Here we address a general issue raised by questions about the "Persian Gulf
Syndrome" and toxic exposure to troops engaged in the Persian Gulf War: where
and how does a new category of illness or disease become established, and how
can that process be improved? Persian Gulf War veterans have reported health
problems that many suggest are related to service in that war during the period
1990-1991. A variety of complaints have been recorded by health care providers
throughout the country, but, for the most part, these have not resulted in a
clear diagnosis or explanation except for a very small number of complaints
which have led to clear diagnoses such as leishmaniasis or malaria. Several
distinguished review panels have examined the evidence that service in the Gulf
is related to alleged chronic health problems (1-6). While these reviews have
caused participants to be impressed and concerned about the veterans'
complaints, no review panel has arrived at a definitive understanding of the
veterans' illnesses. The review panels generally agree that there is unlikely
to be a single explanation for the veterans' complaints. Consequently, health
scientists supported by both private and public funds have been engaged in
laboratory, clinical, and epidemiologic studies to find the cause or causes of
Stress related to war, historically associated with health problems (7), as
well as particular features of the Gulf War (major involvement of reserve
troops, first major conflict with a volunteer force, substantial number of
women soldiers) have been regularly cited as important contributors to
complaints and disability among Gulf War veterans. An unknown number of
complaints are simple those unexplained symptoms and illnesses experienced in
any large population. (Almost 700,000 troops were present at some time during
Operation Desert Shield/Storm.)
The absence of clear explanations for most of the illnesses has frustrated the
veterans as well as health scientists. The Department of Defense's very late
release of information about potential exposure of some of the troops to
chemical or biologic weapons has tended to confirm the belief that the real
causes of the illnesses are being covered up. Contributing to this view are
the absence of adequate medical records about who received special
immunizations that were not in general use (anthrax and botulinum), and about
the use of pyridostigmine bromide pills to counter the anticipated effects of
nerve gases (1). In addition, cutbacks in and limited use of field
epidemiology staff appear to have resulted in inadequate collection and
maintenance of objective information about the biologic or environmental risks
experienced by service personnel in the Gulf region. Given this serious lack
of information about risk factors, many believe that the causes of illnesses
for most of the veterans will never be known.
Confusion With Stress
Despite these problems, some investigators and clinicians treating affected
veterans have continued to seek explanations for those illnesses as well as
effective means of treatment. The suggestion that stress plays an important
role has been largely rejected by the veterans and some of their caregivers.
Instead, suggestions have been made that the illnesses are the expression of
one of several poorly understood syndromes, a result of exposure to agents with
poorly understood health effects, or explained by unconfirmed hypotheses
regarding altered metabolism. Some of the various explanations have included:
syndromes such as chronic fatigue syndrome, fibromyalgia, and multiple chemical
sensitivity, exposure to agents such as depleted uranium, smoke from oil-well
fires, and dental amalgams, and hypotheses about altered metabolism described
as oxidated phosphorylation disorder, brainstem dysregulation syndrome, and
chemically induced porphyria (1).
It is unlikely that any of these hypotheses will provide a unifying explanation
for the problems. Most will not stand the test of time. However, in this
issue of the Journal, Haley(8) calls attention to the inadequacies in
studies that have been cited in support of war-related stress as the major
explanation of the illnesses. While epidemiologists may argue with the
particular approach he takes to adjusting estimates of prevalence of
post-traumatic stress syndrome, Haley's article calls attention to the fact
that stress is at least as difficult to study as some of the other hypotheses
suggested. He argues that investigators should not attribute the veterans'
problems to stress simply because the evidence needed to study physical factors
is not available.
The need for caution that Dr. Haley advises is well taken when one is trying to
identify causal factors. The difficulty in studying stress, however, is no
more reason to reject the role of stress in the veterans' illnesses than it is
a reason to reject physical causes. Landrigan (9) summarized the reason to
include stress in the study and treatment of veterans"
As a nation, we need to get beyond the fallacious idea that diseases of the
mind either are not real or are shameful, and to better recognize that the mind
and the body are inextricably linked (9. p.261)
The Core Issue
The many efforts to understand illnesses in Gulf War veterans call attention to
a poorly recognized problem faced by all investigators who study any purported
new condition or disease. Plaguing all such investigations is the fact that
there is no readily accepted process by which medical science determines that a
previously unrecognized disease should become "recognized."
