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Gulf War illness
Classification and external resources

pyridostigmine, a nerve agent antidote
and one of the implicated toxins
ICD-9 V65.5 (inconclusive)
also nonstandard "DX111"
MeSH D018923

Gulf War syndrome (GWS) or Gulf War illness (GWI) affects veterans and civilians who were near conflicts during, or downwind of a chemical weapons depot demolition after, the 1991 Gulf War.[1][2] A wide range of acute and chronic symptoms have included fatigue, loss of muscle control, headaches, dizziness and loss of balance, memory problems, muscle and joint pain, indigestion, skin problems, immune system problems, and birth defects.[3] Roughly one in four of the 697,000 veterans who served in the first Gulf War are afflicted with the controversial disorder, a condition with serious consequences.[4]

Exposure to toxic chemicals is the cause of the illness. Several specific causes have been investigated, including pyridostigmine bromide nerve gas antidote, organophosphate pesticides, chemical weapons, and depleted uranium. Causes which have been ruled out include post traumatic stress disorder, anthrax vaccinations,[4] and smoke from oil well fires. Antidote pills given to protect troops from nerve agents and insect repellents used during deployment were most closely linked. Exposure to the destruction of the Khamisiyah weapons depot, where large quantities of the chemical weapon sarin was stored, is negatively correlated with motor speed.[5] Epidemiological evidence is consistent with increased risk of birth defects in the offspring of persons exposed to depleted uranium.[6]

Methods of preventing or treating Gulf War syndrome vary. While the treatment of sarin exposure has been studied,[7] other acetylcholinesterase inhibitors such as pyridostigmine bromide and organophosphate insect repellents may or may not involve similar management. Uranium can be decontaminated from steel surfaces[8] and aquifers.[9] Diplomatic reconciliation is a means of prevention of some mental effects.[10][11]

Contents

Classification

Medial ailments associated with Gulf War Syndrome has been recognized by both the US Department of Defense, Department of Veterans Affairs, and Veterans Administration.[12] Since so little concrete information was known about this condition the Veterans administrations originally classified individuals with related ailments believed to be connected to their service in the Persian Gulf a special non-ICD-9 code DX111, as well as ICD-9 code V65.5.[13]

Signs and symptoms

Summary of the Operation Desert Storm offensive ground campaign, February 24-28, 1991, by nationality (click for detail).

About one-fourth of the 697,000 U.S. servicemen and women in the first Gulf War have shown symptoms related to Gulf War Syndrome.

U.S. and UK, with the highest rates of excess illness, are distinguished from the other nations by higher rates of pesticide use, use of anthrax vaccine, and somewhat higher rates of exposures to oil fire smoke and reported chemical alerts. France, with possibly the lowest illness rates, had lower rates of pesticide use, and no use of anthrax vaccine.[14] French troops also served to the North and West of all other combat troops, away and upwind of major combat engagements[15] .

A 2001 study of 15,000 February 1991 U.S. Gulf War combat veterans and 15,000 control veterans found that the Gulf War veterans were 1.8 (fathers) to 2.8 (mothers) times more likely to have children with birth defects.[16] After examination of children's medical records two years later, the birth defect rate increased by more than 20%:

"Dr. Kang found that male Gulf War veterans reported having infants with likely birth defects at twice the rate of non-veterans. Furthermore, female Gulf War veterans were almost three times more likely to report children with birth defects than their non-Gulf counterparts. The numbers changed somewhat with medical records verification. However, Dr. Kang and his colleagues concluded that the risk of birth defects in children of deployed male veterans still was about 2.2 times that of non-deployed veterans."[17]

In a study of U.K. troops, "Overall, the risk of any malformation among pregnancies reported by men was 50% higher in Gulf War Veterans (GWV) compared with Non-GWVs."[18]

