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Gulf War Illness, A Drug and Environmentally-Triggered Condition

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A special issue of International Journal of Environmental Research and Public Health (ISSN 1660-4601).

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 39543

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Prof. Dr. Beatrice A. Golomb

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Department of Medicine, University of California, San Diego, CA 92093-0995, USA
Interests: gulf war illness; organophosphate and carbamate effects

Special Issue Information

Dear Colleagues,

In the 1990–1991 Persian Gulf War, deployed personnel were exposed to an unprecedented array of new, unique, and excessive drug and environmental exposures. Of the ~700,000 deployed U.S. personnel, as well as smaller numbers of military personnel from other nations, about a third of those deployed developed chronic multisymptom health problems known as “Gulf War illness” (GWI). Studies tie these to drug and environmental exposures and show that combat stress is not an independent predictor. Over a quarter-century later, affected veterans continue to suffer, with symptoms including fatigue as well as cognitive, muscle, gastroenterological, and neurological problems, among others. Although many objective physiological alterations have been documented in those affected, the nature and ramifications of GWI remain incompletely understood.

These veterans view themselves as the “forgotten veterans”, given the far greater attention to the signature injuries of later conflicts. GWI represents chemical injury, contrasted with post-traumatic stress disorder (PTSD) (from psychological injury) and traumatic brain injury (TBI) (from mechanical injury).

Here we call for papers germane to GWI, encompassing epidemiological studies, studies examining biomarkers, the impact of the condition, and effects of prospective treatments. Studies involving animal models of GWI are also welcome.

Prof. Dr. Beatrice Golomb
Guest Editor

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Keywords

Gulf War illness
Chemical
Pesticide
Nerve gas
Pyridostigmine bromide
Vaccines
Oil fire
Burn pit

Published Papers (11 papers)

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Research

13 pages, 804 KiB

Open AccessArticle

A Placebo-Controlled, Pseudo-Randomized, Crossover Trial of Botanical Agents for Gulf War Illness: Reishi Mushroom (Ganoderma lucidum), Stinging Nettle (Urtica dioica), and Epimedium (Epimedium sagittatum)

by Jarred Younger, Emily K. Donovan, Kathleen S. Hodgin and Timothy J. Ness

Int. J. Environ. Res. Public Health 2021, 18(7), 3671; https://doi.org/10.3390/ijerph18073671 - 1 Apr 2021

Viewed by 3035

Abstract

This report is third in a three-part clinical trial series screening potential treatments for Gulf War Illness (GWI). The goal of the project was to rapidly identify agents to prioritize for further efficacy research. We used a placebo-controlled, pseudo-randomized, crossover design to test the effects of reishi mushroom (Ganoderma lucidum), stinging nettle (Uritca dioica), and epimedium (Epimedium sagittatum) in 29 men with GWI. Participants completed 30 days of symptom reports for baseline, then a botanical line consisting of 30 days of placebo, followed by 30 days each of lower-dose and higher-dose botanical. After completing a botanical line, participants were randomized to complete the protocol with another botanical, until they completed three botanical trials. GWI symptom severity, pain, and fatigue were contrasted between the four conditions (baseline, placebo, lower-dose, higher dose) using linear mixed models. GWI symptom severity was unchanged from placebo in the reishi lower-dose condition (p = 0.603), and was higher in the higher-dose condition (p = 0.012). Symptom severity was not decreased from placebo with lower-dose stinging nettle (p = 0.604), but was significantly decreased with higher-dose stinging nettle (p = 0.048). Epimedium showed no significant decreases of GWI symptoms in the lower (p = 0.936) or higher (p = 0.183) dose conditions. Stinging nettle, especially at higher daily dosages, may help reduce the symptoms of GWI. Epimedium does not appear to beneficially affect GWI symptom severity, and reishi may exaggerate symptoms in some GWI sufferers. These results are in a small sample and are preliminary. Further research is required to determine if stinging nettle is indeed helpful for the treatment of GWI, and what dosage is optimal. This trial was registered on ClinicalTrials.gov (NCT02909686). Full article

