Report On Gulf War Syndrome

My interest in Gulf War syndrome began in April 1994 when I heard a story about what the vets were suffering and recognized the symptoms as those of about 500 patients whom I had seen over the past year with what is referred to as human adjuvant disease. The clinical spectrum of the disease is variable as laboratory tests are not the same in all patients. The disease is best described as a process whereby normal control mechanisms of the immune system are no longer functioning to maintain homeostasis within the body. The immune system can be likened to The "Defense Department" of the body. Under normal conditions, when the body is under assault by an infectious agent or a chemical insult, various branches of the immune system are activated to rid the body of "the enemy". Once this job is done, the immune system returns to a normal functioning state of surveillance and maintaining the status quo. In the repertoire of things to which the immune system can respond is included the host tissues of the body within which it functions. Different parts of the immune system work in concert with one another and work to check each other on a molecular level in order to maintain themselves in balance. This defines a healthy state.

Autoimmune disease (atypical connective tissue disease, human adjuvant disease, collagen vascular disease) is a deregulation of the normal functioning of the immune system. The normal checks and balances are not functioning properly and immune reactions develop to the body's own tissues. This happens in the development of Lupus, rheumatoid arthritis, schleroderma, mixed connective tissue disease, and undifferentiated connective tissue disease. In human adjuvant disease, the same spectrum of symptoms can occur with variability in presentation of not only symptoms which may be manifested by an individual patient but also degree of severity. Patients will display an array of autoantibodies and autoreactive cells to various components of their bodies. These will be variable based on the immune response genes which are active in that particular patient. There is no way to predict which symptoms will be displayed nor how severe they will be. Symptoms may or may not fit classical diagnostic criteria for the disease as defined by the American College of Rheumatology.

Symptoms of autoimmune disease can range literally from head to toe. They include hair loss, rashes, occular inflammation, joint and muscle pain and weakness, fever, fatigue (frequently debilitating), skin pigmentation changes, skin textural changes, skin ulceration's (due to vaculitis), dry eyes, dry mouth, mouth ulcers, lymphadenopathy, pleurisy, blood, dyscrasias, coagulopathies, neuropathies, seizures and cognitive disorders. Autoimmune disease can affect any and all of the major organ systems of the body. These include pulmonary, cardiac, renal, gastrointestinal, and most devastatingly, the central nervous system. When immune regulatory mechanisms are not in balance, we also see an increase in the number of malignancies of the reticuloendothelial system. Depending on genetic makeup of any given patient, there can be clonal proliferation of various cell types of this system which accounts for these diseases.

Laboratory parameters are never totally indicative of the disease process in naturally occurring autoimmune diseases. We found this to be true also in patients with human adjuvant disease. Each patient must be evaluated by a physician who knows what he is looking at and how to do it. Laboratory should include CBC, SMA-20, Thyroid profile, RA, FANA, ESR, CRP, CPK, CŁ, C$, anti-DNA, anti-RNP, anti-SSA, anti-SSB, anti-SCL70, anti lupus anticoagulant, anti-thyroid microsomal antibodies, anti-liver and anti-kidney microsomal antibodies. If liver functions are abnormal, infectious hepatitis must be ruled out. Additionally, use of alcohol and medications which can cause abnormal liver functions must be monitored. It is important that these lab tests are done by a good laboratory as quality control testing is absolutely critical in immunology for valid information. For those patients who have had symptoms of neurological involvement, EEG's, EMG/NCV's and MRI/CT's are warranted. Atypical neurological disease is caused in the same way as atypical connective tissue disease and presents as Myesthenia Gravis, MS, and variations thereof. Evaluation by a competent neurologist is in order. Neuropsychiatric testing ma be necessary to evaluate cognitive disorders.

Many GW vets have been tested by their local physician and have been found to have positive lab results to the tests listed above. Again I stress, not all of the lab will be positive in all patients. These results and physical symptoms which they manifest indicate this disease process is occurring in this group of patients.

Etiology

The etiology of this disease process is important to find. Many theories have been put forth in the media and among vets as to what actually caused this disease process manifested by a percentage of the troops who served in Desert Storm. There may be a single etiology or one compounded by environmental factors. I believe the vaccines are the most plausible explanation. They are a source of adjuvants. Personnel and their children were affected who never took pyridostigmine bromide. Some were never in areas of SCUD attacks. Some were not around large chemical and pesticide usage. Some were given vaccines but never deployed to the Persian Gulf. The common denominator of all those who are sick with this autoimmune disease including troops from Great Britain is that they received our vaccines.

