GULF WAR SYNDROME

by Dr Robert Baker MRCP, Lecturer and Research Fellow
Dr Andrew Ustianowski MRCP, DTM&H, Lecturer and Research Fellow
Dr Alimuddin Zumla FRCP, PhD, Director and Consultant Physician Centre for Infectious Diseases, University College London Medical School

The land war of Operation Desert Storm was fought for four days in February 1991, after a 39-day air war. More than 800,000 personnel from 11 countries participated in the field in a US-led alliance. Casualties on the allied side were light.

However, many Gulf War veterans have become ill since returning to their native countries. Some cases are clearly related to overseas service - people with malaria for instance - but a much larger number have reported a wide range of nebulous symptoms that defy diagnostic classification.

Does gulf war syndrome exist?

Some evidence in the non-scientific press apparently confirms what veterans have been saying for some time - that there is a real illness related to service in the Persian Gulf. Soldiers from the USA, UK and Canada have all presented with similar types of illness to a varying degree, while those from France, Egypt, Saudi Arabia, Syria, Kuwait and Morocco have not.(1)

This evidence, although compelling, is confounded by a major problem - that the syndrome does not sit happily in any convenient system of categorisation. This is why there is continuing debate over the very existence of Gulf War syndrome (GWS). In fact, the UK Ministry of Defence prefers the term 'Gulf War veterans' illnesses' as a more precise term in the absence of the clear definition of any syndrome.(2) Some authorities point out that similar post-conflict syndromes are nothing new, and were even reported after the American Civil War.(3) The issue remains politically fraught.

There are claims that Gulf War veterans are no more sick than the civilian populations as a whole; that GWS is a myth invented by the press. It is argued that as the cause of the veterans' symptoms cannot be determined, it is not associated with Operation Desert Storm, and that the problems will settle without treatment.(4) Many veterans, however, feel - perhaps with some justification - that the burden now lies with the medical, scientific and military establishments to attempt to disprove the existence of GWS rather than for veterans to provide further positive evidence.

This article make no claims for the existence of a syndrome or otherwise, but simply summarises current information which may be helpful to GPs.

Epidemiology

Studies of Gulf War veterans' health are difficult for a number of reasons. In the early studies the groups investigated were self-selected, the symptoms were self-reported and no useful baseline data had been collected. Later studies(5-8) have been more systematic, with some attempt to include controls, but have still not conclusively proved any aetiology, or provided a clear definition of GWS.

It is almost impossible even to establish any hard facts about the incidence of GWS. Estimates of the numbers affected range from 5,000 to 80,000. One study has, however, shown that deployed veterans are twice as likely to report physical health symptoms as non-deployed veterans (14.7% compared with 6.6%).(9)

Variation between groups has confounded investigation. In the 7 months between August 1990 and March 1991, the US deployed 697,000 troops in the Persian Gulf, of whom 7% were women.(2) During the same period, the UK sent 53,000 service personnel, of whom 2.3% were women. Other nations supplied widely ranging numbers. Denmark, for example, sent about 800 personnel.

Different groups had different patterns of exposure to noxious agents, and only some are well documented. The positions of some field units on the battlefield could be identified with comparative precision; other armies were uncertain of the positions of whole units.

Clinical presentation

The symptoms of GWS are not localised to one organ system. There are no consistent physical findings or laboratory-determined abnormalities, and so far no identifiable links have been made to any military component, weapon, chemical or geographical risk factors.

The US Department of Veterans Affairs Persian Gulf Registry lists fatigue, skin rash, headache, muscle and joint pain, memory loss, shortness of breath, sleep

disturbance and diarrhoea as the most common complaints in GWS. The proportions of individuals suffering from each in a study of 52,216 personnel are listed in Box 1.

