Posted by Tony from ? (220.127.116.11) on Thursday, October 03, 2002 at 2:26PM :
COMMITTEE ON GOVERNMENT REFORM
Subcommittee on National Security, Veterans’ Affairs and International Relations
UNITED STATES HOUSE OF REPRESENTATIVES
January 24, 2002
Dr. Garth Nicolson is currently the President, 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, Professor and
Chairman at the University of Texas M. D. Anderson Cancer Center in Houston, and Professor of Internal Medicine and
Professor of Pathology and Laboratory Medicine at the University of Texas Medical School at Houston. He was also
Adjunct Professor of Comparative Medicine at Texas A & M University. Among the most cited scientists in the world,
having published over 520 medical and scientific papers, edited 14 books, served on the Editorial Boards of 20 medical and
scientific journals, including the Journal of Chronic Fatigue Syndrome, and currently serving as Editor of two (Clinical &
Experimental Metastasis and the Journal of Cellular Biochemistry), Professor Nicolson has held numerous
peer-reviewed research grants. He is a recipient of the Burroughs Wellcome Medal of the Royal Society of Medicine,
Stephen Paget Award of the Metastasis Research Society and the U. S. National Cancer Institute Outstanding Investigator
It is now over a decade since the Persian Gulf War, but over 100,000 U. S. veterans still suffer from various illnesses
attributed to their service [1-4]. Although some Gulf War Illnesses (GWI) patients have unique signs and symptoms , most
do not have some new syndrome (Gulf War Syndrome) . These illnesses are more properly called GWI, and we believe
that they are due to accumulated toxic insults that cause chronic illnesses with relatively nonspecific signs and symptoms
Over the last few years researchers have published much higher prevalence rates of GWI in deployed than in non-deployed
forces [8-10]. Case control studies of Gulf War veterans showed higher symptom prevalence in deployed than in
non-deployed personnel from the same units [9,10]. For certain signs and symptoms, this difference was dramatic (for
example, the rate of diarrhea in the deployed group was over 13-times greater than in the non-deployed group ). Steele
 showed that in three studies, Gulf War-deployed forces had excess rates of GWI symptom patterns, indicating beyond a
doubt that GWI is a major problem that needs to be adequately addressed.
TEN YEARS LATER -- OBTAINING AN ADEQUATE DIAGNOSIS OF GWI
For years the Departments of Defense (DoD) and Veterans’ affairs (DVA) promoted the notion that Post-Traumatic Stress
Disorder (PTSD) was a major factor in GWI . Most researchers doubt that stress is a major cause of GWI [1-5,7], and
it certainly does not explain how some immediate family members presented after the war with the same signs and symptoms
[2,3,12]. Even psychiatrists who have studied GWI do not believe that GWI is explainable as PTSD . Researchers find
that GWI cases differ from PTSD, depression, somatoform disorder and malingering [7,14]. Although most GWI patients do
not appear to have PTSD, they are often paced in this diagnosis category by DoD and DVA physicians. GWI can be
diagnosed within ICD-10-coded diagnosis categories, such as fatiguing illness (G93.3), but they often receive a diagnosis of
‘unknown illness.’ This, unfortunately, results in their receiving reduced disability assessments and benefits and essentially little
or no effective treatments. It’s not that they are any less sick than their compatriots with ICD-10 diagnoses, they just don’t fit
within the military’s or DVA’s diagnosis systems. In addition, many active-duty members of the Armed Forces are hesitant to
admit that they have GWI, because they feel strongly that it will hurt their careers or result in their being medically discharged.
They have good reason to fear this, because many officers that we have assisted eventually retired or resigned their
commissions because of imposed limits to their careers .
