Armed Forces Medical Developments 2000


THE ROLE OF CHEMICAL, BIOLOGICAL AND RADIOLOGICAL EXPOSURES
IN GULF WAR ILLNESSES

Prof. Garth L. Nicolson


The Institute for Molecular Medicine 
http://www.immed.org
15162 Triton Lane 
Huntington Beach, California 92649-1041 U.S.A.

 e-mail: gnicolson@immed.org
 TEL: +1-714-903-2900    
 FAX: +1-714-379-2082


 Gulf War Syndrome or Gulf War Illnesses (GWI) are a collection of chronic
illnesses reported by veterans of Operation Desert Storm (ODS, 1991).
Between 15 and 18% of the veterans of ODS returned and slowly (6-18 months
or more) presented with a variety of complex signs and symptoms
characterized by disabling fatigue, intermittent fevers, night sweats,
arthralgia, myalgia, impairments in short-term memory, headaches, skin
rashes, intermittent diarrhea, abdominal bloating, chronic bronchitis,
photophobia, confusion, transient visual scotomata, irritability and
depression and other signs and symptoms that until recently have defied
appropriate diagnoses (1-3).  GWI signs and symptoms are chronic, systemic
and in general cannot be placed into ICD-9 diagnosis categories.   Also,
routine laboratory test results are not consistent with a single, specific
disease (1), often resulting in veterans not receiving a clinical diagnosis
for their condition. GWI has been reported by various nations (except
France) who¹s forces were deployed against Iraqi units in ODS.  Possible
reasons for the French Forces escaping GWI casualties will be discussed
below as well as some of the possible exposures that occurred, the types of
illnesses that resulted from these exposures, and some of the treatments
that have been used on GWI patients.

ANALYSIS OF MULTIFACTORIAL ILLNESSES OF THE GULF WAR

Most investigators do not believe that GWI is a separate, new syndrome (2,
3).  It has been called Mucocutaneous-Intestinal-Rheumatic Desert Syndrome
by Murray-Leisure et al. (4), who placed patients into three broad
categories: (a) mucocutaneous lesions with pustular dermatitis, (b)
intestinal disorders with irritable bowels and (c) rheumatic lllnesses with
large-joint polyarthralgias and night sweats.  Minor criteria included:
heartburn, rectal fissures, bleeding or hemorrhoids, lactose or meat
intolerance, splenomegaly and splenic tenderness, weakness and/or chronic
fatigue, headaches, muscle aches, polymyalgias, memory loss, hair loss,
fevers of unknown origin, unexplained leukocytosis or neutropenia, nasal
ulcers or sores, chronic sinus or nasal congestion, atypical chest pain,
new-onset asthma or chronic bronchitis, ear infections or tinnitus and
dental infections.  Using factor analysis six syndrome categories were
described by Haley et al. (3) after studying 249 veterans of the U.S. Navy¹s
24th Reserve Mobile Construction Battalion.  The most important were (d)
impared cognition characterized by problems in attention, memory, reasoning,
insomnia, depression and headaches; (e) confusion-ataxia characterized by
problems with thinking, disorientation, balance, vertigo and impotencc; (f)
artho-myo-neuropathy characterized by polyarthralgias and myalgias, muscle
fatigue, difficulty lifting and extremity paresthesias (similar to c,
above); (g) phobia-apraxia; (h) fever-adenopathy; and (i)
weakness-incontinence.  The last three groups overlapped with groups d and e
and involved weaker clustering in their analysis (4). These groups differed
from Post-Traumatic Stress Disorder (PTSD), depression, somatoform disorder
and malingering (4).  Baumzweiger and Grove (5) have described GWI as
neuro-immune disorders that involve the central, peripheral and autonomous
nervous and immune systems.  They attribute a major source of illness to be
brainstem damage due to central, peripheral and cranial nerve neuropathy
with demyelination.  Their patients tended to have muscle spasms, memory
deficits, attention deficits, ataxia, and increased muscle tone, which are
often seen in neurotoxin-induced brain stem dysfunction (5).  GWI patients
can also have chronic bacterial and viral infections that are an important
source of morbidity and symptoms (2, 6, 7).

GWI are usually not fatal (8); however, there are now thousands of U. S.
veterans dead after service in ODS (6).  The possible reasons why these
deaths have not been reported in official studies could be due to the
limited sizes of study groups and time intervals used for analysis, the lack
of information on veterans who have left the Armed Forces, and the primary
use of military hospitals for such analyses (9).  In the U. S. estimates of
between 15,000 and 25,000 or more dead have been advanced, but the exact
figures are unknown.  The exact figures have not been carefully analyzed so
it is difficult to determine if ODS veterans are at higher risk than
non-deployed personnel.  Although for years the U. S Department of Defense
and the U. K. Ministry of Defense officially stated that there were no
unique illnesses associated with deployment to ODS (10), just the opposite
appears to be the case (3-6), although these studies have been questioned on
the basis that similar clusters can be found in non-ODS veterans deployed to
Bosnia (11).