Some investigators have cited six distinct specific syndromes (Box 2) in an effort to establish cause by factor analysis.(8)

In a much smaller study of 284 British veterans there was a slightly different pattern of frequency of complaints, although their nature was much the same.(10)

Women Gulf veterans have been shown to suffer from a cluster of common health problems including skin rash, cough, depression, unintentional weight loss, insomnia and memory problems.(11)

Mortality

The excess mortality that has been documented in Gulf War veterans (relative risk of death 1.09 compared with non-Gulf veterans) is due to 'external causes', almost exclusively accidental.(12) There has been no excess of deaths from suicide, murder, cancer or any other specific disease.

Birth defects

A study of more than 30,000 children of partners of Gulf veterans and 3,847 children of veterans has shown the incidence of congenital abnormalities in these groups to be no higher than in non-deployed controls.(13)

Proposed causes of GWS

Causes proposed for GWS range from immunisation to exposure to sand and pigeon droppings (Box 3).

Immunisation

There are very few convincing scientific hypotheses as to the causes of GWS. One that has some supporting circumstantial evidence suggests that an imbalance of T helper (Th) lymphocytes is involved. These cells can be divided into two mutually inhibitory groups, Thl and Th2, according to the cytokines they can secrete.(14)

An imbalance towards a Th2 state would promote allergy-type responses, and result in diminished cell-mediated immunity. This could cause many of the symptoms seen, including mood disturbance, because the stress response is partially regulated by cytokines.(15)

There are several potential causes of such an imbalance. Particular types of immunisations such as plague, anthrax, typhoid, tetanus and cholera, and added adjuvants such as pertussis, can encourage Th2 responses,(16) especially if given over a short period of time(17-19) and in stressful circumstances.(20-22) Exposure to organophosphorus insecticides and carbamate can also be involved in Th2 responses.(23) It is likely that all these factors occurred in the Gulf.

In addition, it may be relevant that personnel who received different vaccination regimes, such as French troops, have not reported GWS.(1)

Chemical/biological weapons

It has been suggested that illness in some Gulf War veterans may be related to chronic neurotoxicity caused by low-dose exposure to chemical warfare agents.(5)

Some neurotoxic chemicals, in particular sarin, may have been accidentally released during military action, although this is unproven. Sarin is a cause of chronic neurotoxicity in survivors of acute poisoning. Whether low-dose exposure without acute symptoms leads to delayed neurotoxicity is unclear.

Reported release of these agents was confined to specific areas, so it is unlikely that all sufferers from GWS were exposed to sarin.

Insecticides

Insecticides used to impregnate the uniforms of Desert Storm personnel have been implicated in GWS. It has been suggested that exposure to diethyltoluamide (DEET) and other pesticides may be a cause of neuropsychological impairment.(5) However, the evidence is far from conclusive.

Depleted uranium

Depleted uranium ammunition was used extensively for the first time in the Gulf War.(23) Some veterans retain fragments of uranium shrapnel in their bodies.

However, there is no conclusive evidence of a link between depleted uranium and GWS.

Nerve gas prophylaxis

The anticholinesterase inhibitor pyridostigmine was widely used as a prophylactic agent against nerve gas. One epidemiological study has found an association between exposure to these agents and delayed polyneuropathy.(5)

It is possible that stress or battlefield conditions may render the blood-brain barrier more permeable to pyridostigmine, and thus enhance the pathological effects of the prophylaxis.(25,26)

Infectious diseases

Several infectious agents have been postulated as causes of GWS. At least one organism, Leishmania tropica, has been shown to have a unique presentation in soldiers serving in the Gulf that would account for some of the principal symptoms.(27-29)

The numbers proved to be suffering from viscerotropic leishmaniasis have been small - just 32. Indeed the general incidence of infectious diseases among serving soldiers was low.(30)

The suggestion that an unidentified infectious agent has caused the syndrome is widely circulated on the more extreme sections of the Internet, with a claim that the infection may be capable of spreading to the general population.

