The current study sought to subgroup individuals with
chronic fatigue syndrome. Based on a battery of basic laboratory screening
tests, subgroups of Infectious, Inflammatory and Other were formed. When
compared to controls, all subgroups reported significantly greater physical
disability. Additionally, the Other group reported greater physical disability
when compared to the Inflammatory group. When considering mental disability,
only the Inflammatory group reported greater levels of disability. The
Inflammatory and Infectious groups had an increased rate of current psychiatric
comorbidity, but only in the Inflammatory group had an increased rate of
lifetime psychiatric diagnoses. Interestingly, individuals who identified
themselves as members of minority groups were significantly more likely to
present with an ongoing infectious process when compared to Caucasian
Chronic fatigue syndrome (CFS) affects an estimated 836,000
adults in the United States (Jason et al., 1999), and is 3 to 5 times more
common in women than men. CFS can impact any number of bodily systems including
neurological, immunological, hormonal, gastrointestinal, and musculoskeletal
(Friedberg & Jason, 1998). CFS is a diagnosis of exclusion. There are currently
no specific diagnostic tests for its identification. Researchers have reported
various biological abnormalities when investigating CFS, including hormonal
abnormalities (Cannon et al., 1998; Moorkens, Berwaerts, Wynants & Abs, 2000),
immune activation (Miller, Cohen & Ritchey, 2002), neuroendocrine changes,
(Farrar, Locke & Kantrowitz, 1995) and neurological abnormalities (Cook, Lange,
DeLuca & Natelson, 2001) among others. However, studies involving basic blood
work appear to show no typical pattern of abnormality among individuals with CFS
(Johnson, DeLuca & Natelson, 1999).
It has been suggested that a number of unique subgroups
exist within the overall cluster of individuals diagnosed with this disorder
(Cukor, Tiersky & Natelson, 2000; Jason et al. 2001;
Johnson, DeLuca & Natelson, 1999). In the paper specifying the current US case
definition for CFS diagnosis (Fukuda et al., 1994), the working group that
developed the criteria referred to the importance of subgrouping within cohorts
of individuals diagnosed with CFS. This demonstrates that, even as the current
definitional criteria were being presented, there was an awareness of the
heterogeneity within the identified group. After the publication of these
criteria in 1994, many attempts to subgroup have been undertaken, but to date,
no one method has proven to be consistently superior in differentiating
Psychiatric comorbidity has often been considered a
differentiating variable in research studies aimed at subgrouping (Borish et
al., 1998; Cukor, Tiersky and Natelson, 2000; DeLuca, Johnson, Ellis & Natelson,
1997a; Masuda, Munemoto, Yamanaka, Takei & Tei, 2002). However, when Tiersky,
Matheis, DeLuca, Lange, and Natelson (2003) examined individuals with CFS with
and without psychiatric co-morbidity, they found that physical functional
capacity was not worse in individuals with CFS and a concurrent psychiatric
illness. Morriss and associates (1999) also found that depression was not
associated with the reporting of pain, FM, IBS, or medically unexplained
symptoms in individuals with CFS. Similarly, Ciccone, Busichio, Vickroy, and
Natelson (2003) did not find that psychiatric illness, alone or in combination
with a comorbid personality disorder, was associated with physical impairment.
In contrast to the findings above, Borish, Schmaling,
DiClementi, Streib, Negri, and Jones (1998) found evidence of low level
inflammation, similar to that of allergies, in a subgroup of individuals with
CFS. Borish et al. suggested that there might be two subgroups of individuals
with CFS, those with immune activation (infectious or inflammatory) and those
devoid of immune activation with other illness processes, including psychiatric
disorders. Lutgendorf, Klimas, Antoni, Brickman, and Fletcher (1995) found that
those patients with immune activation had the most severe cognitive deficits,
while Natelson, Cohen, Brassloff and Lee (1993) found that those with ongoing
inflammatory processes reported greater cognitive and mental disabilities.
Buchwald, Wener, Pearlman, and Kith (1997) found individuals with CFS and
chronic fatigue to have significant abnormalities in C-reactive protein (an
indicator of acute inflammation) and neopterin (an indicator of immune system
activation, malignant disease, and viral infections) when compared to controls.