Vaccines and Adjuvants

Vaccines have been viewed as effective prophylaxis for disease since their discovery in use against smallpox. Whilst interest in them waned somewhat after effective polio vaccine was developed in the 1950's and with evolving antibiotics, they have enjoyed a new resurgence of interest with the appearance of AIDS. There is new interest in bacterial vaccines as well due to the increasing number of antibiotic resistant plasmids which seem to evolve and spread with each new generation of antibiotics.

To increase the efficacy of these vaccines, substances known as adjuvants have also been development. Adjuvants have been known for many decades. The first was Freund's adjuvant. It is composed of mycobacterial cell wall fragments and oil. It stimulates a predominately cell-mediated immune reaction much like the cell-mediated reaction of healthy individuals to mycobacterial infections. Mycobacterium tuberculosis shows a walling-off phenomenon in chest x-rays. This reaction does not effectively clear the organism from the infected host, but can slow down its dissemination. Freund's adjuvant was found to have adverse reactions in its use in the late 1950's. When injected by itself into inbred strains of lab rats, it caused an autoimmune disease process to set up in about 25% of the animals. This became the animal model for connective tissue disease and continues in use today as an effective means to study tissue changes and molecular mechanisms involved in autoimmune pathology. Due to this complication, other substances were sought by pharmaceutical concerns. One substance was organosilicon oils. This was found to induce antibody responses. Recent studies have also confirmed immunopathological analysis that cell-mediated immune reactions are also induced.

The recent appearance of AIDS has encouraged the search for new and better adjuvants that could be added to that elusive substance, an AIDS vaccine. There are many synthetic substances being tested which are hoped to enhance immune response to vaccines. Some of them already used in different vaccines have had published reports of adverse reactions which have made them not suitable for more general use. They have not received approval for use from the FDA.

Only one adjuvant has been approved for use by the FDA and this is alum. It has been shown to be inconsistent in its ability to generate an effective cell-mediated immune response and is considered a relatively weak adjuvant. It is in DPT shots which have been associated with neurological problems in infants. It is now in a vaccine being tested for general use though not FDA approved. This vaccines complications include jaundice, hepatitis, rash, lymphadenopathy, dyspnea, convulsions, dizziness, neuropathy, encephalopathy, myelitis, Guillian-Barre syndrome, multiple sclerosis and birth defects. Alum has been demonstrated in the plaques of within the brains of Alzheimer patients. These Alzheimer plaques are fibrous in nature and are associated with precipitation of certain proteins. It has frequently been associated with neurotoxic effects. Animal studies have shown alum to be associated both epidemiologicall and immunopathologically with the development of fibrosarcomas in cats through 2 different vaccines. These vaccines were used in standard dosing regimens. Conclusions that persistence of inflammatory and immunological reactions associated with aluminium may predispose to a derangement of fibrous connective tissue repair responses leading to neoplasia. 1,2,3

Adjuvants have been sought to enhance the potency of vaccines in the area of cell-mediated immunity. This is done through induction of production of cytokines by cells or by injection of cytokines directly to enhance the performance of immune cells within the host. Cell-mediated immune reactions are important in recovery from viral infections, combating malignancies, and in ridding the body of foreign materials which are not good for it. Problems can occur when the balance of processes is disturbed.

One HIV vaccine stimulates the production of autoantibodies to HLA Class 1 antigens. HIV glycoprotien gp 120 is cross reactive with this class of tissue antigens. There is a striking correlation between immunogenicity and the induction of cross-reactive antibodies by the vaccine 4. HLA antigens are histocompatibility antigens which are used in tissue typing. They are our major immune response genes which allow recognition of self from non-self. They are expressed on all cells. They are involved in immune reactions of all sorts. Should an immune reaction develop to these cell surface antigens, all manner of autoimmune disease is possible depending on that persons genetic makeup. There can be significant immune dysregulation 5 which could result in the development of malignancies. Leukemias, lymphomas and myelomas are known to occur with increased frequency in autoimmune diseases. HIV infected patients develop Kaposi's sarcomas and other types of malignancies. Likewise, other malignancies may be possible due to alterations of cell-surface antigens which could affect cell dedifferentiation and cell growth inhibition. For example, seminomas have been shown to express HLA class 1 antigens while they are not detected on normal spermatogenic cells6. Cytokines and immune dysregulation play a role in the development of ovarian cancer as well7,8. Studies have also linked HLA antigens and neural tube defects 9,10,11. Recent animal studies using congenic strains of mice have also shown linkage between the histocompatibilty complex and neural tube defects 12.The impact of manipulation of genes so closely linked on the same chromosome and so involved with cellular regulation and development embryological and dedifferentiation oncogenically has not been studied adequately.