Psychiatrists often decide in the absence of contrary laboratory findings that GWI is a somatoform disorder caused by stress,
instead of organic or medical problems that can be treated with medicines or treatments not used for PTSD or other
somatoform disorders. The evidence that psychiatrists have offered as proof that stress or PTSD is the source of most GWI
is the assumption that most veterans must have suffered from stress by virtue of the stressful environment in which they found
themselves during the Gulf War . However, most veterans do not feel that stress-related diagnoses are an accurate
portrayal of their illnesses. Testimony to the House Committee on Government Reform and Oversight questions the notion
that stress is the major cause of GWI , and the General Accounting Office (GAO) has concluded that while stress can
induce some physical illness, it is not established as the major cause of GWI . Stress can exacerbate chronic illnesses and
suppress immune systems, but most military personnel that we interviewed indicated that the Gulf War was not a particularly
stressful war, and they strongly disagreed that stress was the origin of their illnesses . However, in the absence of
physical or laboratory tests that can identify possible origins of GWI, many DoD and VA physicians accept that stress is the
cause. It has been argued that the arthralgias, fatigue, memory loss, rashes and diarrhea found in GWI patients are
nonspecific and often lack a physical cause , but this conclusion may simply be the result of inadequate workup and lack
of availability of routine tests that could define the underlying organic etiologies for these conditions .
It has also been claimed that there are no unique illnesses associated with deployment to the Gulf War--similar clusters of
illness (albeit at lower rates) can be found in non-Gulf War veterans deployed to Bosnia . Such epidemiological analyses
have been criticized on the basis of self-reporting and self-selection , and the veterans under study may not be
representative . These criticisms notwithstanding, it remains important to characterize signs and symptoms and identify
exposures, if possible, of Gulf War veterans in order to find effective treatments for specific subsets of GWI patients. We
have been trying for years to get the DoD to acknowledge that different exposures can result in quite different illnesses, even
though signs and symptoms profiles may overlap.
HOW DOES GWI DIFFER FROM OTHER CHRONIC FATIGUING ILLNESSES?
GWI patients can have 20-40 or more chronic signs and symptoms, including chronic fatigue, headaches, memory loss,
muscle pain, nausea, gastrointestinal problems, joint pain, lymph node pain, memory loss, increased chemical sensitivities,
among others [1-5]. Often included in this complex clinical picture are increased sensitivities to various environmental agents
and enhanced allergic responses. Civilian patients with similar signs and symptoms are usually diagnosed with Chronic
Fatigue Syndrome (CFS), Fibromyalgia Syndrome (FMS) or Multiple Chemical Sensitivity Syndrome (MCS) [2,3,7].
Although clear-cut laboratory tests on GWI, CFS and FMS are not yet available, some tests that have been used in recent
years for GWI are not consistent with a psychiatric origin for GWI [20-25].
CHRONIC ILLNESSES AND CHEMICAL EXPOSURES
It has been documented that chemical and biological exposures occurred during the Gulf War, and many civilian patients may
have been exposed to chemical and biological substances that could be the underlying causes of their illnesses [1-3,7]. The
variable incubation times, 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 of GWI are consistent with diseases caused by combinations
of biological and/or chemical or radiological agents (Figure 1) [1,7].
Gulf War veterans were exposed to a variety of chemicals, including insecticides, such as the insect repellent
N,N-dimethyl-m-toluamide, the insecticide permethrin and other organophosphates, fumes and smoke from burning oil wells,
the anti-nerve agent pyridostigmine bromide, solvents used to clean equipment and a variety of other chemicals [1,2,7]. This
also includes in some cases, possible exposures to low levels of Chemical Warfare (CW) agents. Some CW exposure may
have occurred because of destruction of CW stores in factories and storage bunkers during and after the war as well as
possible offensive use of CW agents . Although some former DoD physicians feel that there was no credible evidence
for CW exposure , many veterans have been notified by the DoD of possible CW exposures.
Figure 1. Hypothesis on how multiple toxic exposures, including multiple vaccines (2), chemical (3),
radiological and biological (4) exposures, may have resulted in GWI in predisposed, susceptible
individuals (1) [modified from Nicolson et al.(7)].
Exposures to mixtures of toxic chemicals can result in chronic illnesses, even if the exposures were at low-levels
[20,21,28,29]. Such exposures can cause a wide variety of signs and symptoms, including chronic neurotoxicity and immune
supression. Combinations of pyridostigmine bromide, N,N-dimethyl-m-toluamide and permethrin produce neurotoxicity,
diarrhea, salivation, shortness of breath, locomotor dysfunctions, tremors, and other impairments in healthy adult hens .
