory, which was established by VA to be a nationally representative longitudinal cohort of U.S. veterans who served during the 1990â1991 Gulf War era â¦ [combining] survey data, such as demographic, health behavior, and environmental exposure data; medical records; and a linked biorepository of blood specimens that can support a broad range of future research regarding health concerns unique to veterans of this era. (p. 2279) The pilot phase of the effort started with a stratified recruitment panel of 90,000 veterans identified from DoDâs DMDC and drawn from a total population of 4,966,117 veterans who served during August 1990âJuly 1991, without regard to deployment or combat status, health status, or whether the service member had enrolled in or used the Veterans Health Administration for health care. Of these, 10,042 met inclusion criteria (living with valid contact information and meeting residence location requirements), and an additional 168 self-nominated for inclusion. The pilot sample was constructed to frequency-match the geographic distribution of the recruitment panel across the four U.S. Census regions, reflecting geographic variation in the veteran population. The recruited veterans received a mail survey to complete along with consent forms granting permission for their VA and DoD records (including biospecimens) to be accessed for research purposes. Each participant gave a blood sample. The final enrollment consisted of 1,275 veterans who completed all study requirements, 900 (70.6%) of whom deployed to the Southwest Asia theater. Veterans who were female, nonwhite, served in the Army, or were active duty were all slightly overÂ represented relative to the stratified recruitment panel. The most commonly reported exposure in those who had served in theater was âclose proximity to smoke from oil-well firesâ (60%); 39% reported five or more exposures, and just over 2% reported that they had not experienced any of the Gulf region exposures that they were queried about. Participants reported a median of 14 health symptoms that had been persistent or recurring over the last 6 months (range, 0â34 symptoms); 0.9% of participants reported experiencing all of the symptoms surveyed, and 2.8% reported experiencing none of the symptoms. Self-reported health outcomes of symptoms (in the past year) and health care providerâdiagnosed conditions were reported stratified by users (n = 584) and nonusers (n = 679) of VA health care. Three respiratory symptoms were included as well as sleep apnea, COPD, tuberculosis, and lung cancer. Outcomes were not adjusted for confounding factors, and no comparisons between deployed and nonÂ deployed veterans were made, but only between VA users and nonusers. Therefore, the findings are primarily descrip- tive in nature and are of limited utility for assessing the role of Gulf War deployment on respiratory symptoms. Maule et al. (2018) conducted a meta-analysis of 21 studies published through 2017 on the prevalence of health diagnoses and symptoms representing more than 129,000 Gulf Warâdeployed and nondeployed era veterans to characterize the most frequently reported symptoms occurring among deployed versus nondeployed 1990â1991 Gulf War veterans. Pooled analyses were conducted using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. For the meta-analysis of symptom prevalence in Gulf Warâdeployed and Gulf Warâera veterans, separate random-effects binomial-normal models were used to estimate the combined log odds of a symptom and to calculate the pooled prevalence rate of individual symptoms. For the meta-analysis of odds ratios comparing symptom reporting in Gulf Warâdeployed veterans to Gulf Warâera controls, a random effects binomial-normal model was used to estimate combined log odds ratios. In the model estimating log odds ratios, an offset term was included to take into account the different sample sizes of Gulf Warâdeployed and Gulf Warâera veterans within a study. Qualitative and quantitative bias assessments were also performed. The authors stated that there was little evidence to support reporting bias (that is, selective reporting in studies of outcomes