Implications

Adjuvants are being investigated to enhance the potency of vaccines. However, there is no rose without a thorn. No adjuvant or cytokine works selectively. Viruses in naturally occurring infections generate cytokine production and antibody production by immune competent cells. If they have components which cross react with cell surface antigens, autoimmune reactions can occur. Viral infections have been linked to autoimmune hepatitis 13. Use of adjuvants has been increasingly associated with autoimmune phenomenon. Patients receiving immunotherapy for cancer have developed have developed autoimmune reactions including thyroid microsomal antibodies 14,15, factor VIII coagulant protein 16, and in the induction of the animal model for systemic lupus erythematosus in NZB mice.

Cytokines may be involved with oncogenes in the pathogenesis of monoclonal gammapathies and in further progression of the disease toward active myeloma 17. Changes in connective tissue metabolism occur in multiple myeloma 18 illustrating the close connection of the processes. Silicone gels induce plasma tumors in mice 19 depending on the strain of mice, pointing up the variability of response either as an immune dysfunction or malignancy related to the genetic makeup of the animal. Aberrations of immune function are known to precede malignancies 20. One study has shown hyperreactivecellular immunity in multiple myeloma 21. Immune dysfunction has been associated with neuropathies 22,23.

What Does it all Mean

Over the past 40 years we have acquired a great deal of knowledge about molecular biology. We have learned much about the procaryotic organism and how to combat them with antibiotics and vaccines. We have also learned so much about how eucaryotic cells and systems function. The immune system is fascination to study with regards to its structure, function and delicate balance in the states of health and disease. It is a very effective defense force for combating all manner of enemies to the body. There are effective checks and balances within the system to maintain its proper functioning. Each branch of the immune system has its own area of expertise. They function together in concert for effective defense of the organism as a whole. When controls get out of balance, major damage and destruction occur to the body.

Autoimmune disease is very real, very debilitating and very deadly. It is not a somatoform disorder nor is post traumatic-stress disorder. It is missed most frequently where the physician has not had adequate training in immunology or rheumatology. In many patients who served in Desert Storm, the clinical symptoms of connective tissue disease are present. Additionally, many have positive lab results for connective tissue disease. These are not found in healthy individuals. Many have positive FANA, RA, thyroid disease, joint and muscle pain, alopecia, vitiligo, lymphadenpoathy, photosensitve rashes, neuropathies, memory loss, pulmonary problems, cardiac problems, vasculitic lesions which do not heal on their skin, and malignancies. Many of these soldiers are now disabled. If adequate and proper treatment is given to them the quality of their lives may be improved. We owe these military personnel a great deal for the service they have given to this country. If we can restore even some of their health or quality of life and relieve some of the pain and discomfort they suffer, it is the least we can do for them.

Why Does It Matter

As I have looked into the issues of Gulf War Syndrome I have become increasingly concerned due to issues which reflect on the whole of the problem. This disease process has affected some 50,000 individuals who served in the military in the Gulf War. This is close to 10% of the force deployed. The illness began affecting troops while they were there. Most did not show signs of illness until they had returned. This type of disease will cause a small number of deaths right away. This can be due to renal crisis, vasculitic problems, stroke, cardiovascular, or pulmonary emergencies. This can affect the functioning of a military force in combat. Desert storm was a very short military engagement by our standards. If the war had continued longer, we might have seen more severe consequences of this disease in the combat situation.

