Letter Sent to Those Exposed to Chemical Weapons During Gulf War Uploaded 10/11/2017

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• Published: 08 January 2022

Wellness symptom trajectories and neurotoxicant exposures in Gulf War veterans: the Ft. Devens cohort

• Clara G. Zundel^{1,2  na1},
• Timothy Heerenⁱⁱⁱ,
• Megan Yee^ane,iv,
• Avron Spiro^{5,half dozen,seven},
• Susan P. Proctor^one,8,
• Claudia M. Grasso^one &
• Kimberly Sullivan^four

Environmental Health book 21, Article number:seven (2022) Cite this article

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Abstract

Background

Thirty years agone, Gulf War (GW) veterans returned home with numerous health symptoms that take been associated with neurotoxicant exposures experienced during deployment. The wellness effects from these exposures have been termed toxic wounds. About GW exposure-event studies employ group analyses and thus private fluctuations in symptoms may have been masked. This study investigates health symptom trajectories in the same veterans over 25 years.

Methods

Veterans were categorized into 5 a priori trajectory groups for each wellness symptom and Chronic Multisymptom Affliction (CMI) clinical case condition. Multinomial logistic regression models were used to investigate associations betwixt these trajectories and neurotoxicant exposures.

Results

Results bespeak that more than 21 Pyridostigmine Bromide (Lead) pill exposure was associated with consistent reporting of fatigue, pain, and cognitive/mood symptoms too as the development of half dozen additional symptoms over time. Chemic weapons exposure was associated with both consistent reporting and development of neurological symptoms over time. Reported exposure to tent heater frazzle was associated with afterwards evolution of gastrointestinal and pulmonary symptoms. Veterans reporting exposure to more than than 21 PB pills were more than viii times every bit probable to consistently meet the criteria for CMI over time.

Decision

This written report highlights the importance of the continued documentation of the wellness impacts experienced by GW veterans', their resulting chronic health symptoms, and the importance of exposure-effect relationships in these veterans now 30 years mail service-deployment.

Peer Review reports

Groundwork

Thirty years ago, Gulf War (GW) veterans returned dwelling from deployment with a constellation of health symptoms: some have been chronic, some take emerged over time, and others have remitted [1, ii]. Collectively, these symptoms are termed Gulf War Illness (GWI) and have been associated with primal nervous organisation (CNS) dysfunction as a event of neurotoxicant exposures during the state of war and resultant toxic wounds [iii, 4]. These exposures include chemic warfare agents (sarin/cyclosarin), pesticide sprays and creams, pyridostigmine bromide (PB) safety anti-nervus gas pills, smoke from oil well fires, tent heater exhausts, and others [3,4,5,half dozen].

In the early years, research focused on determining the symptoms that characterized GWI, and identifying potential neurotoxicant exposures that could be etiologically related to these symptoms. However, studies which compared GWI cohorts to controls did not allow for the comparison of the carve up GWI health symptom trajectories of an individual veteran. The majority of the studies utilise the two most widely used case criteria for GWI, the Centre for Disease Command (CDC)'s Chronic Multisymptom Illness (CMI) criteria and the Kansas GWI criteria [7, 8]. To date, these 2 criteria are recommended past the Found of Medicine (IOM) and Department of Defense force (DoD) for use in GWI research studies. Yet, both criteria were derived over 20 years ago and reflect what the disease looked like initially post-deployment. In addition, these criteria inquire veterans whether they accept experienced these symptoms over the by half dozen months. Therefore, the instance criteria only capture current symptoms and do not account for potential changes in symptoms over time [nine]. This has made obtaining service-related benefits difficult for veterans with toxic wounds.

Specifically, the CDC criteria include the following symptom domains: fatigue, mood and noesis, and pain, whereas the Kansas criteria as well include gastrointestinal, respiratory, and skin domains [7, 8]. Additionally, the Kansas criteria exclude concomitant illnesses that could account for their chronic health symptoms, including neurologic disorders such as Parkinson's disease, dementia, and stroke [8]. Relying on these case definitions 30 years post-deployment, researchers and clinicians may not exist adequately addressing the sensitivity and specificity of the affliction as a whole, every bit some symptoms may have decreased and new symptoms may take emerged over time [1, 10].