In a case control study veterans with GWI have chronic illnesses at higher
rates than military personnel from the same units that were not deployed to
the Persian Gulf (10).  In the four units that were studied, the deployed
personnel had a variety of chronic illness signs and symptoms that were not
present at the same frequencies in non-deployed personnel (10).  For certain
signs and symptoms, this difference was dramatic (for example, over 13-times
difference in incidence of diarrhea).  This study showed that ODS deployment
was an underlying risk for contracting chronic illnesses.

GWI IS NOT PTSD

Since the signs and symptoms of GWI are not well established as criteria for
particular illnesses found in ICD-9 diagnosis categories (1-3), patients
have often been diagnosed with an "unknown" disorder, or a somatoform
disorder, such as Post-Traumatic Stress Disorder (PTSD) (1, 11, 12).  GWI
has a number of significant signs that are different from PTSD, such as
neuro-muscular problems, skin disorders, gastrointestinal problems, muscle
and joint pain and temperature abnormalities (intermittent fevers) (2-6).  A
recent psychiatric analysis indicates that PTSD cannot explain symptoms of
GWI with fatiguing illness (13).

The variable incubation time of GWI, ranging from months to years after
presumed exposure, the cyclic nature of the relapsing fevers and the other
chronic signs and symptoms and their appearance in immediate family members
are consistent with organic not psychological disease (2, 3, 5, 6).  The
syndromes most similar to GWI are Chronic Fatigue Syndrome (CFS) (or myalgic
encephalomyelitis, ME) and Fibromyalgia Syndrome (FMS) (2, 7).  We have
proposed that the signs and symptoms found in many GWI patients may be
caused by chronic exposures to chemical mixtures and host responses to
infectious agents, resulting in cytokine abnormalities and a variety of
other responses that result in a CFS/ME- or FMS-like disorder (2).  When the
signs and symptoms of GWI were compared to the signs and symptoms of CFS/ME,
the similarity was striking (Figure 1A,B) (7).  CFS/ME is characterized by
persistent or relapsing, debilitating fatigue or easy fatigability in a
person who has no previous history of similar symptoms, that does not
resolve with rest and is severe enough to reduce or impair average daily
activity below 50% of the patient's premorbid activity level.  In addition
to the absence of clinical conditions that could easily explain the
symptoms, such as malignancies or autoimmune diseases, patients present with
mild fever, sore throat, arthralgia, myalgia, generalized muscle weakness,
headaches, painful lymph nodes, sleep difficulties, and neuropsychologic
complaints, such as memory loss, photophobia, confusion, transient visual
scotomata, irritability and depression.  These signs and symptoms closely
parallel those found in GWI (Figure 1A,B) (7).  This suggests that GWI is
not a "new" syndrome; it is a CFS/ME/FMS-like disorder (2).  Interestingly,
patients with chronic illnesses that do not have evidence of chronic
infections do not display as many signs and symptoms as GWI or CFS/ME/FMS
(Figure 1A,B).

There are some differences between GWI and CFS/ME/FMS that may be important
in determining the various possible causes of GWI. Haley et al. (3) and
Baumzweiger and Grove (5) have stressed that unlike CFS/ME and FMS, GWI is
associated with ataxia and increased motor tone, symptomatic of brainstem
dysfunction, such as cranial nerve and peripheral nerve demyelination,
brainstem inflammation, limbic system involvement and personality behavioral
changes.  Using proton magnetic resonance to measure the ratio of plasma
homovanillic acid and 3-methoxy-4-hydroxyphenylgycol Haley et al. (14)
examined GWI patients for evidence of basal ganglia injury and found
reductions in the left basal ganglia dopamine production, supporting the
theory of brain stem injury to dopaminergic neurons in the basal ganglia.
The documentation of brain stem damage in GWI patients strongly suggests
that stress-related causes, such as PTSD, are very unlikely.  Although
stress can exacerbate chronic illnesses, stress alone is unlikely to be the
cause of more than a small fraction of GWI (11, 15).

POSSIBLE CAUSES OF GWI: CHEMICAL EXPOSURES

Part of the confusion in diagnosing GWI is that the overlapping chronic
signs and symptoms displayed by GWI patients can be caused by quite
different types of exposures.  Gulf War participants could have been exposed
to chemical, radiological and/or biological agents, or more likely
combinations of these (Figure 2) (3-7, 11, 12, 15).  Accurate diagnosis and
successful treatment of GWI cohorts will depend on identifying the
underlying exposures, because these illnesses are treated differently if
their origins are chemical, radiological or biological (15).