EVALUATION OF THE EVIDENCE BASE 71 with positive findings) in contributing to the differences in prevalence. The bias assessment also demonstrated that Gulf Warâdeployed veterans continued to have higher odds of reporting all analyzed symptoms compared with Gulf Warâera controls. Odds ratios were reported for each symptom along with I2 statistics (a measure of the heterogeneity, or the percentage of variation across studies that is due to heterogeneity rather than chance). The included outcomes relevant to respiratory outcomes were respiratory symptoms, sinusitis, and asthma. For each of the 56 self-reported symptoms analyzed there was a higher combined prevalence in the Gulf Warâdeployed veterans than in the Gulf Warâera veterans. The meta-analytic approach could not address concerns about either selection biases or information biases (due to self-reports of symptoms), concerns that were common to all of the studies included. Therefore, while this meta-analysis fairly summarizes reported findings on respiratory symptoms and provides assurance that reporting bias played little role, other important deficiencies in the published studies and their impacts on the findings were not addressed. Zundel et al. (2019) compared survey results from a longitudinal cohort of 1990â1991 Gulf War veterans who returned from deployment in 1991 through Fort Devens, Massachusetts, with data from the National Health and Nutrition Examination Survey (NHANES; n = 2,949). The veterans cohort was established in 1991, and the 2013 survey was a follow-up of 448 participants (response rate 35%) that collected self-reports of doctor-diagnosed chronic conditions. These were compared with NHANES 2013â2014 data that were restricted to non-veterans and persons in the age range of the veteran survey respondents. A total of 401 male and 47 female Fort Devens par- ticipants responded to the survey and reported at least one chronic condition. Excess prevalence was calculated as the difference in prevalence estimates from the Fort Devens and the NHANES cohorts. Odds ratios and test-based confidence intervals were calculated from the prevalence estimates and standard errors that had been calculated for the two cohorts. To account for demographic differences between the cohorts, analyses were restricted to include white/Caucasian individuals with a high school education or above, and the analyses adjusted for these demographic differences by modifying the NHANES weights to match the age and education distribution, for men and women separately, of the Fort Devens cohort. The Fort Devens and NHANES cohorts differed significantly in age, sex, race, education, and current smoking status. For the Fort Devens exposure analyses, veterans who were exposed and unexposed did not differ on any of the demographic variables, but analyses for exposure were adjusted for gender and current smoking status. For the Fort Devens cohort, nine chronic medical conditions were compared by exposure/nonexposure to chemical or biologic warfare or pyridostigmine bromide pills. Compared with the NHANES sample from the general U.S. population, Gulf War veterans were at higher risk of chronic conditions. Exposure to chemical or biologic warfare or pyridostigmine bromide pills was associated with a statistically sig- nificant excess prevalence of several of the chronic conditions examined. This study likely suffers from information bias due to its use of self-reports of medical conditions and from selection bias because the sample was drawn from a group that is not representative of the overall population (white with education above high school) who had previously reported a chronic condition. U.S. Studies with Modeled Exposure to Oil-Well Fire Smokeâ Three studies of U.S. service members or veter- ans specifically examined respiratory diagnoses or symptoms associated with modeled exposure to oil-well fires (Cowan et al., 2002; Lange et al., 2002; Smith et al., 2002). Cowan et al. (2002) conducted a caseâcontrol study of 873 Gulf War veterans with a physician diagnosis of asthma versus 2,464 controls without asthma or other respiratory system diagnoses who were participants of the DoD Comprehensive Clinical Evaluation Program. Demographic information was obtained from the DoD Gulf War Registry, and oil-well fire smoke exposure was based on a National Oceanic and Atmospheric Administration (NOAA) atmospheric advection and diffusion model. Exposure was cumulatively modeled (low, intermediate, and high) and adjusted for sex, age, race, military rank, and smoking history. Lange et al. (2002) used a cross-sectional study design to examine exposure to smoke from oil-well fires (self-reported and modeled) and asthma symptoms assessed via structured interviews conducted 5 years after the Gulf War for a subset of 1,560 Iowa veterans. Modeled exposures were developed using a geographic information system to integrate spatial and temporal records of smoke concentrations with troop movements ascertained from Global Positioning Systems records. Exposure was presented by quartiles. Odds ratios were adjusted for sex, age, race, military rank, smoking history, military service, and level of preparedness for war.