Buchwald et al. (1997) stated that groups of individuals with active low-level
inflammatory, infectious processes could be identified and that this was
evidence of an organic process in these patients with CFS. Cook, Lange, DeLuca,
and Natelson (2001) found that individuals with an abnormal MRI and ongoing
inflammatory processes had increased physical disability, suggesting an organic
basis for some individuals with CFS. Conceivably, individuals without evidence
of these infectious or inflammatory processes on basic laboratory screening
tests might be more likely to contain individuals who had other neuroendocrine
or neurologic illnesses that might not be readily identified using the minimum
battery of laboratory of tests recommended by Fukuda and colleagues (1994) in
order to diagnose CFS. However, those with infectious or inflammatory processes
might be expected to be more physically impaired compared to those without these
processes, based on research by Cook, Lange, DeLuca and Natelson (2001) and
Lange, et al. (1999). There is also evidence that those individuals with CFS and
with inflammatory processes report greater mental difficulties when compared to
those individuals without them (Natelson, Cohen, Brassloff & Lee, 1993).
Clearly, individuals diagnosed with CFS are heterogeneous
with varying illness course and disability patterns (Jason, Corradi,
Torres-Harding, & Taylor, 2005). Similar to other disorders such as cancer, it
is likely that a number of distinct types of CFS exist, and that grouping all
individuals who meet diagnostic criteria together is prohibiting the
identification of these distinct biological markers of the individual subgroups.
When specific subgroups are identified, even basic blood work may reveal a
typical pattern of abnormality on diagnostic tests (DeLuca, Johnson, Ellis &
Natelson, 1997b; Hickie et al. 1995;
Jason et al., 2001).
This exploratory study considered several possible
subgroups that fall under the umbrella diagnosis of CFS. It was expected that
clinically significant groups would be found on the basis of abnormal blood
tests. The laboratory tests that formed the basis for subgrouping were part of
the battery of laboratory screening tests recommended by Fukuda et al. (1994).
These groups consisted of an ongoing infectious group, an ongoing Inflammatory
group, and an “Other” group (having neither infectious or inflammatory
processes). Using these subgroups, this study sought to explore the
relationships between membership in a subgroup, reported disability (both mental
and physical), and psychiatric co-morbidity. It was hypothesized that the
individuals with CFS would evidence higher levels of physical and mental
disability than those in a control group, and that those in the Infectious and
Inflammatory subgroup would exhibit higher levels of physical and mental
disability when compared to the Other group. It was also hypothesized that the
Inflammatory group would report greater mental difficulties when compared to the
Infectious and Other groups.
Procedures developed by Kish (1965) were used to select one
adult from each household contacted. The person with the most recent birthday
was asked to complete the interview. A stratified random sample of several
neighborhoods in Chicago was used, and a random sample of adults was screened.
In stage one, 28,673 telephone numbers were contacted, with 18,675 adults
completing the initial interview (see Jason et al., 1999 for further details).
Persons who completed the initial screening stage of the study with indications
that they may have had CFS, as well as a group negative for CFS (control group),
were invited to participate in the second and third stages of the research
study. Stage two involved administration of a structured psychiatric interview,
the SCID, conducted by telephone. Stage three involved a medical exam at Mercy
Hospital, including a physical exam, laboratory tests, including a complete
blood count (CBC), white blood cell differential, antinuclear antibodies (ANA),
sedimentation rate (Sed rate), rheumatoid arthritis (RA factor), chest X-ray, a
detailed medical interview, and a structured medical questionnaire. Participants
were also asked at this time to release previous medical records to the research
study. The authors received IRB approval for conducting the study. Individuals
who participated in the medical examination were provided financial
When each participant completed the study, a team of four
physicians and a psychiatrist made the final diagnosis of CFS, Idiopathic
Chronic Fatigue, Fatigue explained by a medical condition, or no fatigue. These
physicians were familiar with the CFS diagnostic criteria and were blind to the
experimental status of the participant. Two physicians independently rated each
case to determine whether the participant met the CFS case definition (Fukuda et
al., 1994). If a disagreement occurred, a third physician rater was used to
arrive at a diagnostic consensus.