Gulf War veterans were exposed to a variety of chemicals, including
insecticides, such as the insect repellent N,N-dimethyl-m-toluamide and the
insecticide permethrin, battlefield smoke and fumes and smoke from burning
oil wells, the anti-nerve agent pyridostigmine bromide, solvents used to
clean equipment and a variety of other chemicals, including in some cases,
possible exposures to low levels of Chemical Warfare (CW) agents (15).  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
deployment of CW agents (12, 15).

Low level exposures to mixtures of chemicals, such as organophosphates, can
result in chronic illnesses (3, 5, 11, 15), including chronic neurotoxicity
and immune supression.  Abou-Donia and Wilmarth (16) found that 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.
Multiple Chemical Sensitivity Syndrome (MCS) and Organophosphate-Induced
Delayed Neurotoxicity (OPIDN) are examples of chronic illnesses caused by
multiple chemical exposures (Figure 2) (16).  Patients with these syndromes
can present with many (but not all) of the signs and symptoms found in GWI
patients, and in fact, many GWI cases may eventually be explained by complex
chemical exposures (3, 14, 16, 17).  In these patients, memory loss,
headaches, cognitive problems, severe depression, loss of concentration,
vision and balance problems, chemical sensitivities, among others, typify
the types of signs and symptoms found in chronic chemically exposed patients
(16, 17).  Arguments have been advanced that such exposures do not explain
GWI or that they may only be useful for a small subset of GWI patients (11),
but these arguments are for the most part are based on reviewing studies on
the effects of single agent exposures, not the multiple, complex exposures
that were most likely encountered by veterans of ODS.  Since it is unlikely
that any one type of exposure will explain the multiple signs and symptoms
found in GWI patients, studying subsets or clusters of patients is not as
limiting as has been suggested (11).

For most patients, the signs and symptoms of GWI began to present between
six months to two years or more after the end of the war.  This slow onset
of clinical signs and symptoms in chemically exposed individuals is not
unusual for Organophospate-Induced Delayed Neurotoxicity (OPIDN).  As
mentioned above, exposure to organophosphates was probably quite common in
ODS veterans .  That delayed, chronic signs and symptoms similar to OPIDN
were caused by multiple low-level exposure to nerve agents, anti-nerve
agents and other organophosphates remains a distinct possibility (18),
especially in certain subsets of GWI patients (16).  This is considered
unlikely by Sartin (11), who argued that low-level single agent exposures do
not usually cause OPIDN.

Low levels of CW agents were present in the Persian Gulf region from the
bombing of CW factories and storage facilities (and their demolition after
the war), and the probable offensive use of CW delivered by SCUD B (SS1)
missiles, aircraft or vehicles outfitted with CW sprayers or by artillery
shells and rockets, CW mines and other sources (12, 15, 19).  Iraqi Armed
Forces were known to have extensive stores of such weapons, and intelligence
reports indicated that orders to use offensive CW agents were given.  In
testimony to the U. S. Congress, Army CBW officers indicated that over
14,000 CW alarms sounded during but not before or after the ODS air/ground
offensive, and some soldiers were given medals for identifying the types of
CW that were released  (19).  Extensive stockpiles of mustard (blister agent
HN or HT), lewisite (blister agent L), sarin (nerve agent GB or GF), tabun
(nerve agent GA) and other CW agents were present in the region, and an
unknown quantity of these weapons were released into the atmosphere during
the air campaign and by the destruction of Iraqi storage bunkers after the
conflict (12, 19).  That low level exposure to nerve agents combined with
anti-nerve agents and other organophosphate exposures may have resulted in
delayed casualties in at least some subsets of GWI is a possibility that
cannot be so easily dismissed (11).

POSSIBLE CAUSES OF GWI: RADIOLOGICAL EXPOSURES

Depleted uranium (DU) was used extensively in ODS, and it remains an
important contaminant of the battlefield (6).  DU, a by-product of uranium
processing, was used in armor-penetrating ammunition and in protective armor
on tanks and other vehicles.  Depleted uranium contains about 30% U-235, a
dangerous radioisotope with a half-life of over 4 billion years (6).  When a
DU penetrator hits an armored target, it disintegrates due to the resulting
kinetic energy transfer that results in extreme heat and formation of
uranium oxide particles.  The uranium oxide particles that form are usually
small, and due to their high density they settled quickly onto vehicles,
bunkers and onto the surrounding sand where they could be easily inhaled.
One particle of <5 µm in diameter trapped in the pulmonary system for one
year can result in 272-times the annual whole body radiation dose permitted
U.S. radiation workers (6).  Fortunately, exposure can be monitored, and
studies on DU exposures should be initiated as soon as possible to determine
the prevalence and extent of uranium oxide exposure.