(This article belongs to the Special Issue Gulf War Illness, A Drug and Environmentally-Triggered Condition)

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14 pages, 6775 KiB

Open AccessArticle

A Placebo-Controlled, Pseudo-Randomized, Crossover Trial of Botanical Agents for Gulf War Illness: Resveratrol (Polygonum cuspidatum), Luteolin, and Fisetin (Rhus succedanea)

by Kathleen S. Hodgin, Emily K. Donovan, Sophia Kekes-Szabo, Joanne C. Lin, Joseph Feick, Rebecca L. Massey, Timothy J. Ness and Jarred W. Younger

Int. J. Environ. Res. Public Health 2021, 18(5), 2483; https://doi.org/10.3390/ijerph18052483 - 3 Mar 2021

Cited by 13 | Viewed by 3515

Abstract

A chronic multi-symptom illness of unknown etiology, Gulf War Illness (GWI) affects 175,000 to 250,000 veterans of the Gulf War. Because inflammation has suspected involvement in the pathophysiology of GWI, botanical treatments that target inflammation may be beneficial in reducing symptoms. No FDA-approved treatments currently exist for GWI, and rapid prioritization of agents for future efficacy testing is important. This study is part of a larger project that screened nine different botanical compounds with purported anti-inflammatory properties for potential treatment of GWI. We tested three botanicals (resveratrol [Polygonum cuspidatum], luteolin, and fisetin [Rhus succedanea]) on symptom severity of GWI in this placebo-controlled, pseudo-randomized clinical trial. Twenty-one male veterans with GWI completed the study protocol, which consisted of 1 month (30 days ± 3) of baseline symptom reports, 1 month of placebo, 1 month of lower-dose botanical, and 1 month of higher-dose botanical. Participants completed up to 3 different botanicals, repeating the placebo, lower-dose, and higher-dose cycle for each botanical assigned. Linear mixed models were used for analyses. Resveratrol reduced GWI symptom severity significantly more than placebo at both the lower (p = 0.035) and higher (p = 0.004) dosages. Luteolin did not decrease symptom severity more than placebo at either the lower (p = 0.718) or higher dosages (p = 0.492). Similarly, fisetin did not reduce symptom severity at either the lower (p = 0.504) or higher (p = 0.616) dosages. Preliminary findings from this screening study suggest that resveratrol may be beneficial in reducing symptoms of GWI and should be prioritized for future testing. Larger trials are required to determine efficacy, response rates, durability of effects, safety, and optimal dosage. This trial was registered on ClinicalTrials.gov (NCT02909686) on 13 September 2016. Full article

(This article belongs to the Special Issue Gulf War Illness, A Drug and Environmentally-Triggered Condition)

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15 pages, 3103 KiB

Open AccessArticle

A Placebo-Controlled, Pseudo-Randomized, Crossover Trial of Botanical Agents for Gulf War Illness: Curcumin (Curcuma longa), Boswellia (Boswellia serrata), and French Maritime Pine Bark (Pinus pinaster)

by Emily K. Donovan, Sophia Kekes-Szabo, Joanne C. Lin, Rebecca L. Massey, James D. Cobb, Kathleen S. Hodgin, Timothy J. Ness, Carl Hangee-Bauer and Jarred W. Younger

Int. J. Environ. Res. Public Health 2021, 18(5), 2468; https://doi.org/10.3390/ijerph18052468 - 3 Mar 2021

