When Iraq invaded Kuwait in 1990, a coalition of 39 countries responded. 382 US troops died. Those who survived deployments to the 1990-91 Gulf War theater of operations and returned to the U.S. were “safe” from combat but were not “safe and sound.” 37% of them were suffering from a strange constellation of symptoms not seen in other locations or in previous wars. Around 250,000 individuals reported developing a chronic multisystem illness that was medically unexplained and that persisted for years with little improvement.
They reported symptoms including fatigue, headache, memory problems, muscle/joint pain, diarrhea, dyspepsia/indigestion, neurological problems, skin conditions, respiratory problems, and more. Previously known as Gulf War Syndrome, cases have been difficult to classify. Two definitions have emerged: the Kansas definition and the CDC definition. The Kansas definition considers six symptom groups: fatigue and sleep problems, pain, neurologic and mood, gastrointestinal, respiratory symptoms, and skin symptoms. To qualify, patients must have symptoms in at least three of these categories that had developed during or after deploying to the Gulf War theater of operations and other conditions must be excluded. The CDC definition took a symptom-category approach with three categories: fatigue, mood-cognition, and musculoskeletal. It required symptoms in two of the three categories lasting 6 months or longer, and it included a determination of severity. The Kansas definition is more specific and may be more appropriate for research settings, while the CDC definition is broader and may be more useful for clinical purposes.
Armchair speculation was quick to propose a large number of hypothetical causes, some more plausible than others. Most of these failed to pan out. Some of the candidates: multiple vaccinations (anthrax, botulinum toxin, etc.) administered simultaneously, depleted uranium munitions, oil and smoke from burning oil wells, swarms of insects requiring the use of insecticides, sand/particulates, tent heater exhaust, physiological stressors, organophosphate insect repellents, solvents, burn pits, chronic inflammation, combat stress, chemical agent resistant coating (CARC), etc.
Some of these were easily ruled out; for instance, firefighters exposed to smoke from burning oil wells did not develop GWI.
In 2006, a committee report from the Institute of Medicine rejected claims that GWI was not real. It didn’t fit well with proposed psychological diagnoses, and they found a consistent association with the nerve gas antidote pyridostigmine bromide pills that troops were given as an antidote to nerve gas, and with pesticide exposure. They couldn’t rule out multiple exposures and synergism.
The most promising candidates remained those identified by the IOM committee, pyridostigmine pills and pesticides. Until May 11, 2022, when there was a remarkable new development.
I usually rely on medical journals for groundbreaking news but this time I first saw the news on the front page of a free military newspaper my husband picked up at the Army base where we get our health care. The May 19, 2022 issue of The Ranger reported that the true cause of Gulf War Illness had finally been discovered. Apparently the reporter, JM Simpson, was not entirely convinced: his front-page headline had a question mark. It read “Cause of Gulf War Illness discovered?”
The study, by Robert Haley et al., was done at the University of Texas Southwestern Medical Center and was published in Environmental Health Perspectives on May 11, 2022, only a week earlier. Its not-so-catchy title was “Evaluation of a Gene–Environment Interaction of PON1 and Low-Level Nerve Agent Exposure with Gulf War Illness: A Prevalence Case–Control Study Drawn from the U.S. Military Health Survey’s National Population Sample.” To summarize its findings: American soldiers were exposed to sarin gas, and those who had a weaker variant of a gene that helps digest pesticides were nine times as likely to develop symptoms of GWI.
The alarm bells rang on my irony meter. It was common knowledge that Saddam Hussein had weapons of mass destruction (and had used them against Iraqi civilians). When they failed to find WMD in Iraq, faulty intelligence got the blame. But it turned out Saddam Hussein did have WMD and had them ready to deliver, although he did not actually use them in the Gulf War. American forces found Iraqi bunkers full of tons of sarin and mustard gas and blew them up. It was not the Iraqi WMDs themselves but American weapons that released these chemical weapons into the air where they could harm American soldiers. You might say we did it to ourselves.
“I think this is a great example of an issue that has required a long-term effort to solve, but which only a few scientists have persisted in – others giving up and assuming it is either not a real illness or too complex to solve, and funding agencies not wanting to wade too deeply in the politics of it.”
