Medicine, Conflict & Survival 1998; 14: 74-83.

Gulf War Illnesses: Complex Medical and Scientific 
and Political Paradox*

Garth L. Nicolson and Nancy L. Nicolson
The Institute for Molecular Medicine, 16371 Gothard St. H, Huntington Beach, CA  92647  USA

Gulf War Syndrome, or more appropriately Gulf War Illnesses, from Operation Desert Storm in 1991 presents as a collection of disorders that for the most part can be diagnosed and treated, if effective programs exist to assist veterans and in some cases their immediate family members.  Although these illnesses are complex and have multi-organ signs and symptoms, a rather large proportion of these patients can be identified as having Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) and/or Fibromyalgia Syndrome (FMS).  Although there are many possible causes of CFS/ME/FMS, including chronic chemical exposures, chronic infections are attractive as an explanation in at least a subset of patients, because they can account for the appearance of multiorgan chronic and autoimmune signs and symptoms and the transmission of these illnesses to family members.  Unfortunately, many veterans who have been diagnosed with chronic infections, such as mycoplasmal and bacterial infections, cannot  obtain adequate treatment for their conditions, resulting in their reliance on private physicians and clinics for assistance.  This lack of prompt response may be responsible for the slow transmission of the illness to nonveterans. 

KEYWORDS		Chemical and Biological Warfare		Gulf War Syndrome
				Operation Desert Storm			Chronic Infections