72 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES Smith et al. (2002) used DoD hospitalization data (ICD-9-CM codes) from August 1991âJuly 1999 and exposure models to examine associations between respiratory diseases, including asthma, chronic bronchitis, acute bronchitis, and respiratory cancers and different levels of modeled exposure to oil-well fires among service members. The results of the associations for each of these outcomes is presented under the applicable section in Chapter 4. The study population consisted of 405,142 active-duty service members who were deployed to the Gulf War theater of operations for 1 or more days during the period August 8, 1990âJuly 31, 1991, and who were still in the theater of operations during the time of the Kuwaiti oil-well fires but who did not remain in the region after the war. Demographic and deployment data were provided by DoDâs DMDC. Exposure was estimated by using troop location data and estimated oil-smoke concentrations based on NOAA modeling that was used in other studies. Individuals were assigned to one of seven exposure groups, which combined duration and amount of exposure, ranging from no exposure to average daily exposure of >260 Âµg/m3 for >50 days. Individuals with pre-existing conditions (hospitalizations for diagnoses of interest in the 3 years prior to the start of follow-up) were excluded from further analysis for that specific diagnosis. Coxâs proportional hazards time-to-event modeling was used in the statistical analysis, and the time-to-event estimates were calculated by exposure level. Effect estimates were adjusted for demographic and military factors that were found to be statistically significant predictors of the outcomes in exploratory models (specific demographic and military characteristics not specified for each out- come), but no smoking data were available. There was no evidence of a trend of increasing risk of hospitalization for veterans exposed to oil-well fire smoke over all of the exposure groups. The adjusted risk ratios for post-war hospitalization for respiratory diseases (ICD-9-CM 460â519) showed a decreased risk of hospitalization for all six groups of exposed participants compared with the unexposed participants, and the decreased risk for the second highest exposure group (average daily exposure of 1â260 Âµg/m3 for >50 days) was statistically significant (rela- tive risk = 0.69, p <0.05). Additional modeling for specific respiratory diagnoses and exposure to oil-well fire smoke collapsed exposure categories into twoâexposed (n = 337,077) and nonexposed (n = 68,065). Tobacco use and exposure to fine desert dust, exhaust from diesel equipment, and other war-related exposures may have influenced some of the risk findings. Analyses were limited to morbidity severe enough to require admission to a DoD hospital for inpatient care, a major limitation for analysis of some of these respiratory outcomes, which rarely require hospitalization. In addition, personnel in direct combat roles, as a group, are more physically fit than support personnel and thus are less likely to be hospitalized post-deployment. Australian Gulf War Veterans The Australian Gulf War Veteransâ Health Studyâa national study of all Australian Gulf War veteransâwas conducted in 2000â2002 (Sim et al., 2003), and the cohort has been followed since the initial study. A total of 14 derivative studies (Forbes et al., 2004; Gwini et al., 2015; Ikin et al., 2004, 2005, 2015; Kelsall et al., 2004a,b, 2005, 2006, 2007, 2009, 2014; McKenzie et al., 2004; Sim et al., 2015) have been described in volumes of the Gulf War and Health series of reports. Of the derivative studies, few (Gwini et al., 2016; Kelsall et al., 2004b; Sim et al., 2015) have presented outcomes on respiratory symptoms. Kelsall et al. (2004b) used data collected during the 2000â2002 study, Sim et al. (2015) used data from the follow-up assessment conducted in 2011â2013, and Gwini et al. (2016) examined new onset of self-reported conditions using data collected from both the initial and follow-up assessments. In the initial study of the Australian Gulf War veterans, all 1,871 Australian veterans deployed to the Gulf War region from August 2, 1990, to September 4, 1991, were included; naval personnel made up 86.5% of this cohort (Sim et al., 2003). The control group consisted of 2,924 nondeployed Australian Defence Force personnel matched by service type, sex, age, and military status. Participation rates were 81% (n = 1,456) for the deployed and 57% (n = 1,588) for the control group. A mailed 58-item questionnaire was distributed in 2000â2002 (10 years after the Gulf War), which included the 12-Item Short Form Health Survey, General Health Questionnaire-12, and questions regarding physical and psychological health, military service history, and exposures during deployment. The questionnaire asked about problems or conditions that had been diagnosed or treated by a medical doctor and the year in which the condition was first diagnosed. In addition, participants were asked to attend one of 10 Health Services Australia medical clinics to undergo a comprehensive health assessment, a full physical examination, blood work, and fitness tests. Spirometric tests were performed, and a respiratory questionnaire was administered