Several schemes have been proposed for evaluating whether some specified
exposure (broadly defined) causes some specified illness (table 1). For
example, the 1964 report of the Surgeon General's advisory committee on smoking
and health (10) included a list of criteria for causality. Hill (11) published
a frequently cited list in 1965; both reports focused on inferences of cause
and effect from observational data. Much earlier, Koch published "postulates"
about cause-effect inferences in the etiology of infectious disease (12,
pp.22-23). Evans attempted to expand Hill and Koch's criteria to all types of
disease by elaborating ten "Criteria for Causation" (13).
All of these efforts, however, address the relation between some
identified exposure and some recognized health outcome. The
present task is different: it is to determine whether there is another kind of
outcome, either new or not previously recognized, that should be added to our
understanding about human disease. If the answer to this last inquiry is
"Yes," the criteria of Koch, Hill, and/or Evans may then be appropriate
in efforts to further understand this newly described outcome.
In considering criteria that should inform decisions about new diseases, it is
important to consider the different objectives that might be served by
determining that a previously unrecognized condition should be added to the
disease lexicon. For physicians, the primary objective is the need to arrive
at a consensus on diagnostic criteria that will ultimately serve as the basis
for determining appropriate clinical approaches to evaluation, treatment, or
prevention of the condition in persons who may be affected. In addition,
clear diagnostic criteria are needed to determine who suffers from the
condition and sometimes in what degree, so that natural history of the
condition can be studied successfully. These studies can identify relevant
risk factors and etiologic agents that cause the condition and provide a basis
for both treatment and prevention. Some would call this new nosologic entity.
Proper diagnosis and identification of the causal agent (s) for each individual
may also provide the basis (in the United States) for determining who is to pay
for the care of the individual.
For the individual suffering from a candidate for a new nosologic
identification, correct identification of the condition is important so that
proper care or treatment for that condition can be sought. Other benefits of
proper identification include: avoidance of further diagnostic tests that may
be futile and expensive and meeting the need many people have for "diagnostic
closure." In this regard, Eisenberg (14) has emphasized the important
conceptual difference between what he refers to as an illness and as a
To state if flatly, patients suffer "illnesses"; physicians diagnose and treat
"disease". Let me make clear the distinction I intend: Illnesses are
experiences of disvalued changes in states of being and in social
function; diseases in the scientific paradigm of modern medicine, are
abnormalities in the structure and function of body
organs and systems...Illness and disease, so defined, do not stand in a
one-to-one relationship. When disease is extreme...its persuasiveness makes
illness inevitable. However, disease may occur in the absence of illness...[By
contrast,] similar degrees of organ pathology may generate quite different
reports of distress, differences determined by culture, expectation and setting
Disease categories, therefore, should be understood to be a social
constructions reflecting consensus not only among health professionals but
among the lay public. People seeking explanations for their experiences of
poor health achieve consensus among themselves that a set of symptoms and/or
signs signifies something different from other known categories common in
their culture. This in turn often precipitates their contact with health care
professionals and other healers to confirm or reject the normality or
abnormality of the phenomenon.
Health professionals attempt to classify each condition recognized as a disease
within a standard framework or taxonomy of professional construction such as
the International Classification of Diseases (ICD) (15) or the Diagnostic
and Statistical Manual of Mental Disorders (DSM) (16) . When the
classification does not seem to capture important aspects of the condition
(unusual symptoms, presence or absence of recognized causative agents, response
to treatment, etc.), clinicians commonly seek to explain what the condition
represents and its possible etiology. This generally requires the development
of a biologically plausible explanation for the condition compatible with a
more general understanding or normal versus abnormal. This process can lead to
the proposal and acceptance of new disease categories that emerge ultimately as
the product of both lay (patient) and professional constrictions.
