The Role of Combat Zone Exposure in Development of Upper Airway Inflammatory Disease

Soldiers returning from deployment often complain of new-onset respiratory disease upon their return. It is known that exposure to higher levels of air pollution may occur while on deployment, and air pollution exposure has been identified as a risk factor for development of upper respiratory disease. The purpose of this review is to report findings from recent research regarding pollutant exposure and upper respiratory tract disease among military veterans. The prevalence of both allergic rhinitis and chronic rhinosinusitis is increased among deployed veterans compared to non-deployed counterparts. Deployed service members are also exposed to pollutants at up to 100 × that which is considered acceptable in the United States (U.S.). Deployed military members may be more prone to developing chronic upper respiratory conditions compared to their non-deployed counterparts, and this may be related to exposures overseas which are not routinely encountered in the U.S.


Introduction
Chronic rhinosinusitis (CRS) is an upper airway inflammatory disease that affects millions of people in the United States (U.S.), with healthcare expenditures related to CRS exceeding 10 billion U.S. dollars annually [1]. The pathogenesis of CRS is complex, multifactorial, and variable between patients. Air pollution exposure has had increasing investigation recently into its role in inciting or propagating CRS [2]. This was motivated by the recognition that inhabitants in urban setting had a higher incidence of upper airway disease, rhinitis, and sinusitis compared to more rural populations. Prior research has reported on the effects of pollutant exposure on the respiratory tract, and has demonstrated upregulation of pro-inflammatory cytokines, disruption of epithelial barrier membrane, and alteration of apical membrane surface structures [3,4]. How these changes contribute to airway inflammatory diseases, however, continues to be investigated. Additionally, animal studies have been conducted which have attempted to establish a link between pollutant exposure and the development of respiratory disease. Findings of these studies include evidence of increased eosinophilic inflammation, ciliary dysfunction, and mucus hypersecretion. [3,5]. Many of these studies have focused on pollutant exposure within populations of well-developed countries [6,7]. Similar trends have also been observed in military service members returning from deployment when compared to non-deployed populations.
U.S. military members returning from deployment have reported increased respiratory symptoms upon their return at least dating back to the Persian Gulf War and Operation Desert Shield [8][9][10][11]. Deployed soldiers are often exposed to harsh environments and foreign dust storms that have been associated with the development of respiratory disease. In addition, levels of standard air pollutants including particulate matter 2.5 (PM2.5), sulfur dioxide, ozone, and nitrogen dioxide have been shown to be significantly higher in deployment zones compared to allowable levels of these pollutants in the U.S [12]. Furthermore, burn pits are often utilized by the military during deployments for waste disposal, and have been scrutinized recently for potentially contributing to the development of respiratory diseases among exposed service members [13]. Service members are also frequently exposed to pesticides and repellants which have been shown to induce dose-dependent cytotoxicity in sinonasal epithelial cells [14] ( Table 1). Much of the research examining post-deployment respiratory conditions, however, has been retrospective; thus, a definitive causative link between deployment and the development of respiratory disease is largely speculative. The purpose of this review is to report findings from recent research regarding pollutant and chemical exposures and their impact on upper respiratory tract disease among deployed or previously deployed U.S. service members. Active duty service members are exposed to airborne pollutants on a daily basis regardless of deployment status. Prior work has been conducted to attempt to classify the variety of pollutants that veterans are exposed to and factors that may make them more prone to developing respiratory diseases from pollutant exposure ( Table 2). Throughout 2006-2007, ambient air sampling was conducted at 15 deployment locations including several in Iraq and Afghanistan. The levels of PM 2.5 and PM 10 at all locations far exceeded the occupational and military exposure guidelines, and were about 10 times greater than those observed at monitoring sites in the U.S. In fact, PM 2.5 levels were found to routinely exceed 10,000 μg/m 3 , which greatly exceeds the 25μg/m 3 limit in the U.S [15]. The pollutant levels remained fairly consistent at each site throughout the study period, but there was significant variation in pollutant levels between sites. Dust storms within the region were noted to be a major contributor to the variable levels of particulate matter between sites; however, trace metals were also identified, and were a byproduct of burn pits and unregulated industrial processing facilities. Burn pits have received intense scrutiny, as air sampling around a large burn pit at Joint Base Balad exhibited high levels of volatile organic compounds and particulate matter that can be associated with long-term health effects [13]. However, data has suggested that burn pits are not the sole source of air pollution, and there are multiple factors that contribute to poor air quality within these regions [16]. In fact, a recent systematic review on the effects of burn pit exposure on the respiratory tract did not find any association between burn pit exposure and objective measures of upper respiratory tract disease, although data was quite limited [13]. Even without deployment, active duty service members may be exposed to high levels of pollution. Elam et al. [17] conducted a matched case-control review of service members diagnosed with CRS and evaluated ambient air pollution exposure based on Environmental Protection Agency (EPA) data. An odd ratio (OR) of 5.99 (95% confidence interval (CI) = 2.55-14.03) was noted for the development of CRS for every 5μ4 g/m 3 of PM 2.5 . Furthermore, service members have been suggested to be at increased risk of development of respiratory diseases due to lifestyle. It is known that the prevalence of tobacco use among service members far outweighs that of the general U.S. population, with 30-40% of service members identifying as smokers [12,17]. The deleterious effects of smoking on the respiratory tract are widely demonstrated in the literature. However, when Elam et al. adjusted for smoking status, they still reported an OR of 3.15 (95% CI = 1.03-9.68) suggesting that while smoking may play a role in the development of CRS, the impact of PM 2.5 may also play a major role independent of smoking status [17].