Importantly, these two criteria vary greatly in the presumptive rates of disease. The CDC criteria is likely to have increased rates of cases amidst various cohorts of GW veterans relative to the Kansas criteria (i.due east. higher sensitivity but lower specificity) considering the Kansas criteria encompasses more bodily systems and excludes those with other neurologic or other chronic medical conditions [7, 8]. For example, the Kansas criteria excludes diabetes and stroke, when studies take shown that these atmospheric condition are increasing in GW veterans over time and are related to specific neurotoxicant exposures (Atomic number 82 and sarin exposure) [2, x]. These exposures may also be related to delayed or latent health symptoms that develop over fourth dimension and tin outcome in additional toxic wounds [ane]. These strict Kansas criteria exclusions may have helped to characterize the GW veteran population initially, but now, 30 years later, may not be every bit applicable and may exist excluding the very veterans who are the sickest and virtually affected by their deployment. For instance, in our recent study utilizing the population-based Ft. Devens Cohort (FDC) of GW veterans, we found that rates of both the CDC and Kansas instance criteria have increased essentially (past twenty%), over the course of twenty years in these largely non-treatment seeking veterans [two]. Nonetheless, rates of Kansas GWI criteria continue to exist lower than the CDC'south CMI criteria when those with chronic medical conditions are excluded (rates of cases at 66 and 79% respectively) [2].

An additional criticism of these criteria is that some of the symptoms may be sensitive to changes that are associated with normal crumbling (i.east., joint pain and sleep dysfunction), and thus may not reflect the actual deployment-related illness [11]. In a contempo paper using the Department of Veteran Affairs' Millennium Cohort, rates of CMI were compared between GW-era and non-era veterans over v split fourth dimension periods [12]. It was constitute that rates of CMI increased in all veteran groups over fourth dimension, specially in those deployed to the Gulf region. The increased rates of CMI over time in other potentially non-exposed cohorts may suggest that the symptoms used in this criterion may exist susceptible to non-deployment related factors, including normal aging. Further, every bit the GW veteran population ages and the initial rule-out diagnoses of the Kansas criteria are increasing in prevalence, it is imperative that nosotros appraise and potentially revise the detached symptoms and exclusionary criteria. Reevaluating the diagnostic criteria volition lessen the risk of excluding those individuals whose symptoms and medical conditions are related to GW deployment and who too take neurotoxicant-induced accelerated age-related disorders. Additionally, a revised criteria should exclude those who might erroneously meet criteria due to mild symptoms that are expected for their current historic period-grouping (i.e., joint paint and slumber dysfunction that increased with historic period) [10].

A recent re-survey (2014–2016) of the Gulf State of war Era Accomplice and Biorepository (GWECB) was conducted to assess the current rates of GWI using both the CDC and the Kansas criteria, and to evaluate the utility of these criteria now to distinguish health issues reported by GW deployed veterans and GW era veterans [13]. The results of this study replicate what was constitute in Porter, et al [12], in that 80% of non-deployed era veterans reported symptoms consistent with the CDC GWI criteria, suggesting that this criteria has reduced specificity [thirteen]. For the Kansas criteria, deployment status was associated with increased odds of reporting 27 of the 29 symptoms, suggesting its continued utility [thirteen]. All the same, roughly 40% of the GWECB cohort had at least one medical or psychiatric status that is considered an exclusion status in the Kansas criteria. This is a more than 30% increment from the original Kansas cohort, further emphasizing the fact that these exclusion criteria need to be re-evaluated as GW veterans continue to age [thirteen].

One possible explanation for variability of case status and corresponding wellness symptoms beyond samples reported in the literature is that different exposures may result in different types, rates, and longevity and trajectory of health symptoms [ix, 14, fifteen]. Therefore, it is vitally of import to continue to characterize the illness past toxicant exposures, as some toxicant exposures are known to exert latent or delayed wellness effects, for instance, chronic respiratory problems and cancers including brain tumors [16,17,xviii,nineteen]. Although exposure outcome studies have been conducted with both preclinical and clinical models, well-nigh are conducted with exposure mixtures or by case condition (GWI versus controls), and then it is often hard to conclude which symptoms event from specific exposures. Additionally, exposure-issue relationship studies are often flawed because of the small sample sizes, express exposure data, reliance on cocky-report or retrospective remember of exposure, cross-sectional analyses, or the use of treatment seeking populations with numerous wellness complaints [3, 4].

Information technology is specially of import to conduct exposure-outcome studies longitudinally in population-based non-treatment seeking cohorts. To date, several longitudinal studies of health symptoms and rates of case criteria have been conducted in GW veterans from multiple countries including the US, UK and Australia [1, 2, 9, 12, 20,21,22]. Still, few studies have analyzed exposure-based outcomes longitudinally [1, 12]. Nosotros recently reported on data from the longest-running population-based cohort of GW veterans who returned from the state of war through Ft. Devens, MA (FDC) where we examined exposures related to health symptom outcomes [1]. We institute increased rates of mood and cognitive outcomes in those reporting exposures to tent heaters, PB pills, and chemical warfare agents, and that the self-reported rates of these symptoms increased over time [i]. However, the analyses for this paper examined changes at the group rather than the individual level. Thus, it was not clear if specific symptoms fluctuated over time within private veterans. For case, while the study showed that many symptoms increased over time, whether individual GW veteran symptom reporting increased, decreased, or fluctuated over time was not examined.