In addition to battlefield DU contamination, civilian nuclear reactors in
Iraq were destroyed during the air campaign.  This may have resulted in the
release of long half-life isotopes like Sr-90, U-235, or Co-90.  This could
have resulted in some blow-back exposures, since the prevailing winds in the
region were generally unfavorable.  Unfortunately, there appears to be no
available assessment of regional contamination from the release of nuclear
reactor materials (15).

POSSIBLE CAUSES OF GWI: ENVIRONMENTAL EXPOSURES

In addition to the chemicals released by burning oil well fires and ruptured
petroleum pipelines, soldiers were exposed to fine, blowing sand.  The small
size of sand particles (~ 0.1 mm) and the relatively constant winds in the
region resulted in some inhalation.  The presence of small sand particles
deep in the lungs can produce a pulmonary inflammation disorder that can
progress to pneumonitis or Al-Eskan Disease (20).  This usually presents as
a pneumonia or flu-like condition that can eventually progress to more
widespread signs and symptoms, including fibrosis, immunosuppression and
opportunistic infections.  Although it is extremely doubtful that many GWI
patients have Al-Eskan Disease, the presence of silica-induced immune
suppression in some soldiers could have resulted in the appearance of
opportunistic chronic infections in these patients (12, 15).

POSSIBLE CAUSES OF GWI: BIOLOGICAL EXPOSURES

Parasites such as Leishmaniasis and Schistosomiasis and bacteria that cause
Malaria and Cholera  are endemic to the Middle East and could be the cause
of illnesses in at least some of the veterans with GWI (4).  Characteristic
signs and symptoms occur in these illnesses, and diagnostic tests are
available for most of these agents.  Moreover, there have been no reports
that they are the cause of illness in large numbers of GWI patients (15).
In some patients infections by Leishmania tropica, spread by the sandfly
Phlebotomus papatasi, can result in viscerotropic Leishmaniasis and elevated
temperature, lymphadenopathy and hepatosplenomegaly (21).   However, most of
the common signs and symptoms of GWI do not fit with this explanation, and
diagnosis of Leishmaniasis is relatively uncommon (estimated at less than
one hundred) in Gulf War veterans.

Biological toxins were also present (15).  The Iraqi Army had ample stores
of aflatoxin (Aspergillus flavus toxin), ricin (from Ricinus communis
beans), Clostridium botulinum toxin and possibly other toxins.  They also
had tricothecene mycotoxins produced by various species of fungi that can
act quickly by direct cutanous contact and cause erythema accompanied by
blisters, wheezing, pain and burning sensations.  Some of these toxins can
be fatal in very low doses (inhaled ricin in extremely small doses can cause
inflammation of the respiratory mucosa with hemorrhage into the lungs or
edema, hemorrhage of the GI tract and death within 8-72 hours) or cause
delayed carcinogenic or immunosuppressive effects (aflatoxin).  The
preferred method of delivery of these toxins was by BW sprayer onto the sand
or by aircraft (12, 15).  Over 50 Italian-made BW sprayers were found fully
deployed in Southern Iraq and Western Kuwait, and aircraft fitted with BW
sprayers were captured at airfields in Southern Iraq.

In one subset of GWI patients Murray-Leisure et al. (4) have described an
association with cutaneous sand exposure.  This is most likely caused by a
chronic transmittable infection found in sand that is endemic to the region,
such as Bacillus anthracis or Brucella species.  The risk for
sand-associated illness appeared to be highest in the fall.  Although no
infections were ever identified, the slow appearance of the same signs and
symptoms in spouses and children of veterans with GWI suggested that a
slow-growing microorganism was being transferred (4).  Anthrax, caused by
the Gram-positive Bacillus anthracis, a commonly used BW agent, is found in
soil.  It can gain entrance through skin wounds but also by inhalation or
ingestion.  Anthrax infection does not result in a chronic illness, because
its signs and symptoms, such as malaise, fever, fatigue, headache,
respiratory distress and other more severe signs and symptoms, usually
appear within 1-6 days of exposure.  That anthrax exposure caused a subset
of GWI is unlikely since the usual signs and symptoms of anthrax exposure
were not reported in ODS veterans (15).

There is evidence for the presence of transmittable infectious agents in GWI
patients.  In many cases, the veterans' immediate family members appear to
have the same or similar signs and symptoms (7, 22, 23).  One estimate
derived from inquiries of >1,200 GWI families indicated that approximately
77% of spouses and 65% of children born after the war now have the signs and
symptoms of GWI (24).  When immediate family members presented with the same
or similar illness, the onset of their GWI signs and symptoms usually
occurred from 6 months to one year or more after the onset of the veteran's
illness, and not every family member developed GWI signs and symptoms.
Because of the apparent slow rate of transmission to immediate family
members, the general public is probably not at high risk for contracting GWI
from casual contact with GWI patients (4, 7).