Chemical and pesticide exposure
In addition to airborne pollutants, deployed military are exposed to a variety of chemicals that may put them at risk of developing health issues during or after deployment. Exposures to herbicides, such as Agent Orange, pesticides, fungicides, and flame retardants have been commonly reported among service members. Gulf War veterans, for example, were frequently exposed to pyridostigmine bromide pills, as a prophylactic medication, and nerve gas agents such as sarin [18]. Exposure to these substances has been associated with depression and neurologic symptoms [18]. Prior reports have shown increases in serum levels of several chemicals in soldiers deployed to highrisk regions [19]. Additionally, the use of permethrin-coated uniforms yields permethrin biomarker concentrations that are higher than the U.S. reference range concentrations, although still within the range which is considered acceptable by the World Health Organization. Certain factors however may increase exposure, such as ambient temperature, body composition, and physical workload [20]. Some of these chemicals have been shown to have deleterious effects on the upper respiratory tract. For example, cytotoxic effects were noted in an in vitro study of sinonasal epithelial cells exposed to varying concentrations of N,N-diethyl-meta-toluamide (DEET) [14]. This study reported a dosedependent reduction of cell growth and viability upon exposure to DEET. Additionally, morphologic changes were noted to cell structure upon exposure to increasing DEET concentrations, with lower concentrations resulting in fewer viable cells and higher concentrations causing complete cellular destruction [14]. Other studies have identified pronounced genotoxic effects of varying concentrations of permethrin, DEET, and diazinon on human sinonasal epithelial cells, bringing into question the potential carcinogenicity of these substances [21]. Permethrin is another pesticide/insecticide which is used to treat military uniforms to decrease the transmission of insect borne diseases. The effects of permethrin on human sinonasal epithelial cells have also been investigated [22]. At low concentrations, while the cells remained viable, there was a reduced rate of cellular proliferation. However, higher  [23][24][25]. Although a recent meta-analysis found no association between pesticide exposure and allergic rhinitis in children and adolescents, however, only two studies were included in the analysis [26].