EVALUATION OF THE EVIDENCE BASE 73 as part of this assessment. Sim et al. (2003) reported information on some respiratory health outcomes, but these were more thoroughly addressed by Kelsall et al. (2004b). Kelsall et al. (2004b) examined the respiratory health status of Australian veterans using the Sim et al. (2003) data, focusing on the effects of exposure to oil fire smoke and dust storms. The subjects were the same as those in the original study: a deployed cohort comprising 1,456 participants who were compared with 1,588 randomly sampled military personnel who served during the same time period but who were not sent to the theater. The comparison group was frequency matched to the deployed group by service type, age (within 3-year age bands), and rank (officer/non-officer) for Army participants or aircrew/non-aircrew status for Air Force participants. While data were collected for female veterans, there were too few to allow analyses to be conducted, so the results were restricted to male subjects. The studyâs strengths include its use of a comparison group that was similar to the exposed (deployed) subjects with regard to characteristics, such as age and smoking status, that are predictive of health outcomes, and the gathering of some data through a medical assessment and physical examination. Its weaknesses include the high percentage of naval personnel in the cohortâwhich make the attribution of health problems to in-theater airborne exposures problematicâand the use of self-reported exposure and health data collected 10 years after deployment to the 1990â1991 conflict. The investigators also note that participation bias and recall bias could not be ruled out as at least partial explanations for some of the findings. Sim et al. (2015), as noted above, reported the results of the Australian Gulf War Veteransâ Follow Up Health Study, which was conducted in 2011â2013. This study assessed the entire Australian Gulf War cohort 10 years after the 2000â2002 baseline investigation and 20 years after the war. All participants in the original study were eligible to take part; 715 Gulf War veterans and 675 comparison group veterans responded to recruitment efforts (a 50% participation rate). Respiratory health data were available on 697 Gulf War veterans and 659 comparisons. The follow-up study collected much of the same information as the original study, but it also inquired about additional outcomes, including pain, sleep disturbance, injury, musculoskeletal disorders, demoralization, and measures of well-being (quality of life, life satisfaction, life events, financial distress, suicidal ideation, and community partici- pation). The follow-up also extended exposure assessment efforts from those used in the first, or baseline, study. The data were collected by mailed questionnaire, telephone interview, collection of the Australia Department of Veteransâ Affairsâ health data, and claims history from the Australia Medicare, Pharmaceutical Benefits Scheme, and Repatriation Pharmaceutical Benefits Scheme. Other databases included national mortality and cancer registries and information from the baseline study. Respiratory health was assessed at both baseline and follow-up, but the scope of respiratory health data collected and the mode of data collection changed for some factors, which limited the ability to assess change over time for some of the outcomes. The follow-up study collected information on respiratory symptoms and medical conditions, including asthma, using a brief list of outcomes that were assessed via self-report questionnaire. The questions on respiratory symptoms and conditions included at follow-up were pared down or modified from a larger set that were administered by a nurse in the baseline study. Spirometry or other lung function tests were not included at follow-up. The follow-up study included an assessment of respi- ratory health medications dispensed to participants under the Pharmaceutical Benefits Scheme or Repatriation Pharmaceutical Benefits Scheme, which were data sources not included at baseline. Estimates were adjusted for age group, service branch, and rank estimated as of August 1990, and any atopy at baseline and current smoking status (never, former, current smoker). Canadian Gulf War Veterans Goss Gilroy Inc. was contracted by the Canadian Department of National Defence to carry out an epidemio- logic survey of Canadians who had served in the Gulf War to determine their health status (Goss Gilroy Inc., 1998; Statistics Canada, 2005). The survey was mailed to 9,961 Canadian Forces personnel: the entire cohort of Canadian Gulf War veterans who had been deployed to the Gulf War (n = 4,262) and a comparison group of personnel who had deployed elsewhere (n = 5,699) during the same period. The overall response rate was higher among Gulf War veterans (n = 3,113; response rate 73.0%) than among the comparison veterans deployed else- where (n = 3,439; response rate 60.3%). Generally, deployed veterans had higher rates of self-reported chronic
