PROGRESS ON PERSIAN GULF WAR ILLNESSES -

REALITY AND HYPOTHESES

GARTH L. NICOLSON

Department of Tumor Biology

The University of Texas M.D. Anderson Cancer Center

Houston, Texas

EDWARD HYMAN

New Orleans, Louisiana

ANDRÉAS KORÉNYI-BOTH

Department of Military Affairs

Adjutant General's Office

Fort Indiantown Gap

Annville, Pennsylvania

DAMACIO A. LOPEZ

BernalilIo, New Mexico

NANCY NICOLSON

Rhodon Foundation for Biomedical Research

Kingwood, Texas

WILLIAM REA

Environmental Health Center-Dallas

Dallas, Texas

HOWARD URNOVITZ

Calypte Biomedical

Berkeley, Californi

Approximately 50,000 veterans in the United States and 4,000 in allied countries who served in Operation Desert Storm (1991) have subsequently presented with a variety of ailments; the most common complaints, however, have been the appearance of a collection of chronic symptoms that do not fit easily with any known syndrome. This condition has been called Gulf War Syndrome (GWS) or Desert Storm Illness, and its origin and cause(s) have remained elusive. The most common symptoms of GWS include: aching joints, chronic fatigue, memory loss, headaches, sleeping difficulties, skin rashes, loss of concentration, depression, muscle spasms, nervousness, diarrhea, blurred vision, anxiety, problems breathing, chest and heart pain, dizziness, nausea, stomach pain, sight sensitivity, loss of balance, hives, frequent coughing, chemical sensitivity, eye pain and other vision problems, and bleeding gums and other dental problems (see Figure 1). Not shown in the figure are the autoimmune-like symptoms seen in some veterans. In some cases, immediate family members have also presented with similar symptoms, suggesting that in a subset of Desert Storm veterans, the disorder is transmittable. Veterans Administration data indicate that at least 1,300 veterans have died from cancers and that several thousand more have died from other diseases.

In an effort to identify possible diseases or syndromes that could account for the variety of symptoms listed above, develop appropriate diagnostic tests, provide potential treatments, assist veterans with these disorders, and initiate and coordinate political efforts on behalf of afflicted veterans, a Persian Gulf War National Unity Conference convened in Irving, Texas, on March 10-12, 1995, to bring together representatives from all states and experts from a variety of fields to discuss GWS. Previously, a Technology Assessment Workshop was organized by the NIH with the task of examining information and reports on GWS, recommending working case definitions for those illnesses, and developing plausible etiologies and biological explanations. A report on this conference appeared, but it failed to accomplish its goals (NIH Technology Assessment Workshop Panel, 1994).

The Medical/Scientific Panel of the Persian Gulf War National Unity Conference met and considered the collective GWS symptoms listed in Figure 1 and concluded, similarly to previous panels, that they do not fit easily with any known syndrome or disease; therefore, multiple disorders were probably represented in these veterans. Although the signs and symptoms present in GWS are complex, they do fit quite well with the symptoms seen in chronic fatigue/immune dysfunction syndrome, as shown in a study of GWS and CFIDS patients (Nicolson and Nicolson, 1995a). In some of the Desert Shield/Storm veterans who have multiple chronic symptoms, the causes eventually may be linked to endogenous sources, such as fine sand, and chemical exposures in the Persian Gulf War. Chemical exposures can result in many of these same symptoms, including immune system dysfunction (Vojdani et al., 1992). Soldiers were exposed to oil spills and fires, smoke from military operations, chemicals on clothing, pesticides, chemoprophylactic agents, and chemical weapons, among other things. In some cases, this exposure may have resulted in multiple chemical sensitivity syndrome (MCS). MCS shares some, but not all, of the GWS symptoms listed in Figure 1; in some of the soldiers, however, the infectious nature of the illness and its apparent spread to immediate family members precludes simple explanations, such as exposure to sand and toxic chemicals that were present at certain Persian Gulf locations. In this latter subset of veterans, the causes may be linked to local infectious diseases or exposures to biological weapons.