The participants for this project consisted of individuals
with CFS and a control group. For the purposes of this study, it was important
that the control sample include only individuals who presented themselves as
mentally and physically healthy, due to the fact that abnormal medical test
results were a primary variable. A total of 19 of 47 individuals in the control
group were excluded from this study (e.g., on-going medical, sleep or severe and
untreated psychiatric problems). The final sample included 31 in the CFS group
(1 CFS participant was excluded due to lack of data on a critical variable), and
28 healthy controls. The CFS group consisted of 23 females and 8 males. The
control group had 18 males and 10 females. Further demographic breakdown
indicated that the CFS group had 5 African American, 14 Caucasian, 9 Latino, and
3 individuals who identified themselves as “other”. The control group consisted
of 4 African American, 20 Caucasian, 2 Latino, and 2 individuals who identified
Individuals with CFS were then sub-grouped into three
groups according to medical evidence of possible inflammatory processes (as
evidenced by abnormal eosinophils count, antinuclear antibodies [ANA], abnormal
rheumatoid arthritis factor [RA factor], and abnormal sedimentation rate in the
presence of one of the prior mentioned inflammatory markers), medical evidence
of possible current infection (as evidenced by abnormal results on lymphocytes
count or sedimentation rate [Sed rate] without the presence of an inflammatory
marker), and a group without evidence of either of these organic processes. Each
of these medical markers is discussed in the measures section below. When
subgrouped based on these criteria, 8 participants with CFS were categorized
into the Other group, 8 in the Infectious group, and 15 in the Inflammatory
Measures used for this study included laboratory blood
tests, a self-report of disability, and a structured clinical interview for the
determination of psychiatric diagnosis. 1
measures did not total 59 as all participants did not complete every measure.
Standard laboratory tests were conducted during phase three
of the full-scale study. Results used in the current study include: White blood
cell (WBC) differential (specifically lymphocytes and eosinophils), rheumatoid
arthritis factor (RA factor), antinuclear antibodies (ANA) and sedimentation
rate (Sed rate). These laboratory tests were chosen for inclusion into the study
based upon the recommendations of Fukuda and colleagues (1994) for diagnosing
CFS. These tests are all part of the recommended minimum battery of laboratory
screening tests suggested by this group in order to exclude other physiological
causes of fatigue or another disease process. All blood-work completed for this
study was analyzed through the laboratories at Mercy Hospital in Chicago
Illinois, or National Health Laboratories Incorporated-Chicago, in Elmhurst, IL.
Eosinophils and Lymphocytes
Eosinophils and lymphocytes are specific types of
leukocytes. To obtain the values presented and considered in this study,
automated white blood cell differentials were performed. Differential white
blood count is part of the complete blood count (CBC) and is composed of five
types of leukocytes (WBCs whose chief function is to protect the body against
microorganisms causing disease). These five consist of eosinophils, lymphocytes,
neutrophils, basophils, and monocytes. The differential WBC is expressed in
cubic millimeters and percent of total number of WBCs.
When elevated, eosinophil counts can indicate the presence
of allergic inflammation, some forms of cancer, and parasitic disease.
Significantly higher rates of allergy and allergic type reactions have been
reported in the CFS population (Borish, et al., 1998). Several studies have also
reported significant elevations of the eosinophil counts of individuals with CFS
(Conti, Magrini, Priori, Valesini & Bonini, 1996; Baraniuk, Clauw, Yuta,
Gaumond, Upadhyayula, Fujita, et al. 1998; Priori, Conti, Luan, Aprino &
Valesini, 1994). The normal range endorsed by Mercy Hospital Laboratories for
eosinophil count is 100-300 mL. This variable was coded as normal or abnormal
depending on the test results from Mercy Hospital Laboratory.
When elevated levels of lymphocytes are found, this can be
an indication of viral infection, chronic infection, and Hodgkin’s disease,
among others. Elevated lymphocytes have been reported in the CFS population
(Patarca, 2001), and abnormal lymphocyte responses have also been noted (Krueger
et al., 2001). However, elevated levels and abnormal responses have not been
found in all studies (Brimacombe, Zhang, Lange & Natelson, 2002). The normal
range endorsed by Mercy Hospital Laboratories for lymphocytes is 800-4400mL.