Burning oilfields

Smoke and other petrochemical compounds were released from the 605 oil well fires that raged after hostilities ended, but no matter how plausible the link might seem, no causal relationship has been established with GWS.(31)

Sand and dust

A small group of soldiers became unwell with a variety of allergic pneumonitis believed to have been triggered by a combination of sand and pigeon droppings. The condition is known as Al Eskan disease or Desert Storm pneumonitis.(32)

This is unlikely to be the cause of GWS in the majority of individuals.

Management of ill gulf veterans

While the aetiology of GWS remains unclear, management will have to be on an ad hoc basis. Counselling, support and symptomatic treatment are very important, but no specific interventions have been shown to be of any benefit.

Patients who attribute their symptoms to service in the Gulf may be referred to the Gulf War Veterans Assessment Programme at St Thomas's Hospital in London, where a comprehensive medical assessment will be carried out according to an established protocol.(33)

The Gulf War Veterans Association provides support for individuals. It accepts self-referrals, and advises GPs to pass the telephone number on to patients where appropriate. It will send a questionnaire and membership pack on request.

The Ex-services Mental Welfare Society (also known as Combat Stress) also provides support for sufferers of combat stress.

Possible pitfalls

The management of chronically unwell patients who served in the Gulf is undoubtedly a minefield for GPs, and doctors should beware of dismissing veterans' symptoms as nonexistent, and patients as malingering or compensation-seeking.

Many veterans of the Gulf War will be suffering from stress-related problems, and their symptoms should be managed with this in mind. However, other physical causes of their symptoms should be rigorously sought (Box 4).

The Internet is rife with eccentric theories about US-sponsored testing of germ warfare agents on their own troops, and patients may challenge their GPs, saying that data relating to GWS have been covered up and that no effort is being made to investigate further. In fact, two MRC-sponsored studies are currently investigating the epidemiology of Gulf Veterans' illnesses, one at Manchester University and the other at the London School of Hygiene and Tropical Medicine. A further study, funded by the US Department of Defense, is comparing veterans from the Gulf and Bosnia, and controls. However, many veterans are aggrieved that it has taken so long for these studies to be instigated.

It should be remembered that the primary function of the allied governments during late 1990 and early 1991 was to fight a war, not to provide data for subsequent medical analysis. Effective postconflict surveillance systems may be operational in future conflicts.

Support groups and services

Gulf Veterans Medical Assessment Programme
Baird Health Centre
Gassiot House
St Thomas' Hospital Trust
Lambeth Palace Road, London
SE1 7EH
020-7202 8322/8323

Gulf War Veterans Association
0191-230 1065

Gulf War Families Association
0121-743 6040

Ex-Services Mental Welfare Society (Combat Stress)
Hollybush House
Hollybush
Ayrshire
KA67 7EA
01292 560214

Ex-services Treatment Unit (Dr D.A. Jones)
Ty Gwyn
Bryn-Y-Bia Road
Llandudno
Gwynedd
LL30 3AS

Box 1. frequent complaints in gulf war syndrome(34)
Symptom GWS patients (%)

• Fatigue 20.4
• Skin rash 18.4
• Headache 17.9
• Muscle and joint pain 16.8
• Memory loss 13.9
• Shortness of breath 7.9
• Sleep disturbance 5.9
• Diarrhoea 4.5

Box 2. characteristic gulf war syndromes(8)
Impaired cognition

• Problems with attention, memory, and reasoning
• Insomnia
• Depression
• Daytime sleepiness
• Headaches

Confusion/ataxia

• Problems with thinking
• Disorientation
• Balance disturbances
• Vertigo
• Impotence

Arthromyoneuropathy

• Joint and muscle pains
• Muscle fatigue
• Difficulty with lifting
• Extremity paraesthesiae

Phobia/apraxia

• Numbness, tingling, nausea, faintness, and chest discomfort when in an enclosed space
• Apraxia of the hands

Fever/adenopathy

• Fever with or without night sweats
• Swollen glands

Weakness/incontinence

• Difficulty in bowel control, especially on standing
• Dyspareunia
• Facial tingling