74 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES conditions and symptoms of a variety of clinical outcomes than controls. Respiratory diseases were included in the outcomes of interest. United Kingdom Gulf War Veterans Two studies of the health of UK military veterans who served during the Gulf War addressed respiratory outcomes. Simmons et al. (2004) used data collected as part of a mail survey of UK Gulf War veterans. While the survey was designed largely to assess reproductive outcomes among the veterans, it also contained open-ended questions about the veteransâ current health and about changes in their health since 1990, with the answers cat- egorized, including asthma and respiratory problems not otherwise specified. The exposed cohort consisted of all UK Gulf War veterans, and the unexposed cohort consisted of a random sample of nondeployed UK military personnel from the same period. Although the number of surveys returned in the study was large (25,084 by Gulf War veterans and 19,003 by era Gulf War veterans), the participation rate was low (47.3% and 37.5% of male and female Gulf War veterans, respectively, and 57.3% and 45.6% of male and female nondeployed veterans). Estimates were adjusted for age at time of survey, service and rank at time of the Gulf War, serving status at time of survey, alcohol consumption, and smoking. Unwin et al. (1999) conducted a cross-sectional postal survey from 1997 to 1998 to compare the health profiles of veterans and military service members from the United Kingdom (n = 8,195; overall response rate 65.1%). The study population was randomly selected, and the sample was stratified into three cohorts: deployed male and female Gulf War veterans and military service personnel (n = 2,961) who served in the Gulf region between September 1, 1990, and June 30, 1991 (response rate = 70.4%); deployed military personnel who had served in Bosnia (n = 2,620) between April 1, 1992, and February 6, 1997 (response rate 61.9%); and veterans and military personnel who were in the armed forces on January 1, 1991 (n = 2,614) but were not deployed to the Gulf War (response rate 62.9%). Odds ratios were calculated, and the proportions of symptoms, disorders, and exposures were compared between the Gulf cohort and the two comparison cohorts. Study investigators controlled for potential confounders includ- ing sociodemographic (age, marital status, education, employment), military (rank, still serving or discharged), and lifestyle (smoking, alcohol consumption) factors. The strengths of this study included its use of two different military control groups that came from a large, randomly selected population-based study population and the fact that it accounted for pre-existing health status and cigarette smoking. Among the limitations was its reliance on unverified self-reported medical symptoms and conditions; however, the committee believed that differential non-response or recall bias was unlikely, based on the results of subanalyses presented by study investigators. REFERENCES Abraham, J. H., and C. P. Baird. 2012. A case-crossover study of ambient particulate matter and cardiovascular and respiratory medical encounters among U.S. military personnel deployed to Southwest Asia. Journal of Occupational and Environ- mental Medicine 54(6):733â739. Abraham, J. H., S. F. DeBakey, L. Reid, J. Zhou, and C. P. Baird. 2012. Does Deployment to Iraq and Afghanistan Affect Respiratory Health of US Military Personnel? Journal of Occupational and Environmental Medicine 54(6):740â745. Abraham, J. H., A. Eick-Cost, L. L. Clark, Z. Hu, C. P. Baird, R. DeFraites, S. T. Tobler, E. E. Richards, J. M. Sharkey, R. J. Lipnick, and S. L. Ludwig. 2014. A retrospective cohort study of military deployment and postdeployment medical encounters for respiratory conditions. Military Medicine 179(5):540â546. AFHSC (Armed Forces Health Surveillance Center), Naval Health Research Center, and U.S. Army Public Health Command (Provisional). 2010. Epidemiological studies of health outcomes among troops deployed to burn pit sites. Silver Spring, MD: Department of Defense. https://www.vetshq.com/wp-content/blogs.dir/files/sites/11/2013/10/Epidemiological-Â Studies-of-Health-Outcomes-Among-Troops-Deployed-to-Burn-Pit-Sites.pdf (accessed June 15, 2020). Baird, C. P., S. DeBakey, L. Reid, V. D. Hauschild, B. Petruccelli, and J. H. Abraham. 2012. Respiratory health status of US Army personnel potentially exposed to smoke from 2003 Al-Mishraq Sulfur Plant fire. Journal of Occupational and Environmental Medicine 54(6):717â723.
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