Gulf War Syndrome or Gulf War Illnesses (GWI) are characterized by their complex, multi-organ, chronic signs and symptoms, including neurological, muscular-skeletal, rheumatic, mucocutaneous, gastrointestinal, sinopulmonary, and constitutional, among others.1  On the basis of complex multiorgan signs and symptoms GWI has been called Mucocutaneous-Intestinal-Rheumatic Desert Syndrome by Murray-Leisure et al.1  Also included in this complex clinical picture are increased sensitivities to various environmental agents and chemicals and enhanced allergic responses.2   Often such patients have cognitive problems and are seen by psychologists or psychiatrists who usually decide in the absence of contrary laboratory findings that their condition is a stress-induced somatoform disorder, such as Post Traumatic Stress Disorder.3  Alternatively, many of these patients have received an ‘unknown diagnosis,’ making it extremely difficult for them to receive adequate care and compensation.  There is another, quite different possibility--these patients may suffer from chronic chemical exposure and/or chronic infections that can penetrate the CNS and PNS as well as other tissues and organs and cause the complex signs and symptoms, including immune dysfunction, that are typical of such patients.1, 2, 4-6
	In addition to an unknown number of veterans’ immediate family members with GWI, over 100,000 Desert Storm veterans are experiencing a variety of chronic signs and symptoms characterized by disabling fatigue, intermittent fever, joint and muscle pain, impairments in short-term memory, headaches, skin rashes, diarrhea, vision and gastrointestinal problems and a collection of additional signs and symptoms that has defied a classical clinical case definition.7  These chronic signs and symptoms usually do not progress to cause death, hence the lack of evidence for increased mortality rates,8 but nonetheless there are now thousands of Desert Storm veterans dead for a variety of reasons.2  Part of the confusion in diagnosing GWI is that somewhat similar or overlapping signs and symptoms can be caused by quite different types of exposures (chemical, radiological or biological or more likely combinations of these).  
	The diagnoses and successful treatments of GWI are dependent on identifying the underlying exposures involved, because these illnesses are treated differently if their origins are chemical, radiological or biological.  For the most part, GWI signs and symptoms began to present between six months to one year or more after the end of Operation Desert Storm, and when immediate family members present with the same illness, their onset usually occurred from six months to one year or more after the onset of the veterans' illness, and not every family member has presented with a similar illness.  The U.S. Senate investigated the issue of transmission of GWI by surveying immediate family members; they found in 1994 after surveying over 1,000 veterans’ families that approximately 77% of spouses and approximately 65% of children were complaining of similar health problems as GWI patients.9  Because of the apparent slow rate of transmission of GWI to immediate family members, we do not feel that the general public is at high risk for contracting GWI from casual contact with GWI patients; however, there is likely to be some exposure risk associated with prolonged, close contact in restricted quarters.  
	Our hypothesis (Figure 1) is that GWI is not caused by stress or psychological problems, it is caused by multiple exposures to chemical, environmental, radiological and/or biological exposures that cause chronic multisystem signs and symptoms that for the most part can be diagnosed as existing diseases or syndromes.4-6  We have been particularly interested in veterans with GWI whose family members are now also sick with similar signs and symptoms, suggesting that many GWI patients may have biological, not chemical or radiological exposures, as the principal reason for their condition.  Illnesses caused by chemical or radiological exposures should not be transmitted.  Remarkably, transmission of GWI to immediate family members is still officially denied by the U.S. Departments of Defense (DoD) and Veterans' Affairs (DVA) and in the U.K. by the Ministry of Defense (MoD).  Although some family members with the same complex signs and symptoms could have developed their illness by contact with chemically exposed war souvenirs, packs or uniforms, only biological causes of GWI can account for the overwhelming fraction of family members contracting the same apparent illness in this important subset of GWI patients.
	The DoD previously claimed from their clinical evaluation program that Gulf War veterans do not show higher rates of health problems than the U.S. population as a whole.  They failed to mention, however, that all U.S. personnel that served in the Gulf received health clearances before they were deployed, and yet many returned with or later developed illnesses that cannot be explained.  National Guard and Air Force Reserve units were studied by the Center for Disease Control (CDC) in Atlanta for evidence of chronic health problems associated with deployment to the Persian Gulf, and it is clear from this CDC study that the Persian Gulf deployed soldiers have much higher frequencies (from 2.5-times to 13.5-times higher) of chronic health problems (> 6 months duration) than those who were not deployed to the Persian Gulf Theater of Operations.10  
	A major problem for Gulf War veterans with GWI has been obtaining adequate care for their illnesses.  Unfortunately, the signs and symptoms of GWI are not well established as criteria for particular diseases treated by the DoD, DVA or MoD.  Indeed, most GWI patients do not readily fit into DoD or VA diagnosis categories.  When we studied 650 veterans of Operation Desert Storm and their immediate family members who suffer from GWI, we found that their multiple chronic signs and symptoms were very similar to patients with Chronic Fatigue Syndrome (CFS) (often called Chronic Fatigue-Immune Dysfunction Syndrome or CFIDS) or Myalgic Encephalomyelitis (ME) and/or Fibromyalgia Syndrome (FMS).2-4    Although these chronic conditions can have stress as an exacerbating factor, they are extremely unlikely to be solely caused by stress or psychiatric problems.   In addition, the fact that many immediate family members have also presented with similar signs and symptoms precludes such a diagnosis for many GWI patients.  The variable incubation time of GWI, ranging from months to years after presumed exposure, the cyclic nature of the relapsing fevers and other signs and symptoms, and the types of signs and symptoms are consistent with diseases caused by combinations of biological and/or chemical or radiological agent(s) (Figure 1).