Box 3. Proposed causes of gulf war syndrome

• Immunisation
• Chemical/biological weapons
• Insecticides
• Depleted uranium
• Nerve gas prophylaxis
• Infectious diseases
• Burning oilfields
• Sand and dust

Box 4. Differential diagnosis of gulf war syndrome

• Chronic fatigue syndrome
• Depression
• Post-traumatic stress disorder
• Alcohol/substance abuse
• Hyperventilation syndrome
• Obstructive sleep apnoea syndrome
• Hypothyroidism
• Occult tuberculosis and other chronic infections
• Occult malignancy
• Electrolyte imbalance, particularly hypokalaemia
• Myasthenia gravis
• Autoimmune collagen vascular disease such as systemic lupus erythematosus
• Infectious mononucleosis, toxoplasmosis or viral illnesses
• Degenerative and demyelinating neuromuscular disorders such as multiple sclerosis or motor neurone disease
• Viscerotropic leishmaniasis

Practical points

• Gulf veterans' illnesses have a wide differential diagnosis.
• Some evidence suggests that there may be a medical basis for GWS, in that veterans from some countries were not affected. This is unconfirmed in the scientific press.
• The existence of the syndrome is disputed because it cannot easily be classified.
• Exposure to numerous agents has been documented, but no pathological cause has yet been established.
• The two most plausible explanations to date are multiple immunisations at a time of high stress and organophosphate poisoning.
• The syndrome involves a constellation of symptoms, including (in order of frequency) fatigue, skin rash, headache, myalgia and arthralgia, memory loss, breathlessness and cough, sleep disturbance, diarrhoea and weight loss, depression, impotence and adenopathy.
• Conspiracy theories abound, particularly on the Internet.
• So far, excess mortality among Gulf veterans has been shown to be due to accidents and no other cause.
• There is no evidence of an increased risk of birth defects in offspring of Gulf veterans.
• Treatment is supportive and symptomatic.
• Referral of patients to the Gulf War Medical Assessment programme is advised.
• Several support organisations exist.