The setting of diagnostic criteria for a condition is ultimately a social
process, and as such is influenced by multiple social forces. Among these are:
1) belief systems prevalent in the culture/society about the phenomenon (i.e.,
the categories we have chosen to accept as legitimate) (17, 18); 2) power
relationships (who has the power to declare a phenomenon a disease, or abnormal
condition) (19); 3) consequences of the diagnosis (insurance coverage, social
ostracization); 4) dominant frames of reference for explaining the diagnosis
(e.g., clinician does or does not get paid; patient does or does not have
access to effective therapy).
When considered together, there are risks and benefits for patients , for
physicians, and for society when a new diagnostic category is invoked and acted
on. These were well summarized in the case of mitral valve prolapse, when
Quill et al. (21) examined the border between normal variants in the
population and the developing interest in characterizing a variant as a
disease. Here the risks and benefits they described have been supplemented by
adding consideration of not acting on a new diagnostic category.
Just as there are risks and benefits associated with diagnosing a disease,
there are also risks and benefits of not making a diagnosis. For patients, not
being assigned a diagnosis may imply that their complaints are not valid or
serious, or forestall treatment while an incorrect diagnosis may lead
to treatment that is inappropriate or harmful. For clinicians, the risk of not
making a diagnosis include losing the respect of one's patient (and potential
loss of income), but benefits include avoiding premature labeling and
consequent initiation of inappropriate therapy. Risks to the society of no
diagnosis may, for example, stigmatize individuals as malingering or feigning
illness, or allow an infectious condition to spread to others. Benefits of
making no diagnosis may include cost savings associated with no treatment and
availability of a larger segment of the population to contribute to the work of
society (because they are not excused by a diagnosis a problem may provide a
beneficial impetus for study to enlarge our understanding of what the problem
is, and development of accounts to predict and explain its occurrence.
Diagnostic categories have evolved over the years, resulting at intervals of
roughly ten years in a revision of formal codes for disease classification such
as the International Classification of Diseases (ICD) or the
Diagnostic and Statistical Manual of Mental Disorders (DSM). For the
most part, changes in these codifications represent refinements that result
from improved understanding of physio- or psycho pathology. Entirely new
disease categories generally emerge when there is recognition of a new
clustering of symptoms in a population, usually with replication of their
presentation across a series of patients. Once this happens, a provisional
nomenclature is applied to the phenomenon. Clinicians' confidence about
differentiating the new phenomenon from other known phenomena increases most
commonly when there are technological developments or an objective marker
(e.g., an etiologic test or a biopsy finding) that has a high probability of
differentiating those with, from those without, the condition. Although an
objective indicator is desirable, it may not be necessary and may not even
exist. Use of these indicators reflects clinicians' working models of
causation or of pathologic processes. Finally, as a consensus grows among
professionals, formal diagnostic criteria emerge and modification in a taxonomy
such as the ICD or DSM ensues.
While the above describes the general progression followed as a new disease
category becomes accepted, it does not indicate how this acceptance actually
In order to address the general concern that Persian Gulf veterans have some
new disease or diseases, we need to develop a way to group events or symptoms
into one or several classes that will eventually allow generalizations
regarding the events and their various causes. This requires that ill persons
be grouped into categories so that members of each category can be
distinguished from those of every other. The categories, in turn, need to be
distinguished from already existing categories.
The difficulty in accomplishing this goal is described by Susser (12):
The criteria of determinants and effects do not correspond with each other,
first because determinants have many effects and second because effects have
many determinants....A single experience can give rise to multiple and diverse
manifestations;...A single manifestation, on the other hand, can arise as a
consequence of multiple and diverse experiences....
(12, p. 45).
For example, there are many causes of inflammation, while cigarette smoking has
many health effects.