Although low levels of individual organophosphate chemicals may not cause signs and symptoms in exposed, non-deployed
civilian workers , this does not negate a causal role of multiple chemical exposures in causing chronic illnesses such as
GWI. Organophosphate-Induced Delayed Neurotoxicity (OPIDN)  is an example of chronic illness that may be caused
by multiple, low level chemical exposures (Figure 1). Multiple Chemical Sensitivity Syndrome (MCS) has also been
proposed to result from multiple low level chemical exposures . These syndromes can present with many of the signs and
symptoms found in GWI patients, and many GWI cases may eventually be explained by complex chemical exposures.
In chemically exposed GWI patients, memory loss, headaches, cognitive problems, severe depression, loss of concentration,
vision and balance problems and chemical sensitivities, among others, typify the types of signs and symptoms characteristic of
organophosphate exposures. Arguments have been advanced by former military physicians that such exposures do not
explain GWI, or that they may only be useful for a small subset of GWI patients . These arguments for the most part are
based on the effects of single agent exposures, not the multiple, complex exposures that were encountered by Gulf War
veterans . The onset of signs and symptoms of GWI for most patients was between six months and two years or more
after the end of the war. Such slow onset of clinical signs and symptoms in chemically exposed individuals is not unusual for
OPIDN . Since low-level exposure to organophosphates was common in U.S. veterans, the appearance of delayed,
chronic signs and symptoms similar to OPIDN could have been caused by multiple low-level exposures to pesticides, nerve
agents, anti-nerve agents and/or other organophosphates, especially in certain subsets of GWI patients.
RADIOLOGICAL EXPOSURES AND GWI
Depleted uranium (DU) was used extensively in the Gulf War, and it remains an important battlefield contaminant. When a
DU penetrator hits an armored target, it ignites, and between 10% and 70% of the shell aerosolizes, forming uranium oxide
particles . The particles that form are usually small (less than 5 µm in diameter) and due to their high density settle quickly
onto vehicles, bunkers and the surrounding sand, where they can be easily inhaled, ingested or re-aerosolized. Following
contamination, DU can be found in the lungs and regional lymph nodes, kidney and bone. Additionally, the Armed Forces
Radiological Research Institute (AFRRI) found DU in blood, liver, spleen and brain of rats injected with DU pellets .
Studies on DU carriage should be initiated as soon as possible to determine the prevalence of contamination, and extent of
body stores of uranium and other radioactive heavy metals. Procedures have been developed for analysis of DU metal
fragments  and DU in urine . However, urine testing does not detect uranium in all body sites . So far, analysis
of DU-contaminated Gulf War veterans has not shown them to have severe signs and symptoms of GWI , but few Gulf
War veterans have been studied for DU contamination.
OTHER ENVIRONMENTAL EXPOSURES AND GWI
In addition to chemical exposures, soldiers were exposed to burning oil well fires and ruptured petroleum pipelines as well as
fine, blowing sand. The small size of sand particles (much less than 0.1 mm) and the relatively constant winds in the region
probably resulted in some sand inhalation. The presence of small sand particles deep in the lungs can produce a pulmonary
inflammatory disorder that can progress to pneumonitis or Al-Eskan Disease . Al-Eskan disease, characterized by
reactive airways, usually presents as a pneumonitis that can eventually progress to pulmonary fibrosis, and possibly
immunosuppression followed by opportunistic infections. Although it is doubtful that many GWI patients have Al-Eskan
Disease, the presence of silica-induced immune suppression in some soldiers could have contributed to persisting
opportunistic infections in these patients.
BIOLOGICAL EXPOSURES AND GWI
System-wide or systemic chemical insults and/or chronic infections that can penetrate various tissues and organs, including the
Central and Peripheral Nervous Systems, are important in GWI [1-5,7]. When such infections occur, they can cause the
complex signs and symptoms seen in CFS, FMS and GWI, including immune dysfunction. Changes in environmental
responses as well as increased titers to various endogenous viruses that are commonly expressed in these patients have been
seen in CFS, FMS and GWI. Few infections can produce the complex chronic signs and symptoms found in these patients;
however, the types of infection caused by Mycoplasma and Brucella species that have been found in GWI patients, can
cause complex problems found in GWI [reviews: 23,40,41]. These microorganisms are now considered important emerging
pathogens in causing chronic diseases as well as being important cofactors in some illnesses, including AIDS and other
immune dysfunctional conditions [23,40,41].