This variable was coded as normal or abnormal depending on the test results from
Mercy Hospital Laboratory.
Rheumatoid Arthritis Factor (RA Factor)
RA factor measures antibodies in the serum of individuals
with rheumatoid arthritis. When this test is abnormal, it indicates an
inflammatory process such as rheumatoid arthritis, autoimmune disease and
occasionally, infectious diseases. The presence of rheumatoid arthritis factor
has been reported in the CFS population (Kerr et al., 2001). This laboratory
test was conducted by National Health Laboratories Incorporated-Chicago, in
Elmhurst, IL. Serum samples were first run undiluted, and if a positive result
was found, the sample was then run diluted at a 1:10 dilution. The reference
value for a normal result is < 1:20 titer. Ranges of 1:20-1:80 are positive for
rheumatoid and other conditions. Results falling above 1:80 are positive for
rheumatoid arthritis. Any positive results on this test were coded as abnormal.
As Rheumatoid Arthritis is an exclusionary disorder for CFS diagnosis, all
participants were screened for Rheumatoid Arthritis during their medical exam
and this disorder was ruled out.
Sedimentation Rate (Sed Rate)
Sed rate measures the sinking velocity of blood cells, or
the degree of rapidity with which the red cells sink in a mass of drawn blood
(Dirckx, 2001). Elevated Sed Rate can indicate bacterial infection, pelvic
inflammatory disease, systemic lupus erythematosus, and red blood cell
abnormalities (Kee, 2001). Abnormal sedimentation rates have been reported in
CFS populations (Richards, Roberts, McGregor, Dunston & Butt, 2000).
Results on this test are reported in millimeters per hour,
and normal ranges depend on sex and age. The Mercy laboratories normal range for
males < 50 is 0-10.4 mm/hr, and for males > 50, 0-11.4 mm/hr. For females < 50
the normal range is 0-11.0 mm/hr and for females > 50, 0-20.0 mm/hr. This
variable was coded as normal or abnormal depending on the test results from
Mercy Hospital Laboratories.
Antinuclear Antibodies (ANA)
ANA tests for the presence of antinuclear antibodies in the
blood. A normal result is negative. When positive, it is an indication of
systemic lupus or other rheumatoid disorders, which are inflammatory diseases.
Occasionally this test can be positive in the presence of specific types of
infections. Elevated rates of ANA have been reported in the CFS population
(Nesher, Margalit & Ashkenazi, 2001). Several reports of a specific type of ANA
found in some individuals with CFS have been published (Itoh et al., 2000;
Nishikai, et al., 2001).
To determine disability level, the SF-36 (Stewart, Hays &
Ware, 1988) was completed by all participants. The SF-36 is a 36-item
questionnaire that assesses individuals’ self-report on physical and emotional
health currently, in the past four weeks, and compared to the same time last
year. The SF-36 has eight subscales, and one reported health transition score.
Two composite scores are available for the SF-36, the Physical Component Summary
(PCS) and the Mental Component Summary (MCS). Internal consistency coefficients
range from .89 -.94 for the PCS, and .84 -.91 for the MCS across age, gender,
race, education, medical diagnosis, and disease severity. The current study used
these summary scales to determine differences in physical health, and mental
health (Ware, Kosinski & Keller, 1994
Initial analyses were conducted to determine if any
significant differences existed between the control and the entire CFS group on
sociodemographic variables. There was only one significant difference, which
occurred for gender. Therefore, gender was run as a covariate in all subsequent
Subgroup Differences for Physical and Mental Disability
To consider the relationship between subgroup membership
and reported physical disability, an ANCOVA was run with subgroup as the
independent variable, PCS as the dependent variable, and gender as a covariate.
Analyses indicated that significant differences could be found between the
subgroups on the PCS (p < .01). Least Significant Difference post hoc analyses
indicated that all three CFS subgroups reported significantly higher levels of
physical disability than the Control group (M = 56.1). The Other group reported
significantly higher levels of physical disability when compared to the
Inflammatory group (Ms = 29.2 vs 39.2, respectively), but it was not
significantly different from the Infectious (M = 34.7) group.