Assessing individual veteran wellness symptom trajectories is also of import when analyzing trends in rates of a chronic disorder such equally GWI. For example, there are many ways in which an individual could come across criteria for the illness. In analyses investigating rates of illness longitudinally, it is oftentimes unclear if the individuals are arriving at clinical status via the aforementioned symptoms, or potentially if some of their symptoms have recovered or if new ones have emerged, thus having the veteran continue to meet GWI criteria merely through dissimilar combinations of symptoms. For example, in that location are 27 different ways in which an individual can come across the CDC'south CMI criteria [23]. Through grouping analyses, this may indicate that individuals have consistently met the criteria over fourth dimension, when in fact, diverse symptoms may have fluctuated or appeared over time, but the private'south case status remained unchanged (i.due east. they all the same met criteria but past a different combination of symptoms).

Therefore, the most accurate fashion of assessing changing symptoms over fourth dimension is to evaluate health symptom reporting longitudinally, in a way that assesses private fluctuations in reporting, that may be masked in group analyses. To do this, each private tin be assigned into a trajectory grouping for every health symptom (i.eastward., no symptom, develops symptom, mixed reporting of the symptom, remission of symptom, and consistent written report of symptom). The FDC, a cohort of deployed GW veterans who take been followed since mail-deployment in 1991 and at 3 fourth dimension points since (1992–1993, 1997–1998, and 2013–2017), is one of the few cohorts which allows for this type of assay. In this paper we evaluated the same 15 health symptoms as well every bit clinical case status (GWI) in three separate time periods over 25 years, comparing individual veterans' fluctuation in symptoms, or 'symptom trajectories', over time. In addition, given the exposure information compiled from this accomplice over the years (beginning virtually immediately post-deployment before some exposures were identified as potentially causative), we analyzed unlike trajectories of symptoms and CMI clinical case status in association with cocky-reported neurotoxicant exposures in the GW theatre.

Methods

Participants and surveys

The FDC has been described previously [one, two]. Briefly, this was a cohort of Agile Duty, Reserve, and National Baby-sit Regular army veterans who were deployed to the GW and returned dwelling house through Ft. Devens, MA. The initial baseline survey in 1991 was designed to assess psychological wellness and gainsay exposure. Subsequent follow-up questionnaires (1992, 1997–1998, and 2013–2017) assessed long term health, psychological and functional well-being, including Post-traumatic stress disorder as measured by the Mississippi Scale for Gainsay Related PTSD ( [24] also as self-report of GW specific neurotoxicant exposures. The current study uses a subset of the FDC participants (North = 293) who completed the Wellness Symptom Checklist at all 3 follow-upwards time points (1992, 1997–1998, and 2013–2017). All participants gave their informed consent for inclusion at each timepoint, before they participated in the surveys. Institutional review board approvals were obtained from VA Boston Healthcare System and Boston University prior to initiating the surveys. The timeline of the FDC is displayed in Fig. 1.

Fig. ane

Ft. Devens cohort reunion survey timeline

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The health symptom checklist

The minor differences in Health Symptom Checklist (HSC) versions across the three follow-up surveys have been explained in a previous report [i]. In brief, the HSC is a list of health symptoms originally adjusted from Bartone, Ursano [25]. Follow-upwardly ane contained a 20-item HSC, in which veterans were asked to indicate the frequency of symptoms over the past 4 weeks using a Likert-calibration rating (none, a little, often, very oft) [26], Follow-up 2 contained a 52-item HSC, in which veterans were asked to indicate whether they experienced each wellness symptom over the past 4 weeks (yes or no) [27, 28], and Follow-up three contained a 34-item HSC, in which veterans were asked to endorse whether they experienced a symptom (yes or no) over the by 30 days [one]. A total of xv symptoms were consistently assessed at all three timepoints. All responses were dichotomized as nowadays or absent. If a veteran indicated non experiencing a symptom, and also endorsed a frequency, the response was recoded as existence present.

CMI criteria

Chronic Multisymptom Illness (CMI) by the Centre for Disease Command (CDC) criteria were determined as the presence of persistent symptoms over six months in two out of 3 domains: fatigue, cognitive/mood, and musculoskeletal [7]. Because a limited number of symptoms [15] were consistently assessed at all three timepoints, our measure of the CMI criterion included: i symptom in the fatigue domain (overly tired/lack of free energy), 4 in the cognitive/mood domain (depressed mood, difficulty concentrating, nervous or tense, problem sleeping), and 1 in the musculoskeletal domain (joint hurting).

Gulf War exposure characterization

The full explanation of how GW exposures were characterized in the FDC has been reported previously [1]. In brief, to minimize the length of time betwixt deployment and recall, exposure data were taken from the Follow-up ii survey, 6 years afterwards deployment. In this newspaper we report the associations between health symptom trajectories and 4 exposures, including Atomic number 82 pills, chemic weapon alert, Khamisiyah weapons depot notification, and tent heater exposure.