MacMahon and Pugh (22) provide some guidance by noting that two different types
of criteria, manifestational and causal, have been used to group ill persons:
1. Manifestational criteria: The ill persons are grouped according to their
similarity with respect to symptoms, signs, changes in body fluids or tissues,
physiologic function, behavior, prognosis, or some combination of these
features. Examples of diseases defined by manifestational criteria are
fracture of the femur, diabetes mellitus, mental retardation, the common cold,
schizophrenia, and cervical cancer.
2. Causal criteria: Here the grouping depends on the similarity of individuals
with respect to a specifies experience believed to be a cause of their illness.
Examples of diseases defined by causal criteria are birth trauma, silicosis,
syphilis and leading poisoning (22, p. 48).
MacMahon and Pugh describe several additional important features related to the
task of defining a new disease. First, they call attention to the fact that
"Polymorphous effects of newly isolated causal agents may be understood, indeed
expected" (22, p. 49). In this regard, they refer to the many different
illnesses associated with cigarette smoking. Equally, they note that a causal
agent may not be associated with all those who are ill with the particular set
Finally they note that:
In the absence of knowledge of causal factors, manifestational criteria provide
the only basis for...classification. Here the setting of the limits of disease
entities appears to be a highly intuitive process, having as a governing
principle the assumption that the greater the similarity of the manifestations
of illness, the more properly the illness of the persons exhibiting the
manifestations may be considered an entity (22, p. 51).
It is rare that a first effort at collecting a set of manifestations will prove
to be the final characterization of a disease. Increased attention to and
study of the condition may lead to more precise criteria for diagnosis as well
as some redefinition of the condition. Indeed, it has been suggested that the
patient described by Alzheimer (23) did not have what we now call Alzheimer's
disease (16). Such diagnostic "drift" is not rare. Moreover, the more
heterogeneous the presentations and potential causes, the more difficult it
will be to define a new disease or syndrome. The knowledge that accrues after
the "disease" is first defined, however, allows, amendments that contribute to
better specification of the condition. Ultimately, the "disease" may be
grouped with others or separated into more than one category as the newly
defined condition comes under systematic study.
For example, after evidence had been gathered on two separately defined disease
categories spinabifida and anencophaly, the natural history of the two disease
in a variety of populations suggested they could be reasonably considered as
one entity now known as "neural tube defect." Conversely, there was a time
when two patients, one with typhoid and one with typhus infections but each
presenting with a high fever and rash, would have been diagnosed as having the
same disease. Isolation of causative agents and better specification of the
disease course led to recognition that these were two quite distinct diseases
requiring separate diagnostic categories. In similar situations today, further
study of an initial disease definition generally leads to improved
understanding of the disease and its determinants, which in turn leads to a
change over time in the manifestations of the disease that are considered as a
central to its definition (24). Sometimes the definition of disease may shift
entirely from being based on clinical history and physical examination to the
related physiologic or laboratory observations, as has occurred with
hypertension and osteoporosis.
Proposed Steps In The Analysis
Recognizing that the process of defining a new disease is necessarily
iterative, we propose five criteria to initiate this process and evaluate the
evidence that a new disease, or a new category of diseases, should be
recognized. No single step is indispensable; they are meant, rather, to guide
analysis and to provide some structure to deal with a problem that may be
difficult to resolve.
1. Difference from known conditions
The complex of signs, symptoms, and/or other findings, must be
sufficiently different from recognized disease entities or syndromes to merit a
new designation at some level of the diagnostic hierarchy. There may be a
conceptual problem in determining that some condition is a separate entity
versus a variant of something already recognized. There will always be
boundary problems between illness and health. An answer of "Yes" requires a
complete and accurate description of the new entity and of how it differs from
entities already recognized.