	We suggested that GWI/CFS/ME/FMS can be explained in many patients by exposure of veterans to various biological agents (chronic pathogenic infections) in combination with chemical exposures and in veterans' family members to biological agents transported back home by the veterans (Figure 1).  To confirm or eliminate the possibility that chronic infections are an important factor in GWI, and especially in immediate family members with GWI, we began by examining a variety of biological agents (bacteria, viruses, etc.) that can cause the chronic, overlapping, system-wide signs and symptoms seen in GWI.  We could eliminate most of the acute or fast acting bacteria (shown in Figure 1), because of the chronic nature of GWI and the slow appearance and nature of signs and symptoms.  After examining GWI patients' blood for the presence of chronic biological agents, the most common infection found was an unusual microorganism, Mycoplasma fermentans (incognitus strain), a slow-growing mycoplasma located deep inside blood leukocytes (white blood cells) of slightly under one-half of GWI patients studied. 11, 12  This microorganism is similar to a bacterium without a cell wall, and although mycoplasmas are often found at superficial sites in humans, such as in the oral cavity, they are rarely found in the blood.  When they are in the blood, similar to other bacteria, they can cause a dangerous system-wide or systemic infection. 13  In addition, cell-penetrating mycoplasmas, such as Mycoplasma fermentans, may produce unusual autoimmune-like signs and symptoms when they escape from nerve and other cell types and stimulate host immune responses to host cell antigens carried on the mycoplasma surface.  Our detection of mycoplasmal infections in the blood leukocytes of ~45% of the GWI patients examined (76 out of 170 patients), including 4 out of 6 British Desert Storm veterans with GWI, indicate that systemic infections may be a major contributor to GWI. 12  
	In response to our published studies2, 4-6, 11, 12 and formal lectures at the DoD (in 1994 and 1996) and DVA (in 1995), Dr. Steven Joseph, then Assistant Secretary of Defense for Health Affairs, and Dr. Kenneth Kizer, Undersecretary for Health, DVA, stated in attachments to letters to the press and various members of the U.S. Congress that this type of infection is commonly found, not dangerous and not even a human pathogen, and our results have not been duplicated by other laboratories.  Notwithstanding such misleading statements from the senior leadership of the DoD and DVA, the Uniformed Services University of the Health Sciences, the U.S. military's medical school, has been teaching its medical students for years that this type of infection, although relatively rare in the U.S. civilian population, is very dangerous and can progress to system-wide organ failure and death. 14  In addition, the Armed Forces Institute of Pathology (AFIP) has been publishing for years that this type of infection can result in a fulminant infection that results in death in nonhuman primates15  and in man.16   The AFIP has also suggested treating patients with this type of infection with doxycycline, 17 one of the antibiotics that we have recommended. 11-12  The DVA has issued guidelines stating that GWI patients should not be treated with antibiotics like doxycycline, even though in a significant number of patients it has been shown to be beneficial. 5, 6, 11-12  In addition, a certified diagnostic clinical laboratory, Immunosciences Laboratories of Beverly Hills, CA, has been conducting diagnostic tests on mycoplasmal infections in blood of GWI and CFS/ME patients, and they are finding essentially the same results as we have published.  Thus our results have been replicated by a certified commercial laboratory.  The DoD and DVA have also claimed that we have not cooperated with them or the CDC in studying this problem.  In fact, as stated above we have lectured to the DoD and DVA on several occasions on this subject, and we formally invited DoD and DVA scientists and physicians to the Institute for Molecular Medicine to learn our diagnostic procedures.  We recently received a contract (DAMD17-97-M-1452) from the DoD to train their scientists in the types of procedures that we used to diagnose chronic infections in GWI patients.  
	GWI patients that test positive for mycoplasmal infections in their blood can be successfully treated with multiple 6-week courses of specific antibiotics, such as doxycycline (200-300 mg/day), ciprofloxacin (or Cipro, 1500 mg/day), azithromycin (or Zithromax, 500 mg/day), clarithromycin (or Biaxin, 500-1000 mg/day) or minocycline (200-300 mg/day), 4, 6, 11, 12 with nutritional recommendations.  Multiple treatment cycles are required, and patients relapse often after the first few cycles, but subsequent relapses are milder and patients eventually recover. 12  Using the techniques of Nucleoprotein Gene Tracking18  and forensic Polymerase Chain Reaction, slightly under one-half of the Desert Storm veterans and their immediate family members with GWI/CFS/ME signs and symptoms in our studies showed evidence of mycoplasmal infections in their blood leukocytes. 11-12  In contrast, in nondeployed, healthy adults the incidence of mycoplasma-positive tests were <5%. 12  These studies do not involve controlled patient populations, such as all veterans that served in a single unit compared to similar numbers of nondeployed personnel from the same unit; therefore, the percentage of mycoplasma-positive patients overall may be somewhat lower than found in our studies.  Also, the GWI patients that have come to us for assistance may be more advanced patients (with more progressed disease) than the average GWI patient.  In a recent study we found that patients on antibiotic therapy (n=73) relapsed within weeks after their first 6-week cycle of therapy, but 58/73 recovered after up to six cycles of therapy and 14/73 are still undergoing therapy. 12  GWI patients who recovered from their illness after several (3-7) six-week cycles of antibiotic therapy were retested for mycoplasmal infections and were found to have reverted to a mycoplasma-negative phenotype. 11-12  We hypothesize that the therapy requires a significant amount of time because of the type of microorganism(s) involved (a mycoplasma) is slow-growing and is localized deep inside cells in tissues, which are more difficult locations to achieve proper antibiotic therapeutic concentrations.  As stated above, multiple cycles of therapy resulted in eventual recovery in a high percentage of mycoplasma-positive GWI patients.  Only the types of antibiotics that are known to be useful against mycoplasmas were effective; most have no effect at all on the signs and symptoms of GWI/CFS/ME, and some antibiotics make the condition worse.  Thus the antibiotic therapy does not appear to be a placebo effect, because only a few types of antibiotics are effective and some, like penicillin, make the condition worse.  We also believe that this type of infection is immune-suppressing and can lead to other opportunistic infections by viruses and other microorganisms or increases in endogenous virus titers. 