Cited by 9 | Viewed by 4253

Abstract

This report is part of a larger study designed to rapidly and efficiently screen potential treatments for Gulf War Illness (GWI) by testing nine different botanicals. In this placebo-controlled, pseudo-randomized, crossover clinical trial of 20 men with GWI, we tested three botanical agents with putative peripheral and central anti-inflammatory actions: curcumin (Curcuma longa), boswellia (Boswellia serrata), and French maritime pine bark extract (Pinus pinaster). Participants completed 30 +/− 3 days of baseline symptom reports, followed by 30 +/− 3 days of placebo, 30 +/− 3 days of lower-dose botanical, and 30 +/− 3 days of higher-dose botanical. Participants then repeated the process with a new botanical until completing up to three botanical cycles. Data were analyzed using linear mixed models. Curcumin reduced GWI symptom severity significantly more than placebo at both the lower (p < 0.0001) and higher (p = 0.0003) dosages. Boswellia was not more effective than placebo at reducing GWI symptoms at either the lower (p = 0.726) or higher (p = 0.869) dosages. Maritime pine was not more effective than placebo at the lower dosage (p = 0.954) but was more effective than placebo at the higher dosage (p = 0.006). This study provides preliminary evidence that curcumin and maritime pine may help alleviate symptoms of GWI. As a screening study, a final determination of the efficacy of these compounds for all individuals with GWI cannot be made, and further studies will need to be conducted to determine strength and durability of effects, as well as optimal dosage. These results suggest that GWI may, at least in part, involve systemic inflammatory processes. This trial was registered on ClinicalTrials.gov (NCT02909686) on 13 September 2016. Full article

(This article belongs to the Special Issue Gulf War Illness, A Drug and Environmentally-Triggered Condition)

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11 pages, 311 KiB

Open AccessArticle

A Pilot Study of Bioenergetic Marker Relationships in Gulf War Illness: Phosphocreatine Recovery vs. Citric Acid Cycle Intermediates

by Beatrice A. Golomb, Hayley J. Koslik, Jun Hee Han, Anna Helena Preger Guida, Gavin Hamilton and Richard I. Kelley

Int. J. Environ. Res. Public Health 2021, 18(4), 1635; https://doi.org/10.3390/ijerph18041635 - 9 Feb 2021

Cited by 3 | Viewed by 2191

Abstract

Impaired bioenergetics have been reported in veterans with Gulf War illness (VGWIs), including prolonged post-exercise recovery of phosphocreatine (PCr-R) assessed with ³¹Phosphorus magnetic resonance spectroscopy. The citric acid cycle (CAC) is considered the most important metabolic pathway for supplying energy, with relationships among CAC markers reported to shift in some but not all impaired bioenergetic settings. We sought to assess relations of CAC markers to one another and to PCr-R. Participants were 33 VGWIs and 33 healthy controls 1:1 matched on age–sex–ethnicity. We assessed seven CAC intermediates, and evaluated PCr-R in a subset of matched case–control pairs (N = 14). CAC markers did not significantly differ between cases and controls. Relationships of alpha-ketoglutarate to malate, isocitrate, and succinate were strongly significant in cases with materially weaker relationships in controls, suggesting possible shifts in these markers in concert in VGWIs. PCr-R correlated strongly with five of seven CAC markers in controls (succinate, malate, fumarate, citrate, isocitrate, range r = −0.74 to −0.88), but bore no relationship in VGWIs. In summary, PCr-R related significantly to CAC markers in healthy controls, but not VGWIs. In contrast, relations of CAC markers to one another appeared to shift (often strengthen) in VGWIs. Full article

(This article belongs to the Special Issue Gulf War Illness, A Drug and Environmentally-Triggered Condition)

11 pages, 791 KiB

Open AccessArticle

Grappling with Gulf War Illness: Perspectives of Gulf War Providers

by Girija Kaimal and Rebekka Dieterich-Hartwell

Int. J. Environ. Res. Public Health 2020, 17(22), 8574; https://doi.org/10.3390/ijerph17228574 - 19 Nov 2020

Cited by 11 | Viewed by 2447

Abstract

Background: Although the Gulf War occurred almost 30 years ago, the chronic symptoms of Gulf War illness (GWI), which include respiratory, gastrointestinal, and skin problems, as well as fatigue, pain, and mood alterations, currently affect over 200,000 veterans. Meanwhile, healthcare providers lack clear guidelines about how to best treat this illness. The objective in this study was to learn about the perceptions and experiences of healthcare providers of GWI veterans in terms of medical symptoms, resources for treatment, and quality of care. Methods: We interviewed 10 healthcare providers across the United States and subsequently conducted a qualitative grounded theory study which entailed both systematic data analysis and generating a grounded theory framework. Results: Our findings indicated multiple challenges for providers of veterans with GWI, including gaps in knowledge about GWI, lack of treatment options, absence of consistent communication within the Department of Veterans Affairs (VA) system, and personalized care that was limited to validation. Conclusion: While this study had several limitations, it supported the notion that healthcare providers have inadequate knowledge and awareness about GWI, which leads to continued uncertainty about how to best care for GWI veterans. This could be remedied by the creation of a comprehensive curriculum for a Massive Open Online Course (MOOC) to serve as an educational tool for those attending to this largely overlooked veteran population. Full article