Veterans with transmittable biological exposures could have received these
through natural contact (soil, water, etc.) or from other types of exposures
(15).  Infectious agents have been found in GWI patients' urine (6) and
blood (7, 22, 23).  Using a microscopic technique for determining bacterial
infections in urine, Hyman (25) has found evidence of bacterial infections
in GWI patients that can be successfully treated with several courses of
broad spectrum antibiotics.  We found that most of the signs and symptoms in
subsets of GWI patients can be explained by chronic pathogenic bacterial
infections, such as mycoplasmal infections (7, 15, 22, 23).  Mycoplasmal
infections usually produce relatively benign diseases limited to particular
tissue sites or organs, such as urinary tract or respiratory infections
(26).  However, the types of mycoplasmas that we have detected in ODS
veterans, such as Mycoplasma fermentans, are very pathogenic, colonize a
variety of organs and tissues, and are difficult to treat (16, 17).  In
studies of over 300 patients, including both U. S. and British veterans with
GWI and their symptomatic family members, evidence of mycoplasmal infections
has been found in just under one-half of the GWI patients' blood (22, 23,
27, 28).  The incidence of mycoplasmal infections in nondeployed, healthy
subjects was found to be approximately 6-9% (reviewed in 28).  The
appearance of mycoplasmas in the leukocytes of some controls could indicate
that these individuals are in a very early stage of the illness or that they
are nonsymptomatic carriers of the infection.

Since the subgroup of mycoplasma-positive patients may be more symptomatic
than the average GWI patient, it is likely that the final incidence of
mycoplasmal infections in GWI will be lower than the incidence rate reported
above (28).  Over 80% of mycoplasma-positive GWI patients had Mycoplasma
fermentans infections, and this has now been confirmed in a large VA study.
Interestingly, when civilian patients with CSF/ME or FMS were examined for
systemic mycoplasmal infections, high frequencies of mycoplasmal infections
were also found (approximately 60%), indicating another link between these
disorders, but in addition to M. fermentans several other species of
mycoplasmas were found in CSF/ME and FMS (27-29).  The types of assays
performed in these studies were molecular tests of active infections, using
polymerase chain reaction (26-29), and not antibody tests (11), because the
latter do not usually detect intracellular mycoplasmas that do not elicit a
strong antibody response (7, 26).  The presence of mycoplasmal infections
could also explain the recent observation of activation of the coagulation
system in GWI patients (30), since mycoplasmal infections can cause these
changes.

Other chronic infections have also been found in GWI patients.  For example,
in contrast to official reports (31), there is some preliminary evidence for
Brucella infections (Unpublished observations).  Inhalation of Brucella
spp. (Brucella melitensis strains predominantly) can cause the slow onset of
brucellosis, a chronic illness that shares many but not all of the signs and
symptoms of GWI.  Other possible infections include Q Fever (32), caused by
Coxiella burnetii, anthrax caused by Bacillus anthracis, botulism caused by
the botulinum toxin released from Clostridium botulinum, Yersinia pestis, a
gram-negative, non-spore forming bacillus obtained from the bite of insects
(fleas), Malaria, caused by P. falciparum or P. vivax from the bite of
infected Anopheline mosquitos and other possible infectious agents.  The
prevalence of these infections has not been determined in GWI patients but
it is likely to be low.

One possible source for chronic bacterial infections is the multiple
vaccines that were used in ODS. Unwin et al. (33) found an association of
GWI with the multiple vaccines received during deployment.  In the U.S.
there have been GWI signs and symptoms in personnel who recently received
the anthrax vaccine.  In some cases this has resulted in chronic illnesses
in as many as 7-10% of personnel receiving the vaccine (34).  Some of the
chronic signs and symptoms associated with anthrax vaccination are very
similar to those found in GWI patients, suggesting that at least some of the
chronic illnesses suffered by veterans of the 1991 Gulf War may have been
caused by multiple vaccines in combination with other exposures (33, 34).
Relatively minor microorganism contaminants in vaccines could have resulted
in illness in chemically exposed, immune depressed individuals.  The French
forces deployed to ODS did not receive multiple vaccines to protect against
biological warfare agents, and this may turn out to be one of the most
important reasons why the French reported few if any GWI cases.  The other
possible reasons were the locations of French forces and the types of
protective suits used in ODS.