Participants were asked to point how many anti-nervus gas (PB) pills they took in the GW, on a calibration of 0, 1–two, 3–10, 11–21, and > 21. Responses were coded into whether they took more than 21 Pb pills, dichotomized into yes (> 21) and no (< 21) responses, as the blister pack given troops included 21 pills and 21 pills has previously been associated with higher rates of GWI symptoms [29]. Similarly, participants were asked to indicate how many times they were on "formal alert" for a chemical attack (e.thousand., had to put on total MOPP gear) on a scale of 0, one–two, 3–10, eleven–twenty, and twenty or more times. Responses were coded into whether they were on "formal alert" for more than than xx times, dichotomized into aye (> 20) and no (< 20) responses, as self-reported frequency of chemic alarms has been associated with adverse effects on brain construction, with the strongest effect observed for both 7–30 days and thirty+ days of hearing chemical alarms [30].

Veteran'due south exposure to the Khamisiyah weapons demolition was determined. In March of 1991, the Regular army Corp of engineers detonated underground munition bunkers which unbeknownst to them housed thousands of Iraqi rockets, with chemic weapons sarin/cyclosarin in the tips of the rockets. When the explosions occurred, it was estimated that over 100,000 GW veterans were exposed to low-level sarin/cyclosarin due to their proximity to the air plumes from the explosions [31, 32]. The Department of Defense (DoD) eventually notified exposed veterans by letter and a registry was established. A listing of FDC veterans who received notification letters of potential exposure to sarin based on their proximity to the Khamisiyah weapons depot detonations and presumed to be exposed to depression levels of sarin/cyclosarin based on wind feather modeling in 2000 was obtained from the DoD. These exposures were categorized as a dichotomous variable, yes (received a notification letter from the 2000 DOD exposure model) or no (never received a notification letter of the alphabet) for Khamisiyah exposure status as a proxy for sarin chemic weapons exposure during their deployment [32].

Lastly, participants were also asked whether they had a tent heater or stove in the area where they slept (yes vs. no).

Symptom (Sx) trajectory groups

In order to evaluate health symptom trajectories over time, five a priori symptom trajectory groups were created based on responses at the iii time points (No Sx, No Sx then Develops Sx, Mixed, Remitting Sx, Consistent Sx) for each symptom assessed (meet Tabular array i). The No Sx grouping contains veterans who never endorsed the symptom on all three follow-up surveys. The No Sx then Develops Sx group contains both veterans who initially did not study the symptom on the first follow-up survey, but later endorsed the symptom on Follow-upwardly 2 and Follow-up 3 or veterans who initially did not report the symptom on the beginning two follow-upward surveys but endorsed on Follow-up 3. The Mixed group contains veterans whose symptoms of endorsement fluctuated across the follow-ups (i.e., endorsed on follow-upwards 1, not endorsed on follow-up 2, and so endorsed again on follow-up 3; and not endorsed on follow-up 1 endorse on follow-up 2 and so not endorsed over again on follow-up iii). The Remitting Sx group contains veterans who initially endorsed the symptom on follow-up 1 just they did not endorse the symptom on follow-up two and 3, as well as veterans who initially endorsed the symptom on follow-ups 1 and 2 merely did not endorse on follow-up 3. Finally, the Consistent Sx group contains veterans who endorsed the symptom on all three follow-upwards surveys. Participants were classified into trajectory groups for each health symptom and CMI clinical case condition.

Table 1 Descriptions of Symptom Trajectory Groups

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Data analysis

Demographics and characteristics of the full FDC and the current study sample were presented using descriptive statistics. A multinomial logistic regression model was built with each health symptom trajectory grouping every bit the dependent variable, and one of the GW-specific exposures (i.e., PB pills, cocky-reported exposure to chemical warfare agents, notification of proximity to Khamisiyah sarin/cyclosarin air plumes, and tent heater exposure) as the independent variable. Covariates included in the model were age, sex, and post-traumatic stress disorder (PTSD) status (score of > 89 on the Mississippi PTSD Calibration indicative of PTSD), all derived from the baseline survey conducted in 1991. Nosotros chose to include baseline PTSD status as a covariate to control for the cognitive, mood, and somatic symptoms that may arise from trauma, and therefore not neurotoxicant exposures [33, 34] . Additionally, for each individual exposure model, we included all other neurotoxicant exposures as covariates, to control for effects on symptoms from other exposures. Odds ratios (OR) and 95% confidence intervals (CI) were calculated from the logistic regression models. P values < 0.05 were considered significant. All analyses were performed using SAS 9.4 (SAS, Cary, NC).