	We consider it quite likely that many of the Desert Storm veterans suffering from the GWI/CFS/ME/FMS signs and symptoms may have been exposed to chemical/biological cocktails (or endogenous sources of these agents) containing slowly proliferating microorganisms, including pathogenic mycoplasmas and quite possibly other bacteria and viruses.  Such infections, although not usually fatal, can produce various chronic signs and symptoms long after exposure.  The DoD and MoD have maintained that Iraqi offensive Chemical and Biological Weapons were not released during or after the Gulf War, but we did not have the appropriate detection equipment deployed to be able to determine whether Biological Weapons were present.  The Iraqi armed forces were operating under Soviet War Doctrine, which stresses offensive use of combinations of Chemical and Biological Weapons together with conventional weapons.  Although chemical and/or radiological exposure(s) can result in somewhat similar signs and symptoms, this does not explain the apparent contagious nature of GWI and the delayed appearance of similar GWI/CFS/ME/FMS signs and symptoms in immediate family members.
	There were several potential sources of chronic biological agents in the Persian Gulf Theater of Operations.19  First, deployed soldiers received multiple vaccine inoculations that were given all at once instead of using an appropriate schedule. Multiple vaccinations given simultaneously can result in immunosuppression and leave an individual susceptible to opportunistic infections.  Next, there is the question concerning the use of experimental vaccines in unproven immunization schemes.   Although hotly denied by the DoD and MoD, many veterans are testing positive for the presence of a squalene adjuvant (MF59) in their blood, and such adjuvants are only approved for use in experimental vaccines, suggesting that deployed (and some nondeployed personnel who were vaccinated and now have GWI) received experimental vaccines.  Some of these experimental vaccines could have been contaminated with small amounts of slow-growing microorganisms.  Alternatively, one of the experimental vaccines could have been similar to the HIV-1 vaccine that uses a mycoplasma containing the HIV-1 env gene . This is probably the Mycoplasma fermentans incognitus strain  containing the env gene that was found in veterans’ blood leukocytes by us.  Secondly, the Iraqis were known to have extensive stockpiles of Biological Weapons and the potential to deliver these weapons offensively, at short range in modified biological sprayers that deliver Biological Weapons onto the sand to create exclusionary zones or 'biological minefields' and at long range in modified SCUD-B (SS-1) missiles with 'skyburst' warheads.  Many of the storage and factory facilities where Chemical and Biological Weapons were stored were destroyed immediately up to, during and after the Desert Storm ground offensive, releasing plumes containing these agents high in the atmosphere where they could be carried downwind ('blow-back' exposures) to our lines.  These and other possible mechanisms of potential exposure must be carefully examined, not categorically dismissed by DoD or MoD personnel in Washington or London with little first-hand knowledge of the conditions on the ground.  There are a number of possible reasons why the DoD and DVA deny that our forces were exposed to Chemical and Biological agents during the Gulf War, and these were discussed by us in a previous article in this journal.19
	Finally, can GWI be completely explained by chronic bacterial and/or other infections?  The answer to this is no.  GWI is not one disease; it appears to be a collection of various disorders and illnesses caused mainly by chemical and/or biological exposures that produce complex chronic signs and symptoms.  Desert Storm veterans were exposed to a variety of toxic agents in the Persian Gulf, including oil well fires, battlefield smoke, anti-nerve agents, insecticides, or multiple chemical agents, and in some cases radiological agents (Depleted Uranium), and many GWI patients now have multiple sensitivities to various chemicals because of these exposures.  Chemical exposures can cause toxicological effects and can produce many but not all of the signs and symptoms of GWI. 20, 21  In addition, chemical exposures can result in immunosuppression and leave an individual susceptible to infections.  
	Future efforts should be directed at determining the types of exposures that occurred in the Persian Gulf region, including chemical, radiological and biological exposures, and how combinations of these could be involved in causing chronic illnesses.  In the case of biological agents or infections where treatments exist, controlled clinical trials will have to be designed and initiated, and the necessary resources to conduct and evaluate these trials will have to be allocated.  There is, however, an unexpected benefit from our efforts at understanding the role of chronic infections in GWI.  We and other laboratories have now found similar types of chronic infections in a rather large subset of civilian cases of CFS/ME and FMS, and patients with these illnesses have been diagnosed and successfully treated, resulting in recovery of these patients after years of unexplained illnesses.  Thus millions of patients with undiagnosed chronic illnesses may be able to finally obtain a diagnosis and regain their health using the treatment suggestions developed for treating GWI patients.
	Finally, we believe that GWI research decisions cannot be left solely to the DoD, DVA or MoD, because they have not shown themselves to be especially effective or responsive to the health problems of afflicted Gulf War veterans and their family members.  We consider it appropriate that civilian scientists and physicians collaborate closely with their counterparts in government to study and solve this problem in as objective manner as possible.