(This article belongs to the Special Issue Gulf War Illness, A Drug and Environmentally-Triggered Condition)

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18 pages, 1843 KiB

Open AccessArticle

Effects of Incubation of Human Brain Microvascular Endothelial Cells and Astrocytes with Pyridostigmine Bromide, DEET, or Permethrin in the Absence or Presence of Metal Salts

by Jessica F. Hoffman and John F. Kalinich

Int. J. Environ. Res. Public Health 2020, 17(22), 8336; https://doi.org/10.3390/ijerph17228336 - 11 Nov 2020

Cited by 3 | Viewed by 2649

Abstract

Gulf War Illness (GWI) is a chronic, multi-symptom illness suffered by over one-third of American military veterans who served in the Persian Gulf War between 1990 and 1991. No current single-exposure scenario accounts for all the symptoms observed in GWI, and instead may be due to a multi-exposure scenario. As a larger effort to understand how one category of multi-exposure scenarios of organic compounds such as nerve gas prophylactic pyridostigmine bromide, or insecticides/pesticides such as N,N-diethyl-m-toluamide (DEET) and permethrin, plus heavy metals found in inhaled dust particles (Al, Fe, Ni, Sr, DU, Co, Cu, Mn, and Zn) might play a role in neural aspects of GWI, we begin this initial study to examine the toxicity and oxidative damage markers of human brain endothelial cell and human astrocyte cell cultures in response to these compounds. A battery of cytotoxicity assessments, including the MTT assay, Neutral Red uptake, and direct microscopic observation, was used to determine a non-toxic dose of the test compounds. After testing a wide range of doses of each compound, we chose a sub-toxic dose of 10 µM for the three organic compounds and 1 µM for the nine metals of interest for co-exposure experiments on cell cultures and examined an array of oxidative stress-response markers including nitric oxide production, formation of protein carbonyls, production of thiobarbituric acid-reactive substances, and expression of proteins involved in oxidative stress and cell damage. Many markers were not significantly altered, but we report a significant increase in nitric oxide after exposure to any of the three compounds in conjunction with depleted uranium. Full article

(This article belongs to the Special Issue Gulf War Illness, A Drug and Environmentally-Triggered Condition)

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20 pages, 371 KiB

Open AccessArticle

The Prevalence of Mild Cognitive Impairment in a Convenience Sample of 202 Gulf War Veterans

by Linda L. Chao

Int. J. Environ. Res. Public Health 2020, 17(19), 7158; https://doi.org/10.3390/ijerph17197158 - 30 Sep 2020

Cited by 8 | Viewed by 3690

Abstract

Gulf War Illness (GWI) is a chronic, multisymptom disorder estimated to affect approximately 25–32% of Gulf War veterans (GWVs). Cognitive dysfunction is a common symptom of GWI. On the continuum of cognitive decline, mild cognitive impairment (MCI) is conceptualized as a transitional phase between normal aging and dementia. Individuals with MCI exhibit cognitive decline but have relatively spared activities of daily function and do not meet criteria for dementia. The current study sought to investigate the prevalence of MCI in a convenience sample of 202 GWVs (median age: 52 years; 18% female). Twelve percent of the sample (median age: 48 years) had MCI according to an actuarial neuropsychological criterion, a rate materially higher than expected for this age group. GWVs with MCI also had a smaller hippocampal volume and a thinner parietal cortex, higher rates of current posttraumatic stress disorder and major depressive disorder compared to GWVs without MCI. Because people with MCI are more likely to progress to dementia compared to those with normal cognition, these results may portend future higher rates of dementia among deployed GWVs. Full article