Results

Demographics and baseline characteristics

A total of 2949 FDC veterans completed the initial baseline survey in 1991. A total of 295 veterans completed all follow-upwardly surveys. Two veterans did not have complete health symptom data for all three follow-upwards surveys and were thus excluded from the report sample for a final sample size of 293. The veterans in the study sample were approximately 32 years quondam at the time of the initial 1991 baseline survey and 54 years onetime by the last follow-up survey (Table 2). Veterans were predominately male (87.4%) and White (92.8%). Over 16% of the veterans were on active duty at the time of the GW and 5.5% of the study sample exceeded the clinical cutoff of the Mississippi calibration for PTSD. The full accomplice from the initial 1991 baseline survey did not differ from the study sample with regards to PTSD score or condition. The written report sample differed from the full FDC, equally veterans were older, more than probable to exist White, and less likely to be male and initially on agile duty. Demographics and characteristics for both the full FDC sample and the study sample are summarized in Table 2.

Tabular array 2 Demographics and Characteristics

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Private symptom trajectories

The prevalence of trajectory groups for each symptom are described in Fig. two (sample sizes of each group are presented in Table three). Less normally reported symptoms (greater than 50% of veterans never endorsed across all three follow-up surveys) were crying hands, hands sweating, rapid heartbeat, dizziness, and shortness of breath. Symptoms that showed an increase in prevalence over time (greater than 20% of veterans did not study initially but reported at later follow-ups) were muscle twitching, depressed mood, trouble sleeping, fatigue, nervousness, and articulation pain. The only symptom that waxed and waned over time was nervous or tense (with xx% of veterans in the mixed trajectory grouping). Remitting symptoms included headaches and nausea (with more than 20% of veterans in these trajectory groups). More than unremarkably reported symptoms (greater than 30% of veterans consistently reported these symptoms across all iii follow-upwardly surveys) were fatigue, trouble sleeping, and joint pain.

Fig. two

Pct of veterans by symptom trajectory group for each health symptom

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Table three Associations between GW-Specific Neurotoxicant Exposures and Symptom Trajectories Adjusted for other exposures

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The prevalence of trajectory groups for CMI clinical case status are described in Fig. three (sample sizes of each group are presented in Tabular array 4). Nearly veterans (45%) consistently met criteria for CMI across all 3 follow-ups, followed by 19.5% of veterans who met criteria for CMI as fourth dimension went on, 12.9% of veterans had a mixed trajectory of CMI clinical case condition, and 11.1% of veterans never met criteria for CMI across all follow-ups.

Fig. iii

Per centum of veterans by chronic multisymptom affliction (CMI) trajectory group

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Table 4 Associations between Exposures and CMI – GWI Trajectories

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Associations between individual symptom trajectories and neurotoxicant exposures

PB pill (more 21) exposure

Veterans who reported taking more than 21 PB pills were more than twice as likely to develop difficulty concentrating, dizziness, nervous or tense, shortness of jiff, depressed mood, and skin rash over time, as compared to those reporting < 21 Atomic number 82 pill exposure (0–21 pills) (p'due south < 0.05). This exposure was likewise associated with fluctuating reporting of nervous or tense, hands sweating, and depressed mood over fourth dimension (p's < 0.05). No associations were observed betwixt Atomic number 82 pill (more 21) exposure and symptom trajectories of headaches, muscle twitching, rapid heartbeat and crying easily (p'due south > 0.05). Veterans who reported taking more than 21 Pb pills were more than than twice every bit likely to consistently report these symptoms over iii time periods, including the following: dizziness, fatigue, nervous or tense, problem sleeping, upset breadbasket/nausea, and depressed mood as compared to those reporting < 21 Pb pill exposure (0–21 pills) (p'due south < 0.05). These results and odds ratios are reported in Table 3.

Chemical alert (20 or more than) exposure

Veterans who reported experiencing 20 or more chemical alerts were more than four times as likely to fluctuate reporting of headaches over time (p < 0.05). Additionally, veterans who reported this exposure were less likely to develop skin rash over time (p < 0.05).

No associations were observed between chemical alert exposure (20 or more times) and symptom trajectories of hands sweating, trouble sleeping, rapid heartbeat, joint hurting, difficulty concentrating, dizziness, fatigue, crying hands, nervous or tense, upset tum/nausea, shortness of jiff, depressed mood, and musculus twitching (p'southward > 0.05). These results and odds ratios are reported in Tabular array 3.

Khamisiyah weapons demolition sarin air plume notification letter received –

Veterans who reported receiving a Khamisiyah notification letter from DoD were more than than twice as likely to consistently written report difficulty concentrating, dizziness, and depressed mood over the three fourth dimension periods assessed compared to those who did not report receiving a Khamisiyah notification alphabetic character (p'south < 0.05). Those reporting this exposure were also more than than 3 times as likely to recover from depressed mood over fourth dimension (p < 0.05). Those reporting this exposure were more four times every bit probable to fluctuate on reporting hands sweating (p < 0.05). Those reporting this exposure were significantly less likely to fluctuate in reporting upset tummy/nausea or to recover from this symptom over fourth dimension (p's < 0.05). Those reporting this exposure were significantly less likely to report headaches initially and then recover over fourth dimension (p < 0.05). Significant associations were not observed between Khamisiyah exposure and symptom trajectories of shortness of breath, musculus twitching, pare rash, trouble sleeping, rapid heartbeat, joint pain, fatigue, crying easily, and nervous or tense (p's > 0.05). These results and odds ratios are reported in Table three.