Evidence for infectious agents has been found in GWI patients' urine  and blood [12,26,42-44]. We [12,26,42,43] and
others  have found that most of the signs and symptoms in a large subset of GWI patients can be explained by chronic
pathogenic bacterial infections, such as Mycoplasma and Brucella infections. In studies of over 1,500 U. S. and British
veterans with GWI, approximately 40-50% of GWI patients have PCR evidence of such infections, compared to 6-9% in the
non-deployed, healthy population [review: 23]. This has been confirmed in a large study of 1,600 veterans at over 30 DVA
and DoD medical centers (VA Cooperative Clinical Study Program #475, S. Donta and C. Engel, statements at the NIH
Chronic Fatigue Syndrome Coordinating Board, 2/00). Historically, mycoplasmal infections were thought to produce
relatively mild diseases limited to particular tissues or organs, such as urinary tract or respiratory system [23,40,41].
However, the mycoplasmas detected in GWI patients with molecular techniques are highly virulent, colonize a wide variety of
organs and tissues, and are difficult to treat [23,45,46]. The mycoplasma most commonly detected in GWI, Mycoplasma
fermentans (found in >80% of those GWI patients positive for any mycoplasma), is found intracellularly. It is unlikely that
this type of infection will result in a strong antibody response, which may explain the DoD’s lack of serologic evidence for
these types of intracellular infections .
When civilian patients with CSF or FMS were similarly examined for systemic mycoplasmal infections 50-60% of these
patients were positive, indicating another link between these disorders and GWI . In contrast to GWI, however, several
species of mycoplasmas other than M. fermentans were found in higher percentages of CSF/ME and FMS patients and
most had multiple infections [48,49].
GWI CAN SPREAD TO IMMEDIATE FAMILY MEMBERS
During the last year we have documented the spread of GWI infections to immediate family members . According to one
U. S. Senate study , GWI has spread to family members, and it is likely that it has also spread in the workplace .
Although the official position of the DoD/DVA is that family members have not contracted GWI, these studies [12,50]
indicate that at least a subset of GWI patients have a transmittable illness. Laboratory tests revealed that GWI family
members have the same chronic infections  that have been found in ~40% of the ill veterans [42-44]. We examined
military families (149 patients; 42 veterans, 40 spouses, 32 other relatives and 35 children) with at least one family complaint
of illness) selected from a group of 110 veterans with GWI who tested positive (~41% overall) for mycoplasmal infections.
Consistent with previous results, over 80% of GWI patients who were positive for blood mycoplasmal infections had only
one Mycoplasma species, M. fermentans. In healthy control subjects the incidence of mycoplasmal infection was 7%,
several mycoplasma species were found, and none were found to have multiple mycoplasmal species (P<0.001). In 107
family members of GWI patients with a positive test for mycoplasma, there were 57 patients (53%) that had essentially the
same signs and symptoms as the veterans and were diagnosed with CFS or FMS. Most of these patients also had
mycoplasmal infections compared to non-symptomatic family members (P<0.001). The most common species found in CFS
patients in the same families as GWI patients was M. fermentans, the same infection found in the GWI patients. The most
likely conclusion is that certain subsets of GWI can transmit their illness and airborne infections to immediate family members
As chronic illnesses like GWI (and in some cases CFS and FMS) progress, there are a number of accompanying clinical
problems, particularly autoimmune signs/symptoms, such as those seen in Multiple Sclerosis (MS), Amyotrophic Lateral
Sclerosis (ALS or Lew Gehrig’s Disease, see below), Lupus, Graves’ Disease, Arthritis and other complex autoimmune
diseases. Mycoplasmal infections can penetrate into nerve cells, synovial cells and other cell types [40,41]. The autoimmune
signs and symptoms can be caused when intracellular pathogens, such as mycoplasmas, escape from cellular compartments
and stimulate the host’s immune system. Microorganisms like mycoplasmas can incorporate into their own structures pieces
of host cell membranes that contain important host membrane antigens that can trigger autoimmune responses or their surface
antigens may be similar to normal cell surface antigens. Thus patients with such infections may have unusual autoimmune signs
INVOLVEMENT OF INFECTIONS IN GULF WAR VETERANS WITH ALS
Amyotrophic Lateral Sclerosis (ALS) is an adult-onset, idiopathic, progressive degenerative disease affecting both central and
peripheral motor neurons. Patients with ALS show gradual progressive weakness and paralysis of muscles due to destruction
of upper motor neurons in the motor cortex and lower motor neurons in the brain stem and spinal cord, ultimately resulting in
death, usually by respiratory failure . Gulf War veterans show at least twice the expected incidence of ALS.