Excess prevalence of general symptoms[19]*
Symptom U.S. UK Australia Denmark
Fatigue 23% 23% 10% 16%
Headache 17% 18% 7% 13%
Memory problems 32% 28% 12% 23%
Muscle/joint pain 18% 17% 5% 2% (<2%)
Diarrhea 16% 9% 13%
Dyspepsia/indigestion 12% 5% 9%
Neurological problems 16% 8% 12%
Terminal tumors 33% 9% 11%
Graph showing the rate per 1,000 births of congenital malformations observed at Basra University Hospital, Iraq[20]
Excess prevalence of recognized medical conditions[21]
Condition U.S. UK Canada Australia
Skin conditions 20-21% 21% 4-7% 4%
Arthritis/joint problems 6-11% 10% (-1)-3% 2%
Gastro-intestinal (GI) problems 15% 5-7% 1%
Respiratory problem 4-7% 2% 2-5% 1%
Chronic fatigue syndrome 1-4% 3% 0%
Post-traumatic stress disorder 2-6% 9% 6% 3%
Chronic multi-symptom illness 13-25% 26%

Although Gulf War illness is the most prominent condition affecting Gulf War veterans, it is just one health issue to be addressed in the larger context of the health of Gulf War veterans. Other Gulf War-related health issues of importance include rates of diagnosable medical conditions and post-war mortality among Gulf War veterans, and questions related to the risk of birth defects and other health problems in veterans’ family members.

The three studies most representative of Gulf War era veterans in the U.S. and U.K. have all indicated significant excess rates of birth defects in children of Gulf War veterans. News articles have reported that rates of cancer and birth defects in Iraq increased dramatically during the 1990s, specifically in regions where the greatest quantity of depleted uranium was used in the Gulf War. Conference reports describing an increased incidence of congenital anomalies in Basrah and increased numbers of cancer cases, both in Iraqi military personnel who served in the war and in four Iraqi hospitals, lend some support to these contentions.[4]

Results from two studies, using different methods in different groups of symptomatic veterans, indicate that Gulf War illness is associated with a low-level, persistent immune activation, reflected in elevated levels of the cytokines IL-2, IFN-γ and IL-10. In addition, several studies have reported that NK cell numbers and/or cytotoxic activity are significantly reduced in veterans with Gulf War illness.[22]

Causes

The United States Congress mandated the National Academies of Science Institute of Medicine to provide nine reports on Gulf War Syndrome since 1998.[23] Aside from the many physical and psychological issues involving any war zone deployment, Gulf War veterans were exposed to a unique mix of hazards not previously experienced during wartime. These included pyridostigmine bromide pills given to protect troops from the effects of nerve agents, depleted uranium munitions, and anthrax and botulinum vaccines. The oil and smoke that spewed for months from hundreds of burning oil wells presented another exposure hazard not previously encountered in a warzone. Military personnel also had to cope with swarms of insects, requiring the widespread use of pesticides.

United States Veterans Affairs Secretary Anthony Principi's panel found that pre-2005 studies suggested the veterans' illnesses are neurological and apparently are linked to exposure to neurotoxins, such as the nerve gas sarin, the anti-nerve gas drug pyridostigmine bromide, and pesticides that affect the nervous system. The review committee concluded that "Research studies conducted since the war have consistently indicated that psychiatric illness, combat experience or other deployment-related stressors do not explain Gulf War veterans illnesses in the large majority of ill veterans," the review committee said.[24]

Pyridostigmine bromide nerve gas antidote

The US military issued pyridostigmine bromide pills, PB, to protect against exposure to nerve gas agents such as sarin and soman. PB was used to pretreat nerve agent poisoning and is not a vaccine however taken before exposure to nerve agents, PB was thought to increase the efficacy of nerve agent antidotes. PB had been used since 1955 for patients suffering from myasthenia gravis with dosed up to 1,500 mg a day, far in excess of the 90 mg given to soldiers, and was considered safe by the FDA at either level for indefinite use and its use to pretreat nerve agent exposure has recently been approved.[25]

About half of U.S. Gulf War veterans report using PB during deployment, with greatest use among Army personnel. Concerns have been raised about the possibility of increased health problems from PB when it is combined with other risk factors.