 

 

Continuous exposure to fine sand particles (< I Ám diameter) can result in hyperergic lung conditions, and in more severe cases, pneumonitis (Al Eskan Disease) (Korényi-Both et al., 1995). This disease was first reported by panel member Andreás Korényi-Both (Pennsylvania Army National Guard), who served as the Commander of the 316th Hospital, Army Central Command, Desert Shield/Storm. Fine sand exposure was rather ubiquitous during the Persian Gulf deployment, and continued pulmonary exposure could have resulted in immunosuppression in some soldiers and eventually in infection by opportunistic microorganisms.

Contamination by chemicals in the environment appears to be responsible for the MCSs seen in many Persian Gulf War veterans. William Rea (Environmental Health Center, Dallas, Texas) discussed progress in treating MCS. Similar to many nonveteran MCS patients, 80% of Desert Storm veterans with MCS responded to pollutant avoidance, vitamin and nutrient supplementation, allergen tolerization, and physical therapy (Ross et al., 1989; Rea et al., 1995). This subset of GWS patients showed marked improvement in their MCS symptoms after such combination therapy.

Another contaminant of the Desert Storm environment was the presence of depleted uranium in ammunition and on battlefield weapons and damaged armored vehicles. Damacio Lopez (Bernalillo, New Mexico) discussed the health hazards of depleted uranium, which include radiation and heavy metal exposure. Depleted uranium contains about 30% of the normal amounts of the isotope 235U, a dangerous radioisotope. The isotope with largest weight content in depleted uranium is 238U with 99.8% of the total weight. 238U has a half-life of over four billion years. Depleted uranium particles can be inhaled easily in smoke resulting from the impact of armor-piercing projectiles on hard targets and the aerosolization of uranium into small particles. If even one small particle (< 5 Ám in diameter) is trapped in the lungs, the lungs and surrounding tissues can be exposed to up to 272 times the maximum permitted dose for workers in the radiation industry. Fortunately, exposure can be monitored, and studies on Persian Gulf War veterans should be initiated to determine their exposure.

Exposure to environmental agents (radiation, and chemical and biological agents) can result in activation of endogenous retroviruses (Urnovitz and Murphy, 1996). Howard Urnovitz (Calypte Biomedical, Berkeley, California) presented his results from a pilot study of Desert Storm veterans and their families from Portland, Oregon, who had GWS. Saliva samples were tested for the presence of antibodies against epitopes of recombinant retroviral glycoproteins of human endogenous retrovirus (HERV). Anti-HERV antibodies were found in 13 out of 15 Desert Storm veterans, 8 out of 10 spouses, and 4 out of 5 children with GWS. HERV activation is seen often in autoimmune and neurological disorders and severe infections (Abraham and Khan, 1990), such as AIDS. Thus, the high frequency of HERV activation in GWS may be symptomatic of exposure to chemical and biological agents during Operation Desert Storm.

That Persian Gulf War veterans may have been exposed to endogenous or exogenous biological agents was considered by Edward Hyman (New Orleans, Louisiana). He presented evidence indicating that a large proportion of the American and British veterans of Desert Storm, and in some cases their spouses and children, may be infected with bacteria, as documented by the presence of gram-positive cocci and their residues in urine (Hyman, 1994). Using antibiotic treatments, Hyman has been able to treat successfully a subset of 15 veterans and their family members. These patients had complex symptoms that disappeared after multiple antibiotic treatments.