(This article belongs to the Special Issue Gulf War Illness, A Drug and Environmentally-Triggered Condition)

14 pages, 317 KiB

Open AccessArticle

Radiation Exposure Predicts Reported Vaccine Adverse Effects in Veterans with Gulf War Illness

by Beatrice A. Golomb, Emily Nguyen and Eero Dinkeloo

Int. J. Environ. Res. Public Health 2020, 17(19), 7136; https://doi.org/10.3390/ijerph17197136 - 29 Sep 2020

Cited by 5 | Viewed by 3649

Abstract

Most people have no problems when administered vaccines; however, as with all drugs, reported adverse effects (rAEs) do occur. There is a need to better understand the potential predictors of reported vaccine AEs (rVaxAEs), including modifiable (environmental) predictors. Gulf War Veterans (GWV) who have Gulf War illness (GWI) report increased experiences of drug and chemical rAEs, extending to rVaxAEs. GWV provide an opportunity to examine the relationship between their reported exposures and rAEs. Forty one GWV with GWI and 40 healthy controls reported exposure and rAEs to exposure, including for 14 vaccines. Individual and summed vaccine exposures, rVaxAEs, and reported Vaccine AE Propensity (summed rVaxAEs/summed vaccines exposures) were compared in cases vs. controls. Exposure–outcome assessments focused on GWV, using a multivariable regression with robust standard error. More designated vaccines were reported in cases than in controls: 9.0 (2.3) vs. 3.8 (2.3), p < 0.0001. The fraction of vaccines received that led to rAEs was ten-fold higher in cases: 0.24 (0.21), vs. 0.023 (0.081), p < 0.0001. Multivariable assessment confirmed that radiation and pesticides remained significant statistical predictors of reported Vaccine AE Propensity. Exposure tied to excess rVaxAEs in GWV may contribute to, or underlie, the reported link between rVaxAEs in GWV and later ill health. Full article

(This article belongs to the Special Issue Gulf War Illness, A Drug and Environmentally-Triggered Condition)

18 pages, 5240 KiB

Open AccessArticle

Assessing the Beneficial Effects of the Immunomodulatory Glycan LNFPIII on Gut Microbiota and Health in a Mouse Model of Gulf War Illness

by Ryan S. Mote, Jessica M. Carpenter, Rachel L. Dockman, Andrew J. Steinberger, Garret Suen, Thomas Norberg, Donald A. Harn, John J. Wagner and Nikolay M. Filipov

Int. J. Environ. Res. Public Health 2020, 17(19), 7081; https://doi.org/10.3390/ijerph17197081 - 27 Sep 2020

Cited by 11 | Viewed by 2908

Abstract

The microbiota’s influence on host (patho) physiology has gained interest in the context of Gulf War Illness (GWI), a chronic disorder featuring dysregulation of the gut–brain–immune axis. This study examined short- and long-term effects of GWI-related chemicals on gut health and fecal microbiota and the potential benefits of Lacto-N-fucopentaose-III (LNFPIII) treatment in a GWI model. Male C57BL/6J mice were administered pyridostigmine bromide (PB; 0.7 mg/kg) and permethrin (PM; 200 mg/kg) for 10 days with concurrent LNFPIII treatment (35 μg/mouse) in a short-term study (12 days total) and delayed LNFPIII treatment (2×/week) beginning 4 months after 10 days of PB/PM exposure in a long-term study (9 months total). Fecal 16S rRNA sequencing was performed on all samples post-LNFPIII treatment to assess microbiota effects of GWI chemicals and acute/delayed LNFPIII administration. Although PB/PM did not affect species composition on a global scale, it affected specific taxa in both short- and long-term settings. PB/PM elicited more prominent long-term effects, notably, on the abundances of bacteria belonging to Lachnospiraceae and Ruminococcaceae families and the genus Allobaculum. LNFPIII improved a marker of gut health (i.e., decreased lipocalin-2) independent of GWI and, importantly, increased butyrate producers (e.g., Butyricoccus, Ruminococcous) in PB/PM-treated mice, indicating a positive selection pressure for these bacteria. Multiple operational taxonomic units correlated with aberrant behavior and lipocalin-2 in PB/PM samples; LNFPIII was modulatory. Overall, significant and lasting GWI effects occurred on specific microbiota and LNFPIII treatment was beneficial. Full article