Tent heater exposure

Veterans who reported tent heater exposure were more than 3 times as likely to develop upset breadbasket/nausea and shortness of breath over time compared to those reporting no exposure to tent heaters (p'south < 0.05). Additionally, those reporting this exposure were less likely to develop skin rash over time and less probable to consistently study shortness of breath, compared to those reporting no exposure to tent heaters (p < 0.05). Those who reported this exposure were more than three times as likely to consistently study muscle twitching over time (p < 0.05). Veterans who reported this exposure were too three times as probable to recover from fatigue and crying hands over time as compared to those not reporting tent heater exposure (p < 0.05). No associations were observed between tent heater exposure and symptom trajectories of hands sweating, trouble sleeping, rapid heartbeat, joint pain, difficulty concentrating, dizziness, nervous or tense, depressed mood, and headaches (p's > 0.05). These results and odds ratios are reported in Table 3.

Chronic multisymptom affliction modified criteria (CMI)

Veterans who reported taking more than 21 PB pills were more than than 8 times as likely to consistently run across the criteria for CMI over time compared to those reporting < 21 Lead pill exposure (0–21 pills) (p < 0.05). No significant associations were observed for chemical alert exposure, Khamisiyah weapons demolition exposure, or tent heater exposure for trajectories of meeting the CMI criteria (p's > 0.05). These results are summarized in Table iv and Fig. iv.

Fig. four

Percentage of veterans in chronic multisymptom illness (CMI) trajectory group past more than 21 pyridostigmine bromide (PB) pill exposure

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Give-and-take

To our knowledge, this written report is the start of its kind to evaluate individual wellness symptom trajectories across three time periods over more than 25 years and associations with GW-specific neurotoxicant exposures. In add-on, we do not know of some other study where the same individuals were compared in terms of meeting case definition of CMI and exposures across three time-periods.

Our results showed that fatigue and general aches and pain/joint pain were identified as symptoms consistently endorsed by over 30% of this cohort of GW veterans at 3 fourth dimension periods over the bridge of more than 25 years. These 2 symptoms are currently included in both the CDC and the Kansas criteria, and consist of ii of the most prominent symptom domains: Fatigue and Pain [7, eight]. 4 symptoms (headache, poor concentration, poor sleep, nervousness) were consistently reported by at to the lowest degree 20% of the cohort who were surveyed at three fourth dimension points. The symptoms of poor concentration and nervousness are in the Kansas and CMI criteria of noesis and mood. Headache, nervousness, and poor slumber are as well CNS symptoms that are associated with GW deployment that should be considered in future case criteria iterations [iii]. These findings of consistent health concerns over 25 years in the aforementioned individuals also add together credence for these symptoms' future utility in biomarker and treatment evolution studies of GWI [two].

But two symptoms, headaches (27%) and tummy aches/nausea (21%) were endorsed initially but not endorsed at later timepoints by a quarter and a fifth of the accomplice respectively. We did non measure the extent to which targeted treatments were used for these symptoms, but information technology is possible that these individuals benefitted from such specialty clinic approaches at their local VA or individual healthcare facilities.

Several symptoms were identified that were not credible early on on post-deployment simply appeared later. These symptoms included fatigue, depression, nervousness, musculus aches, poor slumber, aches and pains, and shortness of breath, which were all endorsed by over 20% of the sample. Unique symptoms that were not reported above, and developed over fourth dimension included mood, pain and respiratory domains, indicating their continued utility in current example criteria.

Several symptoms were never endorsed by at least l% of our accomplice. These included crying easily, hands sweating, skin rash, shortness of breath, and rapid heartbeat. These symptoms tend to represent autonomic nervous organisation (ANS) disturbance and although there take been reports of ANS symptoms in GW veterans, it may represent a smaller subgroup and may be consistent with particular toxicant exposure outcomes [35, 36]. Differences in symptom reporting were noted throughout the groupings, which may be related to the exposures that were experienced in theatre.