Further evidence of the presence of unusual biological agents in Desert Storm veterans and their families was presented by Garth Nicolson (M.D. Anderson Cancer Center, Houston, Texas). He and Nancy Nicolson (Rhodon Foundation, Houston, Texas) presented their results regarding the presence of unusual and highly pathogenic mycoplasmas, such as Mycoplasma fermentans (incognitus strain) and other mycoplasmas, in 11 out of 20 veterans and their family members who suffer from GWS. The specific mycoplasmas were detected in the leukocyte fraction of blood samples by the highly sensitive technique of Gene Tracking (Nicolson and Nicolson, 1994). In their study of 73 Desert Storm veterans and their symptomatic spouses and children without MCS, 55 showed good responses and eventually recovered following multiple cycles of doxycycline treatment (Nicolson and Nicolson, 1995b), an antibiotic that is particularly effective against mycoplasma infections (Lo et al., 1991). They concluded that many Desert Storm veterans with GWS, particularly a subset with family members that are presenting with similar symptoms, are infected with invasive microorganisms, such as mycoplasmas and possibly other infectious agents as well. Since the mycoplasmas detected appeared to contain unusual gene sequences (such as the HIV- I env gene or a retroviral gene of extremely high homologous correspondence to the env gene), the Nicolsons concluded that the mycoplasmas probably were modified and may have been used as biological weapons during Desert Storm.

The Medical/Scientific Panel concluded that although the initial progress in the investigation of GWS was encouraging, further research was absolutely necessary to identify the sources of GWS, develop useful diagnostic tests for the various illnesses found in Desert Storm veterans, and initiate clinical trials. The most pressing difficulty for most of the investigators working on GWS has been the appalling lack of financial support for their studies and the failure of the Veterans Administration to cooperate with diagnostic and therapeutic clinical trials. Without the necessary resources and cooperation, the initial findings presented at the Persian Gulf War National Unity Conference cannot be exploited or expanded to include the vast numbers of veterans and their family members who suffer from the multiple disorders called GWS.

REFERENCES

ABRAHAM, G.N. and KHAN, A.S. (1990). "Human endogenous retroviruses and immune disease." Clin. Immunol. Immunopathol. 56:1-8.

HYMAN, E.S. (1994). "A urinary marker for systematic coccal disease." Nephron 68:314-326.

KORÉNYI-BOTH, A.L., KORÉNYI-BOTH, A.L., and JUNCER, D.J. (1995). "Al Eskan Disease Persian Gulf Syndrome." Military Med. In press.

LO, S.-C., BUCHHOLZ, C.L., WEAR, D.J., HOHM, R.C., and MARTY, A.M. (1991). "Histopathology and doxycycline treatment in a previously healthy non-AIDS patient systemically infected by Mycoplasma fermentans (incognitus strain)." Mod. Pathol. 6:750-754.

NICOLSON, G.L. and NICOLSON, N.L. (1995a). "Chronic fatigue illness and Operation Desert Storm." J. Occup. Environ. Med. In press.

NICOLSON, G.L. and NICOLSON, N.L. (1995b). "Doxycycline treatment and Desert Storm." J. Am. Med. Assoc. 273:618-619.

NICOLSON, N.L. and NICOLSON, G.L. (1994). "The isolation, purification and analysis of specific gene-containing nucleoproteins and nucleoprotein complexes." Meth. Mol. Genet. 5:281-298.

NATIONAL INSTITUTES OF HEALTH (NIH) TECHNOLOGY ASSESSMENT WORKSHOP PANEL (1994). "The

Persian Gulf experience and health." J. Am. Med. Assoc. 272:391-396.

REA, W.J., PAN, Y., JOHNSON, A.R., ROSS, G.H., SUYAMA, H., and FENYVES, E.J. (1995). "Reduction of chemical sensitivity by means of heat depuration, physical therapy, and nutritional supplementation in a controlled environment." J. Clin. Ecol. In press.

ROSS, G.H., REA, W.J., JOHNSON, A.R., MAYNARD, B.J., and CARLISLE, L. (1989). "Evidence for vitamin deficiencies in environmentally sensitive patients." J. Clin. Ecol. 6:60-66.

URNOVITZ, H.B. and MURPHY, W.H. (1996). "Human endogeneous retroviruses: nature, occurrence and clinical implications in human disease." Clin. Microbiol. Rev. In press.

VOJDANI, A., GHONEUM, M., and BRAUTBAR, N. (1992). "Immune alteration associated with exposure to toxic chemicals." Toxicol. Ind. Health 8:239-254.