Given both the large body of epidemiological data on myasthenia gravis patients and follow up studies done on veterans it was concluded that while it was unlikely that health effects reported today by Gulf War veterans are the result of exposure solely to PB, use of PB was causally associated with illness.[4]

Organophosphate pesticides

The use of organophosphate pesticides and insect repellants during the first Gulf War is credited with keeping rates of pest-borne diseases low. Pesticide use is one of only two exposures consistently identified by Gulf War epidemiologic studies to be significantly associated with Gulf War illness.[26] Multisymptom illness profiles similar to Gulf War illness have been associated with low-level pesticide exposures in other human populations. In addition, Gulf War studies have identified dose-response effects, indicating that greater pesticide use is more strongly associated with Gulf War illness than more limited use.[27] Pesticide use during the Gulf War has also been associated with neurocognitive deficits and neuroendocrine alterations in Gulf War veterans in clinical studies conducted following the end of the war. The 2008 report concluded that “all available sources of evidence combine to support a consistent and compelling case that pesticide use during the Gulf War is causally associated with Gulf War illness.”[4]

Iraq-gwi-map.jpg

Sarin nerve agent

Many of the symptoms of Gulf War syndrome are similar to the symptoms of organophosphate, mustard gas, and nerve gas poisoning.[28][29] Gulf War veterans were exposed to a number of sources of these compounds, including nerve gas and pesticides.[30]

Chemical detection units from the Czech Republic, France, and Britain confirmed chemical agents. French detection units detected chemical agents. Both Czech and French forces reported detections immediately to U.S. forces. U.S. forces detected, confirmed, and reported chemical agents; and U.S. soldiers were awarded medals for detecting chemical agents. The Riegle Report said that chemical alarms went off 18,000 times during the Gulf War. After the air war started on January 16, 1991, coalition forces were chronically exposed to low but nonlethal levels of chemical and biological agents released primarily by direct Iraqi attack via missiles, rockets, artillery, or aircraft munitions and by fallout from allied bombings of Iraqi chemical warfare munitions facilities.[31]

In 1997, the US Government released an unclassified report that stated, "The US Intelligence Community (IC) has assessed that Iraq did not use chemical weapons during the Gulf War. However, based on a comprehensive review of intelligence information and relevant information made available by the United Nations Special Commission (UNSCOM), we conclude that chemical warfare (CW) agent was released as a result of US postwar demolition of rockets with chemical warheads at several sites including Khamisiyah". Over 125,000 U.S. troops and 9,000 UK troops were exposed to nerve gas and mustard gas when the Iraqi depot in Khamisiyah was destroyed.[32]

Recent studies have confirmed earlier suspicions that exposure that sarin, in combination with other contaminants such as pesticides and PB were related to reports of veteran illness. Estimates range from 100,000 to 300,000 individuals exposed to nerve agents [33][34]

Depleted uranium

Major Gulf War engagements in which DU rounds were used.

Depleted uranium (DU) was widely used in tank kinetic energy penetrator and autocannon rounds for the first time in the Gulf War. DU is a dense, weakly radioactive metal. Munitions made from it often burn when they impact a hard target, producing toxic combustion products. Roughly 320 tons of DU were used during the February, 1991 conflict.[35] After military personnel began reporting unexplained health problems in the aftermath of the Gulf War, questions were raised about the health effect of exposure to depleted uranium.

The use of DU in munitions is controversial because of questions about potential long-term health effects.[36] Normal functioning of the kidney, brain, liver, heart, and numerous other systems can be affected by uranium exposure, because in addition to being weakly radioactive, uranium is a toxic metal.[37] Because uranium is a heavy metal and chemical toxicant with nephrotoxic (kidney-damaging),[38] teratogenic (birth defect-causing),[39][40] immunotoxic,[41] and potentially carcinogenic[42] properties, uranium exposure is associated with a variety of illnesses.[43] The chemical toxicological hazard posed by uranium dwarfs its radiological hazard because it is only weakly radioactive, and depleted uranium even less so. DU has recently been recognized as a neurotoxin.[44] In 2005, depleted uranium was shown to be a neurotoxin in rats.[45] Epidemiological evidence is consistent with increased risk of birth defects in the offspring of persons exposed to DU.[6]

Early studies of depleted uranium aerosol exposure assumed that uranium combustion product particles would quickly settle out of the air[46] and thus could not affect populations more than a few kilometers from target areas,[47] and that such particles, if inhaled, would remain undissolved in the lung for a great length of time and thus could be detected in urine.[48] Uranyl ion contamination has been found on and around depleted uranium targets.[49]

In 2001, a study was published in Military Medicine that found DU in the urine of Gulf War veterans.[50] Another study, published by Health Physics in 2004, also showed DU in the urine of Gulf War veterans.[51] A study of UK veterans who thought they might have been exposed to DU showed aberrations in their white blood cell chromosomes.[52] Mice immune cells exposed to uranium exhibit abnormalities.[53]