References

1. Darkness at noon. The Economist 1997: 87-90.
2. Bolton JPG. Personal communication.
3. Hyams KC, Wignall FS, Roswell R. War syndromes and their evaluation: from the US Civil War to the Persian Gulf War. Ann Intern Med 1996; 125: 398-405.
4. Nicolson GL, Nicolson NL. The eight myths of Operation 'Desert Storm' and Gulf War syndrome. Med Confl Surviv 1997; 13: 140-6.
5. Haley RW, Kurt TL. Self reported exposure to neurotoxic chemical combinations in the Gulf War. A cross sectional epidemiologic study. JAMA 1997; 277: 231-7.
6. Haley RW, Hom J, Roland PS et al. Evaluation of neurologic function in Gulf War veterans. A blinded case-control study. JAMA 1997; 277: 223-30.
7. Self reported illness and health status among Gulf War veterans. A population-based study. The Iowa Persian Gulf Study Group. JAMA 1997; 277: 238-45.
8. Haley RW, Kurt TL, Hom J. Is there a Gulf War syndrome? Searching for syndromes by factor analysis of symptoms. JAMA 1997; 277: 215-22.
9. Stretch RH, Bliese PD, Marlowe DH, Wright KM, Knudson KH, Hoover CH. Physical health symptomatology of Gulf War-era service personnel from the states of Pennsylvania and Hawaii. Mil Med 1995; 160: 131-6.
10. Coker WJ. A review of Gulf War illness. J R Nav Med Serv 1996; 82: 141-6.
11. Pierce PF. Physical and emotional health of Gulf War veteran women. Aviat Space Environ Med 1997; 68: 317-21.
12. Kang HK, Bullman TA. Mortality among US veterans of the Persian Gulf War. N Engl J Med 1996; 335: 1498-504.
13. Cowan DN, DeFraites RF, Gray GC, Goldenbaum MB, Wishik SM. The risk of birth defects among children of Persian Gulf War veterans. N Engl J Med 1997; 336: 1650-6.
14. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986; 136: 2348-57.
15. Rook GA, Zumla A. Gulf War syndrome: is it due to a systemic shift in cytokine balance towards a Th2 profile? Lancet 1997; 349: 1831-3.
16. Mu HH, Sewell WA. Enhancement of interleukin 4 production by pertussis toxin. Infect Immun 1993; 61: 2834-40.
17. Hernandez Pando R, Rook GA. The role of TNF-alpha in T-cell-mediated inflammation depends on the Thl/Th2 cytokine balance. Immunology 1994; 82: 591-5.
18. Aaby P. Assumptions and contradictions in measles and measles immunization research: is measles good for something? Soc Sci Med 1995; 41: 673-86.
19. Bretscher PA, Wei G, Menon JN, Bielefeldt-Ohmann H. Establishment of stable, cell mediated immunity that makes 'susceptible' mice resistant to Leishmania major. Science 1992; 257: 539-42.
20. Brinkman V, Kristofic C. Regulation by corticosteroids of Thl and Th2 cytokine production in human CD4+ effector T cells generated from CD45RO and CD45RO+ subsets. J Immunol 1995; 155: 3322-8.
21. Bernton E, Hoover D, Galloway R, Popp K. Adaptation to chronic stress in military trainees. Adrenal androgens, testosterone, glucocorticoids, IGF 1, and immune function. Ann NY Acad Sci 1995: 774: 217-31.
22. Ramirez F, Fowell DJ, Puklavec M, Simmonds S, Mason D. Glucocorticoids promote a Th2 cytokine response by CD4+ T cells in vitro. J Immunol 1996; 156: 2406-12.
23. Casale GP, Vennerstrom JL, Bavari S, Wang TL. Inhibition of interleukin 2 driven proliferation of mouse CTLL2 cells, by selected carbamate and organophosphate insecticides and congeners of carbaryl. Immunopharmacol Immunotoxicol 1993; 15: 199-215.
24. Doucet I. Desert Storm syndrome: sick soldiers and dead children? Med War 1994; 10: 183-94.
25. Friedman A, Kaufer D, Shemer J, Hendler I, Soreq H, Tur Kaspa I. Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response. Nat Med 1996; 2: 1382-5.
26. Hanin I. The Gulf War, stress and a leaky blood brain barrier. Nat Med 1996; 2: 1307-8.
27. Magill AJ, Grogl M, Gasser RA Jr, Sun W, Oster CN. Visceral infection caused by Leishmania tropica in veterans of Operation Desert Storm. N Engl J Med 1993; 328: 1383-7.
28. Centers for Disease Control. Viscerotropic leishmaniasis in persons returning from Operation Desert Storm 1990-1991. JAMA 1992; 267: 1444-6.
29. Viscerotropic leishmaniasis in persons returning from Operation Desert Storm 1990-1991. MMWR Morb Mortal Wkly Rep 1992; 41: 131-4.
30. Hyams KC, Hanson K, Wignall FS, Escamilla J, Oldfield EC. The impact of infectious diseases on the health of US troops deployed to the Persian Gulf during operations Desert Shield and Desert Storm. Clin Infect Dis 1995; 20: 1497-504.
31. Persian Gulf Veterans Coordinating Board. Unexplained illnesses among Desert Storm veterans. A search for causes, treatment, and cooperation. Arch Intern Med 1995: 155: 262-8.
32. Korenyi Both AL, Korenyi Both AL, Molnar AC, Fidelus Gort R. Al Eskan disease: Desert Storm pneumonitis. Mil Med 1992; 157: 452-62.
33. Department of Health. Chief Medical Officer's Update 16 London: HMSO; 1997; p. 2.
34. Berry C. The Gulf War syndrome (editorial). J Clin Pathol 1997; 50: 360.

Acknowledgments

The authors are grateful to Lt Col J P G Bolton MB ChB, MSc, DRCOG, MRCGP, RAMC, Medical Adviser, Gulf Veterans Illnesses Unit, for his constructive comments and criticism.