We have recently investigated the presence of systemic mycoplasmal infections in the blood of Gulf War veterans and civilians
with ALS . Almost all ALS patients (~83%, including 100% of Gulf War veterans with ALS) showed evidence of
Mycoplasma species in blood samples. All Gulf War veterans with ALS were positive for M. fermentans, except one that
was positive for M. genitalium. In contrast, the 22/28 civilians with detectable mycoplasmal infections had M. fermentans
(59%) as well as other Mycoplasama species in their blood, and two of the civilian ALS patients had multiple mycoplasma
species. Of the few control patients that were positive, only two patients (2.8%) were positive for M. fermentans
(P<0.001). The results support the suggestion that infectious agents may play a role in the pathogenesis and/or progression of
ALS, or alternatively ALS patients are extremely susceptible to systemic mycoplasmal infections . In the GWI patients
mycoplasmal infections may have increased their susceptibility to ALS, which may explain the recent VA studies showing that
there is an increased risk of ALS in Gulf War veterans.
SUCCESSFUL TREATMENT OF GWI MYCOPLASMAL INFECTIONS
We have found that mycoplasmal infections in GWI, CFS, FMS and RA can be successfully treated with multiple courses of
specific antibiotics, such as doxycycline, ciprofloxacin, azithromycin, clarithromycin or minocycline [45,46,53-55], along with
other nutritional recommendations. Multiple treatment cycles are required, and patients relapse often after the first few
cycles, but subsequent relapses are milder and most patients eventually recover [42,43]. GWI patients who recovered from
their illness after several (3-7) 6-week cycles of antibiotic therapy were retested for mycoplasmal infection and were found to
have reverted to a mycoplasma-negative phenotype [42,43]. The therapy takes a long time because of the microorganisms
involved are slow-growing and are localized deep inside cells in tissues, where it is more difficult to achieve proper antibiotic
therapeutic concentrations. Although anti-inflammatory drugs can alleviate some of the signs and symptoms of GWI, they
quickly return after discontinuing drug use. If the effect was due to an anti-inflammatory action of the antibiotics, then the
antibiotics would have to be continuously applied and they would be expected to eliminate only some of the signs and
symptoms of GWI. In addition, not all antibiotics, even those that have anti-inflammatory effects, appear to work. Only the
types of antibiotics that are known to be effective against mycoplasmas are effective; most have no effect at all, 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 have also found Brucella infections in GWI patients but we have not examined
enough patients to establish a prevalence rate among veterans with GWI.
The true percentage of mycoplasma-positive GWI patients overall is likely to be somewhat lower than found in our studies
(41-45%) [12,42,43] and those published by others (~50%) . This is reasonable, since GWI patients that have come to
us for assistance are probably more advanced patients (with more progressed disease) than the average patient. Our
diagnostic results have been confirmed in a large study DVA/DoD study (~40% positive for mycoplasmal infections, VA
Cooperative Clinical Study Program #475). This DVA study is a controlled clinical trial that will test the usefulness of
antibiotic treatment of mycoplasma-positive GWI patients. This clinical trial is based completely on our research and
publications on the diagnosis and treatment of chronic infections in GWI patients [42,43,53-55]. This clinical trial is complete
but the treatment results have not yet been analyzed. There is a major concern that the DoD/DVA will not be forthcoming
about this trial.