References Cited

 1. Murray-Leisure K, Daniels M O, Sees J, Suguitan E, Zangwill B, Bagheri S, Brinser E, Kimber R, Kurban R, Greene W H. Mucocutaneous-Intestinal-Rheumatic Desert Syndrome (MIRDS). Definition, histopathology, incubation period, clinical course and association with desert sand exposure.  Intern. J. Med.  1997; 1: in press.

 2. Nicolson G L, Hyman E, Korényi-Both A, Lopez D A, Nicolson N L, Rea W, Urnovitz H.  Progress on Persian Gulf War Illnesses: reality and hypotheses.   Intern. J. Occup. Med. Tox.  1995; 4: 365-370.

 3. NIH Technology Assessment Workshop Panel. The Persian Gulf Experience and Health. J. Amer. Med. Assoc. (JAMA)  1994; 272: 391-396.

 4. Nicolson G L, Nicolson N L.   Doxycycline treatment and Desert Storm.  J. Amer. Med. Assoc. (JAMA)  1995; 273: 618-619.

 5. Nicolson G L, Nicolson N L.  Chronic Fatigue Illness and Operation Desert Storm.  J. Occup. Environ. Med.  1996; 38: 14-16.

 6. Nicolson G L, Nicolson N L.  Mycoplasmal infections--Diagnosis and treatment of Gulf War Syndrome/CFIDS.  CFIDS Chronicle   1996; 9(3): 66-69.

 7. Boaz Milner I, Axelrod B N, Pasquantonia  J, Silanpaa M.  Is there a Gulf War Syndrome?  J. Amer. Med. Assoc. (JAMA)  1994; 271: 661.

 8. Writer J V, DeFraites R F, Brundage J F.  Comparative mortality among US military personnel in the Persian Gulf region and worldwide during Operations Desert Shield and Desert Storm. J. Amer. Med. Assoc. (JAMA ) 1996; 275: 118-121.

 9. Riegle D W Jr, D’amato A M. U.S. Chemical and Biological Warfare-related duel use exports to Iraq and their possible impact on the health consequences of the Persian Gulf War, Report to U.S. Senate Committee on Banking, Housing and Urban Affairs, 103rd Congress, May 25, 1994.

10. Kizer K W, Joseph S, Rankin J T. Unexplained illness among Persian Gulf War vetrans in an Air National Guard unit: preliminary report--August 1990-March 1995.  Morb. Mort. Week. Rep.  1995; 44: 443-447.

11. Nicolson G L, Nicolson N L.   Diagnosis and treatment of mycoplasmal infections in Gulf War Illness-CFIDS patients. Intern. J. Occup. Med. Immunol. Tox.   1996; 5: 69-78.

12. Nicolson G L, Nicolson N L, Nasralla M.  Mycoplasmal infections and Chronic Fatigue Illness (Gulf War Illness) associated with deployment to Operation Desert Storm.  Intern. J. Med. 1998; 1: 80-92. 