Several associations between GW-specific neurotoxicant exposures and health symptom trajectories were observed. PB exposure of more than than 21 pills was associated with consequent reporting of fatigue and problem sleeping, cognitive and mood symptoms, besides equally nausea/upset tummy, and dizziness. Symptoms that developed over time in this exposed group included dizziness, difficulty concentrating, nervous/tense, shortness of breath, depressed mood, and peel rash. This exposure was not associated with any symptoms remitting over fourth dimension. This exposure had associations with all symptom domains currently encompassed in the two example definitions for GWI [vii, 8], suggesting a widespread effect of CNS-dysfunction affecting all major body systems, which is in line with previous studies that take found associations betwixt this exposure and the illness (CMI) as a whole [7, 28]. They as well stand for many symptoms of the acetylcholinergic system which PB targets [37,38,39]. In fact, the current study found that veterans reporting PB exposure of more than than 21 pills were more than eight times as likely to consistently run across the criteria for CMI over the span of more than 25 years, which is consistent with prior findings and expands upon the cantankerous-exclusive results of Steele, Sastre [forty] and Wolfe, Proctor [28]. Over 250,000 were exposed to PB, which is a significant concern in considering a cause for the development of chronic health outcomes in these veterans [6, 38, 39]. These results advise that an alternative to Pb pills should be used in futurity deployments and that troops who were exposed to more than than 21 Lead pills should be considered under new legislative category of toxic wounds for service connection.

Self-reported exposure to 20 or more chemic alerts was associated with no consistent reporting of any of the symptoms. There were also no symptoms that developed later. However those who reported exposure to 20 or more chemical alerts were likely to testify fluctuating reporting of headaches over fourth dimension.

Suspected sarin exposure at the Khamisiyah weapons demolition was associated with consequent reporting of difficulty concentrating and dizziness over time, and depressed mood similar to what has been reported in previous studies and farther validating the chronic CNS effects of these exposures (i, 42). All the same, they were also three times as likely to recover from depressed mood over time.

Tent heater exposure was associated with consistent reporting of shortness of jiff and likewise to study the development of nausea/upset tum and shortness of jiff over time,. This latter finding is suggestive of a possible delayed or latent upshot of this exposure on the gastrointestinal and respiratory systems. Veterans with this exposure were three times as likely to recover from fatigue and crying hands over time.. These findings are like to other studies that have reported associations between tent heater exposure and neurological and pulmonary symptoms [27, 28]. However, this is the first study to our noesis to report an association between tent heaters with gastrointestinal symptoms.

Limitations and strengths

The current analysis was limited to veterans who responded and had complete wellness symptom data for all three follow-up studies, which may limit the generalizability of our results, not just to the greater FDC, but to the entire GW veteran population. For example, our study sample was more likely to be male and White and less probable to have been active duty during the GW than was institute in the total Devens cohort. Confirmatory studies should be conducted in more than representative samples.

2d, no objective measures of GW-specific neurotoxicant exposures are available. Therefore, although we used self-study measures of these exposures, we minimized recall bias by using exposure data from Follow-up ii, which was less than 5 years afterward veterans returned from the GW and before many exposure-outcome reports had been published. Further, the first 2 follow-up surveys were conducted before the DoD notification letters of suspected sarin exposure at the Khamisiyah weapons sabotage were sent. Thus, veteran'southward reporting of symptoms may exist less biased, as they may not have known that they were exposed to sarin and would not attribute their symptoms to that exposure. In addition, exposures were reduced to binomial aye/no variables with yes denoting a specified amount based on prior enquiry. Unfortunately, we did not have the statistical power to break these categories down. Exposure categories were non mutually exclusive. We were also express to the exposure questions previously asked and therefore, we are not able to look at other acetylcholinesterase inhibitors and the impact on health symptoms over fourth dimension.

3rd, the current written report was express to using 15 health symptoms variables that were reported at all 3 follow-up surveys. Information technology would be of involvement to explore not only other wellness symptoms but also neuropsychological performance and neuroimaging markers longitudinally, to track disease progression, and to potentially identify new or latent effects of exposure. Adjacent, while no data on potential handling use were collected for this cohort, we acknowledge that handling use could have affected not only the symptoms that were observed to resolve over time, only other symptom trajectories as well. Lastly, results should be interpreted with caution every bit analyses were non adjusted for multiple comparisons.

Conclusions

This study highlights the importance of the continued documentation of GW veterans' health condition by GW-specific neurotoxicant exposures, and the importance of exposure-upshot relationships in these veterans at present 30 years post-deployment. Importantly, several symptoms were identified that have been consistently endorsed for nearly 25 years mail-deployment, suggesting chronic effects of the GW-specific neurotoxicant exposures. Therefore, the current recommended case criteria past Fukuda and Steele remain relevant based on this longitudinal analysis and could be further refined and updated with regard to exclusionary criteria and symptom inclusionary criteria based on our reported exposure-issue relationships. Additionally, while several treatments addressing neuroinflammatory and neuroimmune mechanisms are currently being investigated through clinical trials, targeting symptom alleviation would better veteran'due south quality of life until treatments for the illness as a whole become widely available.