TREATMENT OF GWI

The treatment of chemically exposed patients usually involves removal of
offending chemicals from the patients¹ environment, depletion of chemicals
from the patients¹ system and treatment of the signs and symptoms caused by
chemical exposures (15, 24).  Chemically exposed patients are often
extremely sensitive to a variety of commonly encountered chemicals,
including perfumes and air freshners, petrochemical fumes, chlorine,
cleaning solutions and solvents, among others.  They are also very sensitive
to certain foods, and special diets are often necessary, and in some cases
direct skin contact with certain substances can cause strong cutaneous
reactions.  An important part of treatment for chemical exposures requires
limiting future exposures to a variety of common chemicals and removal of
toxic chemicals (15, 35).

Patients with MCS or OPIDN benefit from procedures that slowly remove
offending chemicals from their bodies.  We recommend dry saunas for help in
chemical removal, as well as magnesium sulfate-hydrogen peroxide baths (35).
Some GWI patients may have irreversible nerve damage due to organophosphate
exposure or low level nerve agent exposure potentiated by the effects of the
antinerve agent pyridostigmine bromide, and it may be difficult to reverse
their condition.  Chemicals can be reduced through a program of heat
depuration, physical therapy and nutritional supplementation in a special
environment (35).  In addition to heat, exercise and diet, a variety of
medications may alleviate some of the signs and symptoms of chemical
exposures in GWI patients.  Many patients have benefited from anti-anxiety,
anti-depressant and anti-inflammatory drugs (5), but this may not be
beneficial for some GWI patients, especially those with biological
exposures.

The successful treatment of patients exposed to DU depends on reducing the
body burden of U-235.  Such particles can remain inert in the lungs for
extended periods of time, resulting primarily in local tissue alpha
irradiation and the resulting radiation damage and immune suppression.  In
time the U-235 moves to the bones where it can be difficult to remove.
Systemic U-235 can be slowly removed by chelation therapy, usually with
ethylenediaminetetraacetic acid (EDTA) or penacillamine (15).

Infectious microorganisms can be treated with the appropriate antibiotics.
Treatment with antibiotics can result in improvement and even recovery in
patients exposed to bacteria or mycoplasmas such as M. fermentans (22, 23).
The recommended treatments for systemic mycoplasmal infections require
long-term antibiotic therapy, usually at least 6-12 months of doxycycline,
ciprofloxacin, azithromycin or clarithromycin (36).  Long-term treatments
are required, because few patients recover after only a months treatment
(23), possibly because of the intracellular locations of mycoplasmas, the
slow-growing nature of these microorganisms and their inherent resistance to
antibiotics (37). Once patients recovered and were able to return to active
duty or normal activity, mycoplasma gene sequences could no longer be
detected in their blood leukocytes.  These clinical responses were not due
to placebo effects, because administration of some antibiotics that are not
effective against mycoplasmal infections, such as penicillins, resulted in
patients becoming more not less symptomatic, and they are not due to
immunosuppressive effects that can occur with some of the recommended
antibiotics.  Interestingly, CFS/ME, FMS and GWI patients with systemic
infections that slowly recover on antibiotic therapy are generally less
environmentally sensitive, suggesting that their immune systems may be
returning to pre-illness states.  If such patients had illnesses that were
caused by psychological or psychiatric problems or solely by chemical
exposures, they should not respond to the recommended antibiotics and slowly
recover.   In addition, if such treatments were just reducing autoimmune
responses, then patients should have relapsed after the treatments were
discontinued.

SUMMARY

Gulf War Illnesses (GWI) can produce complex signs and symptoms, such as
polyarthralgia, chronic fatigue, short-term memory loss, sleep difficulties,
headaches, intermittent fevers, skin rashes, diarrhea, vision problems,
nausea, breathing and heart problems and other signs and symptoms.  Although
there is not yet a case definition for GWI, the chronic signs and symptoms
loosely fit the clinical criteria for Chronic Fatigue Syndrome/Myalgic
Encephalomyelitis and/or Fibromyalgia Syndrome.  Some patients have
additionally what appears to be neurotoxicity and brainstem dysfunction that
can result in autonomic, cranial and peripheral nerve demyelination,
possibly from complex chemical exposures.  Often these patients have been
diagnosed with Multiple Chemical Sensitivity Syndrome (MCS) or
Organophosphate-Induced Delayed Neurotoxicity (OPIDN).   Chemically exposed
patients can be treated by removal of offending chemicals from the patient's
environment, depletion of chemicals from the patient's system and treatment
of the neurotoxic signs and symptoms caused by chemical exposure(s).  A
rather large subset (~40%) of GWI patients have systemic infections,
including mycoplasmal and other chronic bacterial infections, that are
probably responsible for the appearance of GWI in immediate family members.
These infections can be treated with antibiotics, vitamin and nutritional
supplementation.  It is likely that GWI patients owe their illnesses to a
variety of exposures:  (a) chemical mixtures, primarily organophosphates,
anti-nerve agents and possibly nerve agents, (b) radiological sources,
primarily depleted uranium and possibly fallout from destroyed nuclear
reactors, and (c) biological sources, primarily bacteria, such as M.
fermentans, and toxins, before, during and after the conflict.  The multiple
vaccines used in ODS are a prime suspect for chronic infections.  The
multiple, complex exposures during ODS resulted in poorly defined chronic
illnesses, but subsets of GWI can be treated using appropriate procedures.