Next, an ANCOVA was conducted with a subgroup as the
independent variable, MCS (a measure of mental disability) as the dependent
variable, and gender as the covariate. Analyses indicated that significant
differences did exist between the subgroups for the MCS variable (p < .01).
Following the significant omnibus test, post hoc analyses indicated that the
Inflammatory group had significantly greater mental disability compared to the
control group (Ms = 36.5 vs 50.8, respectively), but was not significantly
different from the Other (M = 43.6) or Infectious (M = 39.7) groups.
Relationships between Subgroups and Psychiatric Diagnoses
To attempt to understand the relationships that might exist
between subgroups and psychiatric diagnoses, logistic regressions were conducted
considering subgroups as the independent variables (e.g., Other, Infectious,
Inflammatory, and Control) and one psychiatric diagnosis per logistic regression
(with the following dependent variables in separate analyses: current
depression, current anxiety, and current other psychiatric diagnosis). No
significant differences were found among the subgroups and the presence of
depression, anxiety disorder, or other psychiatric diagnosis.
Because prior studies have indicated that the CFS groups
have significantly higher rates of current and lifetime psychiatric comorbidity,
the analyses above were performed on current and any lifetime psychiatric
diagnoses. Two logistic regressions used current psychiatric diagnosis and
lifetime psychiatric diagnosis as dependent variables. The odds that an
individual in the Infectious group also had a current psychiatric diagnosis were
6.13 times higher when compared to individuals in the control group. The odds
that individuals in the Inflammatory group had a current psychiatric diagnosis
were 12.65 times higher when compared to control group members.
The second logistic regression considered lifetime
psychiatric diagnosis of any kind between membership in one of the subgroups,
and membership in the control group. Analyses indicated that the odds that
individuals in the Inflammatory group had a psychiatric diagnosis at some time
in their lives were 18.66 times higher when compared to individuals in the
Prior to subgrouping, no significant differences existed
between the control and CFS groups on ethnicity. However, when examining the
three subgroups separately with the control group, chi square analysis indicated
that significant differences did exist between the four groups [χ2(3, N = 59) = 10.00, p = .019]. The Infectious group (91% minority, 9%
Caucasian) were significantly more likely to be of minority status than the
Other (32% minority, 67% Caucasian) and control (37% minority, 63% Caucasian)
groups, but they were not significantly different from the Inflammatory (56%
minority, 44% Caucasian) group.
While it was hypothesized that the Infectious and
Inflammatory groups would be significantly more physically impaired compared to
the Other group, we found that the Other group reported significantly greater
physical impairment compared to the Inflammatory group. In the present study,
the Other group might have reported greater physical impairment because of other
on-going physiological processes. For example, supplemental analyses indicated
that the Other group was significantly more likely than the Infectious group to
present with symptoms of orthostatic intolerance, specifically, dizziness
immediately following standing, and dizziness when turning the head. The Other
group might have contained individuals with ongoing illness processes that were
not identifiable by the laboratory tests available for this study. Orthostatic
intolerance is best diagnosed using tilt-table testing, which was beyond the
scope of the current study.
The Inflammatory group was significantly different only
from the control group. This result is consistent with past findings of greater
mental disability in the Inflammatory group when compared to the control group,
and is consistent with past research indicating individuals with ongoing
inflammatory processes are more likely to report greater mental difficulties
(Natelson, Cohen, Brassloff & Lee, 1993).
When measuring participants’ psychological status, the
Other group was the only chronic fatigue subgroup that did not have
significantly elevated psychiatric diagnoses. No significant relationships
emerged between membership in the Infectious, Inflammatory, and Other groups,
and current diagnosis of depression, anxiety, and any other psychiatric
diagnosis. However, when examining simply the presence or absence of any current
or lifetime psychiatric disorder, the Inflammatory group was more likely to have
a current or lifetime psychiatric diagnosis when compared to controls. Also,
individuals in the Infectious group were found to be more likely to have a
current psychiatric diagnosis when compared to controls.
It is possible that the presence of a chronic illness may
put enough psychological strain on an individual that this strain contributes to
or caused psychiatric diagnosis, or that the same processes that increase an
individual’s likelihood of having a mental disability when inflammatory
processes are present, may increase the likelihood of a psychiatric diagnosis.