A legal defense?
Louis Jones Jr., a former soldier and decorated Gulf War veteran, used Gulf War Illness as a legal defense in his trial for the murder of Tracie McBride. His attorney argued that he had brain damage from GWI and should be spared the death penalty and his sentence commuted to life in prison. He was convicted of kidnapping McBride, raping her, and beating her to death with a tire iron. His appeals went all the way to the Supreme Court but were unsuccessful. He was executed by lethal injection at a U.S. penitentiary in 2003.
Can GWI be treated?
There is no standard treatment for GWI; the symptoms tend to last for years or decades despite treatment. A wide variety of treatments have been tried, with some interventions initially showing promise for some GWI symptoms. These have included acupuncture, integrative medicine, CoQ10, L-carnosine, nasal irrigation, mifepristone, direct electrical nerve stimulation, repurposing FDA-approved pharmaceuticals, and dietary protocols and/or nutraceuticals. Many studies are ongoing.
In 2008 a federal advisory committee reviewed 1840 published studies; their 454 page report found that “Gulf War illness is real“, that GWI is a distinct physical condition, and that it is not psychological in nature.
Is any treatment effective?
A 2020 systematic review concluded “There is moderate-strength evidence of benefit from CBT (Cognitive Behavioral Therapy) and exercise, and low- strength evidence of benefit from 2 distinct mindfulness-based interventions as well as CPAP (Continuous Positive Airway Pressure). Doxycycline was ineffective and associated with harms (moderate-strength evidence). Emerging evidence examines a wide array of treatments. Larger, more rigorous studies are needed.”
“On the basis of the evidence reviewed, the committee cannot recommend any specific therapy as a set treatment for [Gulf War] veterans who have chronic multisystem illness (CMI). The committee believes that a ‘one-size-fits-all’ approach is not effective for managing [Gulf War] veterans who have CMI and that individualized health care management plans are necessary.”
What does the new study mean?
Ideally, we would like to have reliable data on quantitative exposure to sarin gas. We know that soldiers were exposed to sarin gas when a bunker housing chemical agents was destroyed at the Khamisiyah Ammunition Storage Depot in southern Iraq. A mushroom cloud was observed and a plume of contaminants was tracked over a 25 mile radius; chemical weapons alarms went off on this and several other occasions, triggered by sensors in the M93A1 / M93A1P1 Fox NBC (nuclear,biological and chemical) Reconnaissance Vehicle. In the absence of reliable quantitative data, the researchers had to rely on veterans’ memories of hearing nerve agent alarms during deployment. They made an effort to verify those memories by consulting military records as to whether the veteran’s unit had been deployed in an area known to be exposed to the Khamisiyah plume.
This new study promises to solve a 30-year mystery. Does it? In the opinion of the two scientists who wrote the accompanying “Invited Perspective” article, “the authors’ exploration of a gene–environment interaction between presumed nerve agent exposure and the PON1 gene offers some strong arguments that there is a true causal effect at work.” And it offers a very credible explanation of why some individuals developed GWI while others did not. The paraoxonase-1 (PON1) gene is a known genetic determinant of susceptibility to organophosphate cholinesterase-inhibiting chemicals such as nerve agents. There are only two catalytic enzymes that hydrolyze and inactivate organophosphates, the 192 glutamine (Q) isoenzyme and the 192 arginine (R) isoenzyme. The Q isoenzyme efficiently hydrolyzes sarin; the R enzyme is relatively ineffective. RR homozygotes have only the ineffective version; QQ homozygotes have the most efficient version. QR heterozygotes produce varying quantities of both; their level of Q isoenzyme activity varies by a factor of more than 10. The researchers found a strong correlation between the level of Q isoenzyme activity and the risk of developing GWI. Those who had the weaker gene were 9 times as likely to develop symptoms. This is a very satisfying explanation, but it will require confirmation by other studies; and it may not be the final answer. We may well discover other interacting factors that increase or decrease risk. We can hope that this new knowledge will spur further research that may lead to effective treatments for GWI.
This is a great example of science in action.
This article was originally published in Skeptical Inquirer.