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 6. Nicolson GL, Hyman E, Korényi-Both A, et al.  Progress on Persian Gulf
War Illnesses: reality and hypotheses.  Intern J Occup Med Tox  1995;
4:365-370.

 7. Nicolson GL, Nasralla M, Franco AR, et al. Diagnosis and Integrative
Treatment of Intracellular Bacterial Infections in Chronic Fatigue and
Fibromyalgia Syndromes, Gulf War Illness, Rheumatoid Arthritis and other
Chronic Illnesses. Clin Pract Alt Med 2000; 1:92-102.

8. Writer JV, DeFraites RF, Brundage JF.  Comparative mortality among US
military personnel in the Persian Gulf region and worldwide during
Operations Desert Shield and Desert Storm.  JAMA 1996; 275:118-121.

9. Leisure KM, Nicolson NL, Nicolson, GL.  Hospitalizations for unexplained
illnesses among U.S. veterans of the Persian Gulf War.  Emerg Infect Dis
1998; 4:707-709.

10. Kizer KW, Joseph S, Rankin JT. Unexplained illness among Persian Gulf
War vetrans in an Air National Guard unit: preliminary report--August
1990-March 1995.  Morb Mortal Weekly  Rep 1995; 44: 443-447.

11. Sartin JS. Gulf War Illnesses: causes and controversies.  Mayo Clin Proc
2000; 75:811-819.

12. Nicolson GL, Nicolson NL.  Gulf War Illnesses: complex medical,
scientific and political paradox.  Med Confl Surviv  1998; 14: 74-83.

13. Lange G, Tiersky L, DeLuca J et al. Psychiatric diagnoses in Gulf War
veterans with fatiguing illness.  Psychiatry Res 1999; 89:39-48.

14. Haley RW, Fleckenstein JL, Marshall WW, et al.  Effect of basal ganglia
injury on central dopamine activity in Gulf War Syndrome: correlation of
proton magnetic resonance spectroscopy and plasma homovanillic acid levels.
Arch Neurol 2000; 280:981-988.

15. Nicolson GL, Nasralla M, Haier J, et al. Gulf War Illnesses: Role of
chemical, radiological and biological exposures. In: War and Health, H.
Tapanainen, ed., Zed Press, Helinsiki, 2000.

16. Abou-Donia MB, Wilmarth KR.  Neurotoxicity resulting from coexposure to
pyridostigmine bromide, DEET and permethrin: Implications of Gulf War
exposures.  J Tox Environ Health 1996; 48:35-56.

17. Haley RW, Kurt TL.  Self-reported exposure to neurotoxic chemical
combinations in the Gulf War: a cross-sectional epidemiologic study.  JAMA
1997; 277:231-237.

18. Gordon JJ, Inns RH, Johnson MK et al. The delayed neuropathic effects of
nerve agents and some other organophosphorus compounds.  Arch Toxicol 1983;
52:71-82.

19. Eddington PG. Gassed in the Gulf. Washington D.C.: Insignia Publishing,
1997.

20. Korényi-Both AL, Molnar AC, Korényi-Both AL, et al. Al Eskan disease:
Desert Storm pneumonitis. Mil Med 1992;157:452-462.

21. Magill AJ, Grogl M, Fasser RA, et al.  Viscerotropic leishmaniasis
caused by Leishmania tropica in soldiers returning from Operation Desert
Storm.  N Engl J Med 1993; 328:1383-1387.

22. Nicolson GL, Nicolson NL.  Diagnosis and treatment of mycoplasmal
infections in Persian Gulf War Illness-CFIDS patients.  Intern  J Occup Med
Immunol Tox 1996; 5:69-78.

23. Nicolson GL, Nicolson NL, 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.

24. U. S. Senate Committee on Banking, Housing and Urban Affairs.  U. S.
chemical and biological warfare-related dual use exports to Iraq and their
possible impact on the health consequences of the Persian Gulf War , 103rd
Congress, 2nd Session, Report: 103-900, May 25, 1994.

25. Hyman ES.  A urinary marker for systemic coccal disease.  Nephron  1994;
68: 314-326.

26. Nicolson GL, Nasralla M, Haier J, et al.  Diagnosis and treatment of
chronic mycoplasmal infections in Fibromyalgia and Chronic Fatigue
Syndromes: relationship to Gulf War Illness.  Biomed Ther  1998; 16:266-271.