13. Cassell G H, Cole B C.  Mycoplasmas as agents of human disease.  New Eng. J. Med.  1981; 304: 80-89.

14. Uniform Services University of the Health Sciences, Pathology Syllabus 1993-4; 6: 91-93.

15. Lo S-C, Wear D J, Shih W-K, Wang R Y-H, Newton P B, Rodriguez J F. Fatal systemic infections of nonhuman primates by Mycoplasma fermentans (incognitus strain). Clin. Infect. Diseases  1993; 17(Suppl 1): S283-S288.

16. Lo S-C, Dawson M S, Newton P B, Sonoda A A, Shih W-K, Engler W F, Wang R Y-H, Wear D J.  Association of the virus-like infectious agent originally reported in patients with ADIS with acute fatal disease in previously healthy non-AIDS patients.  Amer. J. Trop. Med. Hyg. 1989; 41: 364-376.

17. Lo S-C, Buchholz C L, Wear D J, Hohm R C, Marty A M.  Histopathology and doxycycline treatment in a previously healthy non-AIDS patient systemically infected by Mycoplasma fermentans (incognitus strain).  Mod. Pathol.  1991; 6: 750-754.

18. Nicolson N L, Nicolson G L.   The isolation, purification and analysis of specific gene-containing nucleoproteins and nucleoprotein complexes.  Meth.  Mol.  Genet.  1994; 5: 281-298.

19. Nicolson G L, Nicolson N L.   The eight myths of Operation Desert Storm and Gulf War Syndrome.  Medicine, Conflict & Survival  1997; 13: 140-146.

20. Abou-Donia M B, Wilmarth K R.  Neurotoxicity resulting from coexposure to pyridostigmine bromide, DEET and permethrin: Implications of Gulf War exposures.  J. Tox. Environ. Health  1996; 48:35-56.

21. Haley R W, Kurt T L, Hom J.  Is there a Gulf War Syndrome?  Searching for syndromes by factor
      analysis of symptoms.  JAMA  1997; 277: 215-222.

Professor Garth L. Nicolson is currently the Chief Scientific Officer and Research Professor at the Institute for Molecular Medicine in Huntington Beach, California.  He was formally the David Bruton Jr. Chair in Cancer Research and Professor at the University of Texas M. D. Anderson Cancer Center in Houston, and he remains Professor of Internal Medicine and Professor of Pathology and Laboratory Medicine at the University of Texas Medical School at Houston.  He is also Adjunct Professor of Comparative Medicine at Texas A & M University.  Among the most cited scientists in the world, having published over 450 medical and scientific papers, edited 13 books, served on the Editorial Boards of 12 medical and scientific journals and currently serving as Editor of two (Clinical & Experimental Metastasis  and the Journal of Cellular Biochemistry), Professor Nicolson has active peer-reviewed research grants from the U. S. Army, National Cancer Institute, National Institutes of Health, American Cancer Society and the National Foundation for Cancer Research.  Dr. Nancy Nicolson is trained in molecular biophysics and is the Chief Executive Officer of the Institute for Molecular Medicine and President of the Rhodon Foundation for Biomedical Research.  She has published over 30 medical and scientific papers and has delivered over 60 international and national scientific presentations.  She is the Who's Who in the World International Woman of the Year for 1996-97.  Drs. Nicolson have been engaged in studying Gulf War Illnesses since their step-daughter returned from service in Desert Storm in 1991 as a Staff Sergeant and Crew Chief of a Blackhawk helicopter in the U.S. Army's 101st Airborne Division (Air Assault) and developed the unusual, multiple signs and symptoms of Gulf War Illness that prevented her from finishing pilot training.  Since then the Nicolsons have been involved in a research effort to identify some of the possible causes of and develop treatments for Gulf War Illness patients.

* Presented to the Committee on Government Reform and Oversight, UNITED STATES HOUSE OF REPRESENTATIVES, June 26, 1997.

Figure 1. Explanation for the delayed appearance of Gulf War Illnesses in personnel deployed to the Persian Gulf Therature of Operations during Operation Desert Storm.  In the figure personnel were exposed to a variety of environmental, chemical and biological agents. 

Figure 2

Figure 2. Possible chronic infections involved in Gulf War Illnesses, incuding cell-penetrating mycoplasmas that can initiate autoimmune-like signs and symptoms.