Physical disease is more obvious. This disease process affects neurological function in devastating ways. We have seen patients develop neuropathies, mood changes, cognitive disorders, myesthenia gravis and muscular sclerosis. These latter two categories would be removed from a combat situation. However, subtle changes can occur in patients with regard to the first three problems. Neuropathies are uncomfortable and distracting. They can affect motor skills and functioning in an unpredictable manner. This would not be good for any soldier shooting a weapon or driving a tank, nor pilot flying fighter or helicopters, nor sailors handling equipment aboard ships. More consequential are mood changes where one develops a hair-trigger temper. This could lead to major problems within the troops or following orders from commanders. More important are cognitive disorders and the development of seizure disorders which are so subtle as to go undiagnosed for some time. A person with cognitive disorders loses the ability to read, or understand verbal commands, or to remember which direction they need to be going. Many Gulf War vets have had problems in familiar locations. They no longer have memories to do their routine jobs. This has occurred in addition to their physical ailments. sometimes they have had no overt physical problems. If there is an undiagnosed seizure disorder, it will cause absent spells where they may not be aware of where they are or what they are doing, though they may appear conscious. If these personnel are driving or flying, they can lose control of the equipment endangering themselves, those around them, and their mission. If they psychomotor seizures as some of my patients have developed, they can become suddenly violent for no apparent reason. These seizures become more pronounced in stressful situations, such as combat. There is no way to predict who will be affected, nor how severely, nor with which symptoms. They can appear quite suddenly or gradually change an individual.

The costs to prevent these problems is far less than the cost to have them as a country. There is a great deal of money and time being invested in each member of the military. Many of the people who have become ill after the Gulf War are highly trained, professional people who can no longer work either as civilians or military. They have special skills which the military can no longer use if it needs them, so they have to go out and train a whole new group. They may not be able to so readily acquire the same calibre of individual if the military uses these people as test subjects for whatever reason and then turns their back to them if and when they become ill from it. An issue like this is made all the more important in a down-sized military force. The cost carries over into the civilian world again because their skills are lost and they have to be supported either through the military, VA, or Social Security. This carries through to their families if the primary bread-winner becomes disabled and needs constant care given. Family violence is on the increase in military families as well. Issues such as this need to be looked at with this perspective in mind. It could be the result of minimal neurological dysfunction which has not been diagnosed and dealt with effectively.

References

(1) Hendrick, MJ, et al, "postvaccinal sarcomas in the cat: epidemiology and electron probe microanalytical identification of aluminium", Cancer Research, ,52, p. 5391 (1992)

(2) Kass, P H, et al, "Epidemiological evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats" J Am Vet Med Assoc, 203, p 396 (1993)

(3) Esplin, D G et al, "Postvaccinational sarcomas in cats" J Am Vet Med Assoc, 202, p 1245 (1993)

(4) De Santis, C , et al, "Cross-reactivity response to human immunodeficiency virus type 1 (HIV-1) gp 120 and HLA Class 1 heavy chains induced by receipt of HIV-1-derived envelope vaccines" J Infect Dis 168, p 1396 (1993)

(5) Lake, D F, et al, :autoantibodies to the alpha/beta T-cell receptors in human immunodeficiency virus infection, dysregulation and mimicry", Proc Natl Acad Sci 91, p 108489 (1994)

(6) Tomita, Y, et al "Immunohistochemical detection of intracellular adhesion molecule-1 (ICAM) and major histocompatibility complex class 1 antigens in seminomas", J Urol 149, p 659 (1993)

(7) Crickard, K, et al, "Basic fibroblast growth factor and receptor expression in human ovarian cancer" Gynecol Oncol 55, p 277 (1994)

(8) Bereck, J S ; Martinez-Maza, O, " Molecular and biological factors in the pathogenesis of ovarian cancer" J Reprod Med 39, p 241 (1994)

(9) Amos, D B, et al, "linkage between HLA and spine development" Transplant Proc 7, p 93 (1975)

(10) Mendell, N R, et al, "Spina Bifida and the HLA system: evidence for linkage", Am J Hum Genet 32, p 60 (1974)

(11) Wong A, et al, "DRw 52.53 and DQ homozygosity in patients with neural tube defects" Jpn J Hum Genet 32, p 319 (1987)

(12) Tyan M, Effects of H-2 on neural tube defects in congenic mice", Proc Soc Exp Biol Med 200, p 487 (1991)

(13) Czaja A J, Autoimmune hepatitis and viral infection" Gastroentrol Clin North Amer 23, p 547 (1994)

(14) Choudry U, "Microsomal antibody and the risk of developing thyroid disease in inteferon-alpha therapy" Am J Gastrenterol 89, p 1597 (1994)