27. Vojdani A, Franco AR.  Multiplex PCR for the detection of Mycoplasma
fermentans, M. hominis and M. penetrans in patients with Chronic Fatigue
Syndrome, Fibromyalgia, Rheumatoid Arthritis and Gulf War Illness.  J
Chronic Fatigue Syndr  1999; 5:187-197.

28. Nicolson GL, Nasralla M, Franco AR, et al.  Mycoplasmal infections in
fatigue illnesses: Chronic Fatigue and Fibromyalgia Syndromes, Gulf War
Illness and Rheumatoid Arthritis.  J Chronic Fatigue Syndr 2000;
6(3/4):23-39.

29. Nasralla M, Haier J, Nicolson GL.  Multiple mycoplasmal infections
detected in blood of Chronic Fatigue and Fibromyalgia Syndrome patients. Eur
J  Clin Microbiol Infect Dis 1999; 18:859-865.

30. Hannan KL, Berg DE, Baumzweiger W, et al.  Activation of the coagulation
system in Gulf War Illnesses: a potential pathophysiologic link with chronic
fatigue syndrome, a laboratory approach to diagnosis.  Blood Coagulat
Fibrinol 2000; 7:673-678.

31. DeFraites RF, Wanat ER, Norwood AE, et al.  Report: Investigation of a
suspected outbreak of an unknown disease among veterans of Operation Desert
Shield/Storm, 123d Army Reserve Command, Fort Benjamin Harrison, Indiana,
April, 1992. Epidemiology Consultant Service (EPICON), Division of
Preventive Medicine, Walter Reed Army Institute of Research, Washington, DC.

32. Ferrante MA, Dolan MJ. Q fever meningoencephalitis in a soldier
returning from the Persian Gulf war.  Clin Infect Dis 1993; 16:489-496.

33. Unwin C, Blatchley N, CokerW, et al. Health of UK servicemen who served
in the Persian Gulf War.  Lancet  1999; 353:169-178.

34. Nicolson GL, Nass M, Nicolson NL. The anthrax vaccine controversy.
Questions about its efficacy, safety and strategy.  Med  Sentinel 2000;
5:97-101.

35. Rea WJ, Pan Y, Johnson AR, et al.  Reduction of chemical sensitivity by
means of heat depuration, physical therapy and nutritional supplementation
in a controlled environment.  J Nutrit Environ Med 1996; 6: 141-148.

36. Nicolson GL.  Considerations when undergoing treatment for chronic
infections found in Chronic Fatigue Syndrome, Fibromyalgia Syndrome and Gulf
War Illnesses. (Part 1). Antibiotics Recommended when indicated for
treatment of Gulf War Illness/CFIDS/FMS. (Part 2).  Intern J Med  1998; 1:
115-117, 123-128.

37. Nicolson GL, Nasralla M, Nicolson NL. The pathogenesis and treatment of
mycoplasmal infections. Antimicrob Infect Dis Newsl 1999; 17:81-88.

FIGURE LEGENDS

Figure 1. Figure 1A and 1B.  Incidence of increase in severity of signs and
symptoms in 300 chronic illness patients.  Severity of illness was scored
using 118 signs and symptoms on a 10-point scale (0, none; 10 extreme) prior
to and after the onset of illness.  Scores were placed into 29 categories
containing 3-9 signs/symptoms and were recorded as the sum of differences
between values before and after onset of illness divided by the number of
questions in the category.  Changes in score values of 2 or more points were
considered relevant.  Patient groups were: CFS/ME, FMS, GWI and chronic
illness patients without evidence of bacterial infection.  The patients
groups had the following incidence of Mycoplasma species infections: CFS/ME,
56.1%; FMS, 64%; GWI, 44.5%; Other chronic illness patients, 0%.  Asterisk
(*) indicates score = 0.

Figure 2. Multiple exposures (chemical, radiological, biological) or
multifactorial causes may have resulted in GWI in susceptible individuals
(modified from reference 15).

ABOUT THE AUTHOR

Prof. Garth L. Nicolson is the President and Chief Scientific Officer of the
Institute for Molecular Medicine in Huntington Beach, California.  He was
formally the David Bruton Jr. Chair in Cancer Research and Professor and
Chairman at the University of Texas M. D. Anderson Cancer Center in Houston
and he was Professor of Internal Medicine and Professor of Pathology and
Laboratory Medicine at the University of Texas Medical School at Houston.
He was also Professor of Comparative Pathology at Texas A & M University.
Among the most cited scientists in the world, having published over 515
medical and scientific papers (including 3 Current Contents Citation
Classics), edited 14 books, and has 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).  Dr. Nicolson has won many awards, such as the Burroughs
Wellcome Medal of the Royal Society of Medicine, Stephen Paget Award of the
Metastasis Research Society and the National Cancer Institute Outstanding
Investigator Award.