An example of a currently evolving syndrome that may ultimately be accepted as
a news disease is chronic fatigue syndrome. While variants of this syndrome
have been traced back possibly as early as Hippocrates, the assignment of
causal mechanisms over the course of the 19th and 20th centuries seems to
reflect more the emerging understanding of more general disease processes than
well-studied specific causal links (20). In the 19th century, a focus on the
nervous system was associated with a condition neurasthenia, while the
mid-20th century's attention to infection characterized a similar condition as
chronic brucellosis. In the second half of this century, new emphasis on
endocrinology led to the suggestion that hypoglycemia was the explanation for
chronic fatigue. Most recently, interest in immuno-toxicity has led to
syndromes labeled "total allergy syndrome" and "chronic candidiasis." On
careful examination, each of these explanations has been dismissed, yet health
practitioners continue to believe that there may be an explainable syndrome
that is characterized most prominently by chronic fatigue. As noted earlier,
efforts to understand and study chronic fatigue syndrome have resulted in
different sets of criteria being proposed for defining the condition.
Recently, investigators from Australian the United Kingdom, and the United
States have proposed a revision to an older definition explicitly for use in
carefully designed studies of chronic fatigue syndrome (25).
2. Appropriate limits of a definition
The description, parameters, and severity of a new condition must not be so
broad as to exclude a common etiology, or so narrow as to suggest either bias
(and possibly mutual redefinition of symptoms) or censoring (of possible
atypical cases). For example, for years, health scientists have noted a
common late afternoon wave of fatigue and have associated it with circadian
patterns of reduced blood sugar in that period of an individual's day. During
the 1960s and 1970s, low blood sugar became an increasingly popular explanation
for persistent fatigue. Along with the emergence of the label hypoglycemia to
explain protracted exhaustion, some caregivers began to argue for the need to
take an elaborate dietary history and to introduce behavioral modification to
correct the condition. Systematic population studies, however, have
demonstrated that the notion includes numerous asymptomatic people with fasting
or postprandial blood sugar levels in the range of 40 to 50 mg/dL (24).
Subsequent to these studies, the term hypoglycemia has gradually returned to
more limited use as an explanation of afternoon fatigue.
3. Replication by appropriate range of practitioners
The condition must have been observed and confirmed by a significant
number of qualifies medical practitioners, drawn from a broad panel of
subdisciplines and places of practice. There would be some suspicion, for
example, if a new disease entity could be recognized by surgeons, but not by
internists, or by doctors of osteopathy but not doctors of medicine, or by
physicians practicing in a specific locality, but not by qualified peers
brought in to evaluate the matter.
Enthusiasm for chronic brucellosis as an explanation for chronic fatigue
syndrome accompanied Evans' original publication (26). Failure to replicate
the findings, and the demonstration that antibodies to brucella were widespread
and unrelated to fatigue in general were widespread and unrelated fatigue in
general population studies, resulted in the ultimate rejection of chronic
brucellosis as a distinct condition characterized predominantly by chronic
In contrast, reports that stomach ulcers could be related to infection with
Helicobactor pylori were initially met with disbelief by many
mainstream physicians and research scientists (27, 28). Yet, widespread
replication of findings associating infection with stomach ulcers and gastritis
has changed these attitudes and treatment of this infection now plays an
important role in therapy of stomach ulcers.
4. Common features and causes
The designation of a new disease category is not entirely independent of
considerations of cause and effect, and adequate demonstration of a
cause-effect linkage can be persuasive that the effect should be
recognized. For example, do affected persons tend to have something in
common, e.g. common exposure(s), common susceptibilities, or common demographic
features? Does it seem that all categories of persons with such features are
susceptible? An answer of "No" is not conclusive, because knowledge may be
incomplete, or because relevant exposure may be so ubiquitous as to make the
condition commonplace, but we would expect such exceptions to be uncommon.
5. Context in which condition occurs
When evaluating the evidence that a new disease or a new category of
disease might deserve to be recognized, it is important to consider whether
there are undue pressures (including social, financial, and political) that
promote or discourage the acceptance of a new disease category. Such
pressures may be generated, for example, by perceived governmental needs to
reduce medical coverage, by desire for incline by physicians or hospitals for
services delivered, by patient-oriented concerns with compensation, by concerns
about political vicissitudes, by incomplete or biased new exposures, or by a
sense of solidarity among members of some possibly affected group. It should
be stressed that such pressures may not be overt, they may be unrecognized by
those they affect, and they may at times even be recognized and seen as
laudable by persons who are dedicated to a cause. These types of pressures
must be prevented from serving as the primary determinant for whether a new
disease category should be established.