(This article belongs to the Special Issue Gulf War Illness, A Drug and Environmentally-Triggered Condition)

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16 pages, 2654 KiB

Open AccessArticle

Assessment of Ketamine and its Enantiomers in an Organophosphate-Based Rat Model for Features of Gulf War Illness

by Jackie Zhu, Elisa Hawkins, Kristin Phillips and Laxmikant S. Deshpande

Int. J. Environ. Res. Public Health 2020, 17(13), 4710; https://doi.org/10.3390/ijerph17134710 - 30 Jun 2020

Cited by 20 | Viewed by 3139

Abstract

Approximately 33% of U.S. soldiers from the first Gulf War suffer from a multi-system disorder known as the Gulf War Illness (GWI). GW veterans suffer from a cluster of symptoms that prominently include fatigue and can include mood-related symptoms. Compared to traditional antidepressants, ketamine (KET) produces a fast-onset and long-lasting antidepressant response, but assessments of KET for GWI-related depression are lacking. The etiology of GWI is multi-factorial and exposure to organophosphates (OP) during deployment is one of the factors underlying GWI development. Here, male Sprague-Dawley rats were repeatedly exposed to an OP DFP and three months later these rats, when assessed on a battery of rodent behavioral assays, displayed signs consistent with aspects of GWI characteristics. When treated with a sub-anesthetic dose of KET (3, 5, or 10 mg/kg, i.p.), DFP-treated rats exhibited a significant improvement in immobility time, open-arm exploration, and sucrose consumption as early as 1 h and much of these effects persisted at 24-h post-KET injection. KET’s stereoisomers, R-KET and S-KET, also exhibited such effects in DFP rats, with R-KET being the more potent isomer. Our studies provide a starting point for further assessment of KET for GWI depression. Full article

(This article belongs to the Special Issue Gulf War Illness, A Drug and Environmentally-Triggered Condition)

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14 pages, 1403 KiB

Open AccessArticle

The Gut-Microbiome in Gulf War Veterans: A Preliminary Report

by Patricia A. Janulewicz, Ratanesh K. Seth, Jeffrey M. Carlson, Joy Ajama, Emily Quinn, Timothy Heeren, Nancy Klimas, Steven M. Lasley, Ronnie D. Horner, Kimberly Sullivan and Saurabh Chatterjee

Int. J. Environ. Res. Public Health 2019, 16(19), 3751; https://doi.org/10.3390/ijerph16193751 - 4 Oct 2019

Cited by 33 | Viewed by 7112

Abstract

Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting the central nervous system (CNS), immune and gastrointestinal (GI) systems of Gulf War veterans (GWV). We assessed the relationships between GWI, GI symptoms, gut microbiome and inflammatory markers in GWV from the Boston Gulf War Illness Consortium (GWIC). Three groups of GWIC veterans were recruited in this pilot study; GWV without GWI and no gastrointestinal symptoms (controls), GWV with GWI and no gastrointestinal symptoms (GWI-GI), GWV with GWI who reported gastrointestinal symptoms (GW+GI). Here we report on a subset of the first thirteen stool samples analyzed. Results showed significantly different gut microbiome patterns among the three groups and within the GWI +/−GI groups. Specifically, GW controls had a greater abundance of firmicutes and the GWI+GI group had a greater abundance of the phyla bacteroidetes, actinobacteria, euryarchaeota, and proteobacteria as well as higher abundances of the families Bacteroidaceae, Erysipelotrichaceae, and Bifidobacteriaceae. The GWI+GI group also showed greater plasma levels of the inflammatory cytokine TNF-RI and they endorsed significantly more chemical weapons exposure during the war and reported significantly greater chronic pain, fatigue and sleep difficulties than the other groups. Studies with larger samples sizes are needed to confirm these initial findings. Full article

(This article belongs to the Special Issue Gulf War Illness, A Drug and Environmentally-Triggered Condition)

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