It is also possible that the psychiatric symptoms are completely unrelated to
the CFS diagnosis (Abbey, 1996). The relationship between psychiatric diagnosis
and CFS diagnosis is one that is far from being understood and therefore is much
in need of further study.
Finally, the Infectious group had a greater number of
minorities compared to other subgroups and the control group. It is well
documented that minority and low SES populations are less likely to have access
to health care (Richman, Flaherty & Rospenda, 1994). Language barriers, past
experiences with the healthcare system, and different medical and religious
beliefs may all contribute to minority participants being less likely to utilize
health care, even if they have the access (Borrayo & Jenkins, 2003; Johnson et
al., 1995). It is also possible that minorities who are immigrants are more
likely to travel to their country of origin and be exposed to different
infectious agents in their travels. In addition to this, minority participants
may be more likely to be employed in hazardous or environmentally stressful
occupations with exposure to infectious agents. It is possible then that
minorities in the present study had poorer health care utilization, and
therefore were less likely to have had infectious processes treated.
The current exploratory investigation had several
limitations. First, the medical tests used as the basis of subgrouping in this
study were not exclusive indicators of infection or inflammation. Further, the
distinction between infection or inflammation is often one that cannot clearly
be made, as these two processes frequently occur together. While inflammation
generally accompanies infection, there are distinct instances when inflammation
occurs in the absence of known infection, such as allergic inflammation, or
sub-clinical level rheumatoid arthritis. Future studies should seek to determine
if clear differentiation can be made, with more accurate tests, between
infection and inflammation. Second, the limited sample size for African
American, Latino, Asian, and other minority groups necessitated the grouping of
all minority participants into one larger minority group. It is difficult to be
certain if the relationships found (i.e. that of minority participants being
more likely to present with on-going infectious processes) are more likely in
individuals who have minority status in general, or if differences in findings
are due to a specific minority group. The current study had small sample sizes,
and this could contribute to instability of results, limited generalizability
and lack of statistical power. Logistic regressions with small sample sizes can
over-fit models and generate high odds ratios. Future research should consider
larger sample sizes of each minority group to explore within-group and
It is notable that these findings emerged when forming
subgroups utilizing only a basic battery of laboratory screening tests. These
laboratory tests were conducted primarily for the purpose of screening out other
major illnesses that might explain a person’s chronic fatigue, as recommended by
Fukuda and colleagues (1994). Many people with CFS exhibit only minimal or
subtle abnormalities on these tests, and these abnormalities often are
inconclusive or may not be acknowledged by the primary care physician because
they do not lead to a diagnosis of another, more recognized disease process.
Further, the more commonly reported physiological abnormalities reported in
people with CFS, such as the presence of RNase L (Suhadolnik et al., 1997),
adrenal insufficiency with subsequent low cortisol levels (Addington, 2000), the
presence of orthostatic intolerance (Schondorf, Benoit, Wein, & Phaneuf, 1999),
and immunological abnormalities (Patarca-Montero, Mark,
Fletcher, & Klimas, 2000), can only be assessed using highly specialized,
expensive, or experimental tests to which people with CFS and their physicians
typically have little access. This study demonstrates that subgrouping is
possible using laboratory tests that are readily available and can easily be
ordered by primary care physicians.
The identification of clinically significant subgroups is
the logical next step in furthering CFS research. There might be multiple
pathways leading to the cause and maintenance of the neurobiologic
disregulations and other symptoms experienced by individuals with CFS. Depending
upon the individual and subtype, these may include unique biological, genetic,
neurological, psychological, and socioenvironmental contributions. Previous
research examining people with CFS as a homogenous group may have missed real
differences that might exist among subgroups of people diagnosed with this
illness. Subgrouping might be the key to understanding how CFS begins, how it is
maintained, how medical and psychological variables influence its course, and in
the best case, how it can be prevented, treated, and cured (Jason et al., 2005).
Request for reprints should be addressed to Leonard Jason,
Center for Community Research, DePaul University, 990 W. Fullerton Avenue,
Chicago, IL 60614.
Financial support for this study was provided by NIAID
(Grant Number A136295).
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