In the Balkans war zone where depleted uranium was also used, an absence of problems is seen by some as evidence of DU munitions' safety. "Independent investigations by the World Health Organization, European Commission, European Parliament, United Nations Environment Programme, United Kingdom Royal Society, and the Health Council of the Netherlands all discounted any association between depleted uranium and leukemia or other medical problems."[35] In Italy, controversy over the health risks associated with the use of DU continues, with a Senate investigation committee was due to release its report into 'Balkan Syndrome' by the end of 2007.[54] Since then, there has been a resurgence of interest in the health effects of depleted uranium, especially since it has recently been linked with neurotoxicity.[44]

The aerosol produced during impact and combustion of depleted uranium munitions can potentially contaminate wide areas around the impact sites or can be inhaled by civilians and military personnel.[55] During a three week period of conflict in 2003 Iraq, 1,000 to 2,000 tonnes of DU munitions were used, mostly in cities.[56] Depleted uranium may have been standard ordnance in the arsenals of both sides during the 2008 South Ossetia war.

Military personnel examine the remains of a Scud during the Gulf War.

Ruled out

Several potential causes beyond vaccinations, stress, and oil well fires—explained in more detail below—have been ruled out. Other ruled-out potential causes include Scud missile fuel and infectious diseases. Limited evidence from several sources suggests that an association with the combined effects of multiple neurotoxicant exposures and receipt of multiple vaccines can not be ruled out.[57]

Anthrax vaccine

Iraq had loaded anthrax, botulinum toxin, and aflatoxin into missiles and artillery shells in preparing for the Gulf War and that these munitions were deployed to four locations in Iraq.[58] During Operation Desert Storm, 41% of U.S. combat soldiers and 75% of UK combat soldiers were vaccinated against anthrax.[59] Like all vaccines, the early 1990s version of the anthrax vaccine was a source of several side effects. Reactions included local skin irritation, some lasting for weeks or months.[60] While the Food and Drug Administration (FDA) approved the vaccine, it never went through large scale clinical trials, unlike most other vaccines in the United States.[61] While recent studies have demonstrated the vaccine’s is highly reactogenic [62], there is no clear evidence or epidemiological studies on Gulf War veterans linking the vaccine to Gulf War Syndrome. Combining this with the lack of symptoms from current deployments of individuals who have received the vaccine led the Committee on Gulf War Veterans’ Illnesses to conclude that the vaccine is not a likely cause of Gulf War illness for most ill veterans.[4]

Combat stress

Research studies conducted since the war have consistently indicated that psychiatric illness, combat experience or other deployment-related stressors do not explain Gulf War veterans illnesses in the large majority of ill veterans, according to a Veterans Administration review committee.

Oil well fires

During the war, many oil wells were set on fire in Kuwait by the retreating Iraqi army, and the smoke from those fires was inhaled by large numbers of soldiers, many of whom suffered acute pulmonary and other chronic effects, including asthma and bronchitis. However, firefighters who were assigned to the oil well fires and encountered the smoke, but who did not take part in combat, have not had GWI symptoms.[63]

Diagnosis

Multisymptom illness is more prevalent in Gulf War I veterans than veterans of previous conflicts, but the pattern of comorbidities is similar for actively deployed and nondeployed military personnel.[64] Management of potentially comorbid toxic exposures requires awareness of the toxins involved.[7] Exposure to the destruction of the Khamisiyah weapons depot, where large quantities of the chemical weapon sarin was stored, is negatively correlated with motor speed.[5] Epidemiological evidence is consistent with increased risk of birth defects in the offspring of persons exposed to depleted uranium[6] and uranium exposure has also been associated with increased cancer rates.[65][66][67][68][69][70]

Management

Diplomatic reconciliation is one means of prevention,[10][11] beyond battlefield air quality management, which often conflicts with established tactical policy. For example, most organized armies practice "secure and hold" tactics which require occupation of areas before they can be decontaminated.