VACCINES GIVEN DURING DEPLOYMENT AND GWI
A possible source for immune disturbances and chronic infections found in GWI patients is the multiple vaccines that were
administered close together around the time of deployment to the Gulf War. Unwin et al.  and Cherry et al.  found a
strong association between GWI and the multiple vaccines that were administered to British Gulf War veterans. Unwin et al.
 and Goss Gilroy  also noted an association specifically with anthrax vaccine and GWI symptoms in British and
Canadian veterans. Steele  found a three-fold increased incidence of GWI in nondeployed veterans from Kansas who
had been vaccinated in preparation for deployment, compared to non-deployed, non-vaccinated veterans. Finally, Mahan et
al.  found a two-fold increased incidence of GWI symptoms in U.S. veterans who recalled they had received anthrax
vaccinations at the time of the Gulf War, versus those who thought they had not. These studies associate GWI with the
multiple vaccines given during deployment, and they may explain the high prevalence rates of chronic infections in GWI
GWI signs and symptoms have developed in Armed Forces personnel who recently received the anthrax vaccine. On some
military bases this has resulted in chronic illnesses in as many as 7-10% of personnel receiving the vaccine . The chronic
signs and symptoms associated with anthrax vaccination are similar, if not identical, to those found in GWI patients, suggesting
that at least some of the chronic illnesses suffered by veterans of the Gulf War were caused by military vaccines [59,60].
Undetectable microorganism contaminants in vaccines could have resulted in illness, and may have been more likely to do so
in those with compromised immune systems. This could include individuals with DU or chemical exposures, or personnel who
received multiple vaccines in a short period of time. Since contamination with mycoplasmas has been found in commercial
vaccines , the vaccines used in the Gulf War should be considered as a possible source of the chronic infections found in
GWI. Some of these vaccines, such as the filtered, cold-stored anthrax vaccine are prime suspects in GWI, because they
could be easily contaminated with mycoplasmal infections and other microorganisms .
INADEQUATE RESPONSES OF THE DOD AND DVA TO GWI
In general, the response of the DoD and DVA to the GWI problem has been inadequate, and it continues to be inadequate.
The response started with denial that there were illnesses associated with service in the Gulf War; it has continued with denial
that what we (biological exposures) and others (chemical exposures) have found in GWI patients are important in the
diagnosis and treatment of GWI, and it continues today with the denial that military vaccines could be a major source of
GWI. For example, in response to our publications and formal lectures at the DoD (1994 and 1996) and DVA (1995), the
DoD stated in letters to various members of Congress and to the press that M. fermentans infections are commonly found,
not dangerous and not even a human pathogen, and our results have not been duplicated by other laboratories. These
statements were completely false. The Uniformed Services University of the Health Sciences taught its medical students for
years that this type of infection is very dangerous and can progress to system-wide organ failure and death . In addition,
the Armed Forces Institute of Pathology (AFIP) has been publishing for years that this type of infection can result in death in
nonhuman primates  and in man . The AFIP has also suggested treating patients with this type of infection with
doxycycline , which is one of the antibiotics that we have recommended [53-55]. Interestingly, DoD pathologist Dr.
Shih-Ching Lo holds the U. S. Patent on M. fermentans (“Pathogenic Mycoplasma”), and this may be the real reason
that in their original response to our work on M. fermentans infections in GWI, the DoD/DVA issued guidelines stating that
GWI patients should not be treated with antibiotics like doxycycline, even though in a significant number of patients it had
been shown to be beneficial. The DoD and DVA have also stated that we have not cooperated with them or the CDC in
studying this problem. This is also not true. We have done everything possible to cooperate with the DoD, DVA and CDC
on this problem, and we even published a letter in the Washington Post on 25 January 1997 indicating that we have done
everything possible to cooperate with government agencies on GWI issues, including inviting DoD and DVA scientists and
physicians to the Institute for Molecular Medicine to learn our diagnostic procedures on 23 December 1996 at a meeting
convened at Walter Reed AMC. We have been and are fully prepared to share our data and procedures with government
scientists and physicians. The DVA has responded with the establishment of VA Cooperative Clinical Study Program #475,
but many Gulf War Referral Centers at VA Medical Centers continue to be hostile to non-psychiatric treatment of GWI. The
DoD and DVA contin
-- signature .
Post a Followup