Impact of deployment exposures on the upper respiratory tract (Table 3)
Prior research has shown that deployed veterans have reported upper and lower respiratory symptoms at significantly higher rates than non-deployed veterans [27••]. Increased environmental exposures, biological warfare agents, endemic infectious diseases, and psychological stressors may all contribute to the increased symptomatology [9]. Within the upper respiratory tract, an increased prevalence of allergic rhinitis and sinusitis has been reported among deployed veterans [28]. Research through the years has been conducted to further characterize these findings, and although most of the data is observational, it is important to review these findings in order to optimize treatment and potentially alter protocols in order to reduce foreign exposures that may increase the risk of development of respiratory disease.
Recognizing that deployed veterans are often exposed to environments and materials that they would not routinely encounter outside of warzones, researchers began to investigate whether these exposures may promote the development of new health conditions. Richards et al. [10] reported their experience with new-onset respiratory diseases among military personnel deployed to Saudi Arabia. A total of 2598 ground troops were included in this survey study, with 15.4% of respondents reporting persistent rhinorrhea. Complaints of rhinorrhea were associated with exposure to the outdoor environment while sleeping in tents, suggesting that environmental exposures may increase the likelihood of developing upper respiratory symptoms. Additionally, longer duration of deployment was associated with a higher likelihood of developing symptoms [10].
Another 63-item symptom survey distributed to Australian veterans of the Persian Gulf War found that deployed veterans reported 56 of the symptoms significantly more frequently than the non-deployed comparison group [8]. Both sinus problems and hay fever were among the 15 most frequently diagnosed medical conditions among these veterans. Both conditions were noted to be more prevalent among the previously deployed population (sinusitis OR = 1.5; 95% CI 1.1-2.0 and hay fever OR = 1.3; 95% CI 1.0-1.8). This study also investigated how overall health symptoms changed with increasing exposure to immunizations, anti-biological warfare medications, pesticides, and insect repellants. While the authors did not focus on how these exposures affected specifically respiratory symptoms, they did identify an association between the total number of health symptoms and increasing number of days that anti-biological warfare tablets were taken [8]. Additionally, increasing number of health symptoms was associated with exposure to pesticides (OR = 1.3; 95% CI 1.2-1.4), insect repellants (OR = 1.2; 95% CI 1.1-1.3), and chemical weapons areas (OR = 1.3; 95% CI 1.2-1.5) [8].
Histopathology specimens of Gulf War veterans have also been examined, with the majority of these specimens coming from the respiratory system including the nasal septum, turbinates, and ethmoid sinus [9]. The most frequently identified pathology on these specimens was noted to be inflammation, with the most frequent diagnoses being chronic sinusitis and allergic rhinitis. However, this study lacks a control group which makes it difficult to infer that deployment alone was responsible to the inflammation noted on histopathology [9].
Research in warzone exposures had renewed interest after the start of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF), when again veterans began experiencing new-onset respiratory symptoms, both during and after return from deployment. The National Health Survey for a New Generation of US Veterans (NewGen) collected data from about 60,000 veterans who served between 2001 and 2008 [29•]. About half of these veterans were deployed during the OEF/OIF conflicts while the other half were veterans from the same era who were not deployed. Barth et al. [29•] published their findings from their review of the survey data and identified sinusitis diagnoses were higher for the deployed group than for the non-deployed group with an adjusted OR of 1.30 (95% CI: 1.13-1.49). Their follow-up report in 2016 [30] reviewed respiratory diseases among veterans who reported exposures to various substances where respondents self-rated their level of exposure. Ninety-five percent of deployed veterans reported at least one respiratory exposure with 70% reporting high exposure levels. Among the non-deployed, still 70% reported at least one respiratory exposure, although only 24% reported high levels of exposure. Regardless of deployment status, however, the authors identified an increased risk of sinusitis with one or more respiratory exposure (deployed adjusted odds ratio (aOR) = 1.82, 95% CI = 1.37-2.41; non-deployed aOR = 1.68, 95% CI = 1.38-2.03). Furthermore, among the deployed veterans, those with at least one respiratory exposure were 80% more likely to report sinusitis, than those without reported exposures [30]. A smaller study of 127 consecutive, previously healthy, deployed military identified a 15% rate of chronic rhinosinusitis, and suggested that this may be due to overseas exposures [31]. Finally, Tam and Lee queried the Veterans Health Administration Support Service Center (VHASSC) database identifying OEF/OIF and non-OEF/OIF veterans seen between 2016 and 2019. This query found that the prevalence of chronic sinusitis among OEF/OIF veterans was nearly 2% compared to non-OEF/OIF veterans where the prevalence was around 0.5% [27••].
Allergy exacerbation is another upper respiratory disease that has been explored among the active duty population, particularly those with pollutant exposure. A 2005 cross-sectional study among veterans of OEF/OIF reported that 22.5% of those surveyed experienced an allergy exacerbation during deployment, while nearly 70% experienced at least 1 cough or cold [32].  [27••]. While these reports are not able to definitively link the development of allergic rhinitis to overseas exposures, it is important to consider this as a possible explanation given that most military members must be free of any major medical problems to meet the requirements for deployment.

Conclusion
It is clear within the literature that deployment overseas may predispose U.S. service members to the development of upper respiratory disease. Furthermore, it has also been demonstrated that exposure to pollutants while deployed may far exceed that which is routinely encountered within the U.S. Data suggest that there may be an association between airborne pollutant exposure during military deployment and upper respiratory disease. However, further work must be conducted to establish more than just an association as exposure has yet to be confirmed as a causative factor in this disease propagation.

Conflict of Interest
The authors declare no competing interests.

Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by the authors.

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