Availability of data and materials

Analyses were performed using raw information that are only bachelor inside the US Department of Veterans Affairs firewall in a secure research environment. VA privacy and information security policies and regulatory constraints provide that only aggregate summary information may be removed from the VA for publication. The authors have provided detailed results of these analyses in the paper. These restrictions are in place in order to maintain patient privacy and confidentiality. Access to these information can be granted to persons who are not an employee of the VA; nonetheless, there is an official protocol that must be followed for doing so. The authors invite those wishing to access the raw information that were used for this analysis to contact Maxine Krengel (Maxine.Krengel@va.gov) to discuss the details of the VA data admission approving procedure.

Abbreviations

ANS:

Autonomic Nervous Organisation

CDC:

Center for Affliction Command

CI:

Confidence Interval

CMI:

Chronic Multisymptom Disease

CNS:

Central Nervous System

DoD:

Department of Defense force

FDC:

Ft. Devens Cohort

GW:

Gulf War

GWI:

Gulf State of war Disease

HSC:

Health Symptom Checklist

IOM:

Plant of Medicine

MA:

Massachusetts

MOPP:

Mission Oriented Protective Posture

NC:

North Carolina

OR:

Odds Ratio

PB:

Pyridostigmine Bromide

PTSD:

Post Traumatic Stress Disorder

SAS:

Statistical Analysis System

Sx:

Symptom

US:

United states

United kingdom of great britain and northern ireland:

United Kingdom

VA:

Veterans Diplomacy

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Acknowledgements

We would like to thank all of the Gulf War veterans who participated in the Ft. Devens cohort studies.

Disclaimer

Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed past the Department of Defense force or the Department of Veteran Affairs. The U.South. Regular army Medical Inquiry Conquering Activity, 820 Chandler Street, Fort Detrick Dr. 21702–5014 is the awarding and administering acquisition office for this work.

Funding

Funds for this study came from the Congressionally Directed Medical Research Program (CDMRP), Gulf War Disease Research Program grant # W81XWH-eleven-one-0818 to Dr. Maxine Krengel. Dr. Spiro was supported by a Senior Research Career Scientist honor from the Clinical Scientific discipline R&D Service, Function of Inquiry and Development, US Department of Veterans Affairs.

Writer data

Author notes

1. Maxine H. Krengel and Clara Thou. Zundel contributed equally to this work.

Affiliations

1. Research Service, VA Boston Healthcare Organisation, 150 South Huntington Ave. 8A-xc, Jamaica Plain, Boston, MA, 02130, United states

   Maxine H. Krengel, Clara G. Zundel, Megan Yee, Susan P. Proctor & Claudia M. Grasso

2. Behavioral Neuroscience Plan, Boston University School of Medicine, Boston, MA, U.s.a.

   Clara G. Zundel

3. Department of Biostatistics, Boston University Schoolhouse of Public Health, Boston, MA, The states

   Timothy Heeren

4. Department of Environmental Health, Boston University Schoolhouse of Public Health, Boston, MA, USA

   Megan Yee & Kimberly Sullivan

5. Massachusetts Veterans Epidemiology Enquiry and Information Center, VA Boston Healthcare System, Boston, MA, USA

   Avron Spiro

6. Department of Epidemiology, Boston University School of Public Health, Boston, MA, Usa

   Avron Spiro

7. Department of Psychiatry, Boston University Schoolhouse of Medicine, Boston, MA, USA

   Avron Spiro

8. Military Performance Division, US Ground forces Research Institute of Environmental Medicine, Natick, MA, USA

   Susan P. Proctor

Contributions

MHK – Conceptualization, Methodology, Investigation, Writing – Original Typhoon, Writing-Review and Editing, Visualization, Supervision, Projection Administration; CGZ - Conceptualization, Methodology, Formal Assay, Investigation, Data Curation, Writing-Original Draft, Writing-Review and Editing, Visualization, Project Assistants; TH – Data Curation, Formal Analysis, Writing-Review and Editing; MY – Writing-Review and Editing, Equally – Writing-Review and Editing, SPP – Writing-Review and Editing, CMG – Data Curation, Writing-Review and Editing, Visualization, Project Administration; KAS – Conceptualization, Methodology, Writing – Original Typhoon, Writing-Review and Editing. The author(s) read and approved the final manuscript.

Corresponding author

Correspondence to Maxine H. Krengel.

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All participants gave their informed consent for inclusion at each timepoint, before they participated in the surveys. Institutional review lath approvals were obtained from VA Boston Healthcare System and Boston University prior to initiating the surveys.

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Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Krengel, Thousand.H., Zundel, C.One thousand., Heeren, T. et al. Health symptom trajectories and neurotoxicant exposures in Gulf War veterans: the Ft. Devens accomplice. Environ Wellness 21, vii (2022). https://doi.org/10.1186/s12940-021-00812-0

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• Received: 26 May 2021

• Accepted: 25 November 2021

• Published: 08 Jan 2022

• DOI : https://doi.org/ten.1186/s12940-021-00812-0

Keywords

• Gulf War
• Veterans
• Toxic wounds
• Neurotoxicant exposure
• Longitudinal Design
• Health symptoms

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