It is difficult to differentiate when pressure is legitimate (the medical
community is properly reluctant to recognized as "new" every condition that
does not fit readily into existing understanding of disease etiology) from when
pressure is undue (because it derived from illegitimate or misguided interests
of affected parties). When there is disagreement between lay and professional
groups and/or among professionals, the search for explanatory models propels
both groups to act. The lay group considers alternative attribution for the
cause of the disease, as well as for the cause of the professionals'
disagreement of failure to name the experience. Development of criteria for
human immunodeficiency (HIV-AIDS) exemplifies the processes in which lay people
organized to prod the professionals to improve their understanding of a new
phenomenon in which there had been little previous interest or attention. Past
breeches of trust between patients and professionals (e.g., over the effects of
the use of diethylstilbestrol (DES) and the Dalkon shield, and in regard to the
effects of black lung and byssinosis) have created a sociopolitical context
against which the public makes inferences about patient/professional
The five criteria proposed for use when exploring the possibility that a new
condition exists are neither exhaustive nor fail-safe. They are proposed in an
effort to promote a more systematic approach to the consideration of
suggestions that an new condition such as a Gulf War syndrome exists.
Determination that a new disease exists is potentially important with respect
to differential diagnosis, treatment decisions, and properly targeted
prevention efforts, as well as the design of research programs. The emergence
of any new disease process presents a serious and difficult challenge to
medical science. Understandably, physicians are comforted by the known, and
troubled by conditions that they cannot readily explain. All of use need help
in finding ways to see out environment in a new light, and learn how that new
light changes what we can subsequently observe.
In the end, we are doubtful that the symptoms linked with Persian Gulf syndrome
can meet these or other reasonable criteria for the diagnosis of a new
condition. However, it is possible that new research findings will shift the
totality of evidence in the other direction. Much research on Gulf War
syndrome is already in progress, and more will surely be undertaken as both our
understanding of the matter and the needed research tools develop.
A portion of this commentary was prepared during the authors' work while
serving on the Institute of Medicine's Committee to Review the Health
Consequences of Service During the Persian Gulf War (2). Helpful comments were
received from several other members of the committee, as well as from Dr. Myron
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Dr. Haley Replies to Wegman et al's Invited Commentary of Gulf War
Robert W. Haley
In their invited commentary on my article (1), Wegman et al. (2) acknowledge
the inadequacies in the studies that have been cited in support of war-related
stress as the explanation of persisting illnesses in Persian Gulf War veterans.
However, they subtly attempt to leave open the door to the stress theory by
reasoning, "The difficulty in studying stress...is no...reason to reject the
role of stress in the veterans' illnesses...." (2, p. 705).
On the contrary, the problem with the stress theory of the Gulf War syndrome is
not a difficulty in detecting post-traumatic stress disorder (PTSD). When PTSD
is present, the diagnosis is readily made with a structured interview by a
trained psychiatrist or psychologist in which the official criteria for PTSD
are satisfied and other conditions with which it ca be confused (e.g., other
psychiatric, neurologic, or neurotoxic disorders) are separated out. As I
demonstrate in my review, the problem in regard to the investigations into Gulf
War syndrome arose from an ill-advised over reliance on nonspecific diagnostic
tools (namely, psychometric PTSD seales) in epidemiologic surveys and a
failure to employ the definitive diagnostic interview technique until after
public positions in favor of the stress etiology had become entrenched.
1. Haley RW, Is the Gulf War syndrome due to stress? The evidence reexamined.
Am J Epidemiol 1997; 146; 695-703.
2. Wegman DH, Woods NF, Bailar JC. Invited commentary: How would we know a
Gulf War syndrome if we saw one? Am J Epidemiol 1997; 146;704-11.