Acetylcholinesterase inhibitors

Nerve agent antidote and insect repellent

In 2008, a paper published in the Proceedings of the National Academy of Sciences suggested that excess illnesses in Gulf War veterans could be explained in part by their exposure to organophosphate and carbamate acetylcholinesterase inhibitors.[71] A federal report released in November, 2008, agreed, stating that exposure to two substances "are causally associated with Gulf War illness":[72]

Sarin

Exposure to sarin, a nerve gas, is a possible comorbidity. Chemical weapons classified as nerve agents are also strong acetylcholinesterase inhibitors. A 2004 review discusses symptoms, signs, and treatment of nerve agent exposure.[7]

Uranium exposure

Genotoxic mutagens such as uranium should be treated with chelation therapy[74] or other means shortly after exposure.[75] Incorporated uranium becomes uranyl ions, which accumulate in bone, liver, kidney, and reproductive tissues. Uranium can be decontaminated from steel surfaces[8] and aquifers.[9]

Epidemiology

Epidemiologic studies have been performed evaluating many suspected factors for Gulf War illness as seen in veteran populations. Below is a summary of epidemiologic studies of veterans displaying multisymptom illness and their exposure to suspect conditions from the 2008 U.S. Veterans Administration report.[76]

A fuller understanding of immune function in ill Gulf War veterans is needed, particularly in veteran subgroups with different clinical characteristics and exposure histories. It is also important to determine the extent to which identified immune perturbations may be associated with altered neurological and endocrine processes that are associated with immune regulation.[22] No studies that have evaluated birth outcomes and birth defects among Gulf War veterans and their children have assessed whether there is any connection between reproductive outcomes and uranium exposure in the Gulf War.[77] Very limited cancer data have been reported for U.S. Gulf War veterans in general, and no published research on cases occurring after 1999. Because of the extended latency periods associated with most cancers, it is important that cancer information be brought up to date and that cancer rates be assessed in Gulf War veterans on an ongoing basis. In addition, cancer rates should be evaluated in relation to identifiable exposure and location subgroups.[78]

Epidemiologic Studies of Gulf War Veterans: Association of Deployment Exposures With Multisymptom Illness[79]
Preliminary Analysis (no controls for exposure) Adjusted Analysis (controlling for effects of exposure) Clinical Evaluations
GWV population in which association was assessed GWV population in which association was statistically significant GWV population in which association was assessed GWV population in which association was statistically significant Dose response effect identified?
Pyridostigmine bromide 10 9 6 6 Associated with neurocognitive and HPA differences in GW vets
Pesticides 10 10 6 5 Associated with neurocognitive and HPA differences in GW vets
Physiological Stressors 14 13 7 1
Chemical Weapons 16 13 5 3 Associated with neurocognitive and HPA differences in GW vets
Oil Well Fires 9 8 4 2
Number of Vaccines 2 2 1 1
Anthrax Vaccine 5 5 2 1
Tent Heater Exhaust 5 4 2 1
Sand/Particulates 3 3 3 1
Depleted Uranium 5 3 1 0

Controversy

Similar syndromes have been seen as an after effect of other conflicts — for example, 'shell shock' after World War I, and post-traumatic stress disorder (PTSD) after the Vietnam War. A review of the medical records of 15,000 American Civil War soldiers showed that "those who lost at least 5% of their company had a 51% increased risk of later development of cardiac, gastrointestinal, or nervous disease."[80]

A November 1996 article in the New England Journal of Medicine found no difference in death rates, hospitalization rates or self-reported symptoms between Persian Gulf veterans and non-Persian Gulf veterans. This article was a compilation of dozens of individual studies involving tens of thousands of veterans. The study did find a statistically significant elevation in the number of traffic accidents suffered by Gulf War veterans.[81] An April, 1998 article in Emerging Infectious Diseases similarly found no increased rate of hospitalization and better health overall for veterans of the Persian Gulf War vs. Veterans who stayed home.[82]

Despite these studies, on November 17, 2008 a congressionally appointed committee called the Research Advisory Committee on Gulf War Veterans' Illnesses, staffed with independent scientists and veterans appointed by the Department of Veterans Affairs, announced that the syndrome is a distinct physical condition. The committee recommended that Congress increase funding for research on Gulf War veterans' health to at least $60 million per year.[83] In January 2006, a study led by Melvin Blanchard and published by the Journal of Epidemiology, part of the "National Health Survey of Gulf War-Era Veterans and Their Families", stated that veterans deployed in the Persian Gulf War had nearly twice the prevalence of chronic multisymptom illness, a cluster of symptoms similar to a set of conditions often called Gulf War Syndrome.[84]

See also

References

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