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Chronic fatigue syndrome: Harvey and Wessely's (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways

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In a recently published paper, Harvey and Wessely put forward a 'biopsychosocial' explanatory model for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is proposed to be applicable to (chronic) fatigue even when apparent medical causes are present. Here, we review the model proposed by Harvey and Wessely, which is the rationale for behaviourally oriented interventions, such as cognitive behaviour therapy (CBT) and graded exercise therapy (GET), and compare this model with a biological model, in which inflammatory, immune, oxidative and nitrosative (IO&NS) pathways are key elements. Although human and animal studies have established that the pathophysiology of ME/CFS includes IO&NS pathways, these abnormalities are not included in the model proposed by Harvey and Wessely. Activation of IO&NS pathways is known to induce fatigue and somatic (F&S) symptoms and can be induced or maintained by viral and bacterial infections, physical and psychosocial stressors, or organic disorders such as (auto)immune disorders. Studies have shown that ME/CFS and major depression are both clinical manifestations of shared IO&NS pathways, and that both disorders can be discriminated by specific symptoms and unshared or differentiating pathways. Interventions with CBT/GET are potentially harmful for many patients with ME/CFS, since the underlying pathophysiological abnormalities may be intensified by physical stressors. In contrast to Harvey and Wessely's (bio)psychosocial model for ME/CFS a bio(psychosocial) model based upon IO&NS abnormalities is likely more appropriate to this complex disorder. In clinical practice, we suggest physicians should also explore the IO&NS pathophysiology by applying laboratory tests that examine the pathways involved.
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Correspondence
Chronic fatigue syndrome: Harvey and Wessely's
(bio)psychosocial model versus a bio(psychosocial)
model based on inflammatory and oxidative and
nitrosative stress pathways
Michael Maes*
1
and Frank NM Twisk
2
Abstract
Background: In a recently published paper, Harvey and Wessely put forward a 'biopsychosocial' explanatory model for
myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is proposed to be applicable to (chronic) fatigue
even when apparent medical causes are present.
Methods: Here, we review the model proposed by Harvey and Wessely, which is the rationale for behaviourally
oriented interventions, such as cognitive behaviour therapy (CBT ) and graded exercise therapy (GET), and compare this
model with a biological model, in which inflammatory, immune, oxidative and nitrosative (IO&NS) pathways are key
elements.
Discussion: Although human and animal studies have established that the pathophysiology of ME/CFS includes
IO&NS pathways, these abnormalities are not included in the model proposed by Harvey and Wessely. Activation of
IO&NS pathways is known to induce fatigue and somatic (F&S) symptoms and can be induced or maintained by viral
and bacterial infections, physical and psychosocial stressors, or organic disorders such as (auto)immune disorders.
Studies have shown that ME/CFS and major depression are both clinical manifestations of shared IO&NS pathways, and
that both disorders can be discriminated by specific symptoms and unshared or differentiating pathways.
Interventions with CBT/GET are potentially harmful for many patients with ME/CFS, since the underlying
pathophysiological abnormalities may be intensified by physical stressors.
Conclusions: In contrast to Harvey and Wessely's (bio)psychosocial model for ME/CFS a bio(psychosocial) model
based upon IO&NS abnormalities is likely more appropriate to this complex disorder. In clinical practice, we suggest
physicians should also explore the IO&NS pathophysiology by applying laboratory tests that examine the pathways
involved.
Background
In a recent commentary, Harvey and Wessely [1] pro-
posed a (bio)psychosocial model for all manifestations of
chronic fatigue: myalgic encephalomyelitis/chronic
fatigue syndrome (ME/CFS), unexplained fatigue, fatigue
as a result of psychiatric conditions, and fatigue associ-
ated with an apparent medical cause, such as cancer,
AIDS and autoimmune disorders. Figure 1 shows the
Harvey and Wessely model [1].
In the view of Harvey and Wessely [1], stress, a viral
infection or another trigger instigate 'fatigue' in predis-
posed individuals, which, mediated by prolonged bed
rest, 'boom and bust activity' and biological sequelae (the
maintaining factors), result in ME/CFS. The biological
component of this model is restricted to the potential
triggers (infections) and 'biological responses' to the ini-
tial fatigue, which, accompanied by 'behavioural
responses' contribute to a prolonged severe fatigue. Per-
petuating factors are principally behavioural ones; biolog-
ical aberrations are considered to be a consequence not a
cause. All predisposing factors, with one exception
* Correspondence: crc.mh@telenet.be
1 Maes Clinics @ TRIA, Piyavate Hospital, Bangkok, Thailand
Full list of author information is available at the end of the article
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(childhood illness), are behavioural or characterological
ones.
Harvey and Wessely's [1] model strongly resembles the
psychosocial model of Vercoulen et al. [2]. Figure 2 shows
the Vercoulen et al. model. Fatigue and impairment are
considered to be the end result of behavioural (psycho/
sociogenic) factors only. According to this model attrib-
uting complaints to a somatic cause (physical attribution)
negatively influences physical activity, which in turn has a
negative impact on severity of fatigue and impairment.
Focusing on symptoms also contributes to impairment
and fatigue, and a low perceived sense of control over
symptoms also induces fatigue. We will refer to both
models as psychosocial models, since biological abnor-
malities are considered to play no role at all (the Vercou-
len et al. model) or just a minor one (the Harvey and
Wessely model) in explaining the symptomology of ME/
CFS.
These psychosocial explanatory models for fatigue and
ME/CFS and fatigue in general are the rationale for the
combination of cognitive behavioural therapy (CBT) and
graded exercise therapy (GET). In the biopsychosocial
view, the patient can 'recover' by adjusting dysfunctional
beliefs and behaviour and reversing deconditioning,
which are proposed to be the maintaining factors in ME/
CFS. CBT is aimed at eliminating psychogenic maintain-
ing factors, for example illness beliefs, unhelpful, anxiety-
provoking thoughts and kinesiophobia ('fear of move-
ment'); CBT challenges the negative cognitions and dys-
functional beliefs of the patients [3]. CBT is indissolubly
attached with GET, a rehabilitative approach of graded
increase in activity to address deconditioning [3].
This paper examines Harvey and Wessely's [1] (bio)psy-
chosocial model for ME/CFS and chronic fatigue in gen-
eral and compares this model to a bio(psychosocial)
model based on disorders in immune, inflammatory, oxi-
dative and nitrosative stress (IO&NS) pathways.
Comparison between the psychosocial models and
a biological model based upon aberrations in
IO&NS pathways
The biological pathophysiology
A medical model should explain how (a) precipitating
and perpetuating factors induce (b) the biological
Figure 1 The (bio)psychosocial model for 'chronic fatigue' of Harvey and Wessely.
 Viral infections
 Stress
 Other triggers
Biological sequels
CF(S)
Chronic Fatigue
(Syndrome)
Predisposing factors:
Personality traits, etc.
Intervention
Prolonged bed rest
Boom and bust activity
Fatigue
?
??
Precipitating factors
Pathophysiology
Symptoms (clinical expression)
Predisposing factors
Perpetuating factors
Legenda
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Figure 2 The (bio)psychosocial model for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) of Vercoulen et al. Fatigue: the
subjective feeling of fatigue; fatigue subscale of the Checklist Individual Strength. Focusing on (Bodily) Symptoms: somatisation subscale of the Symp-
tom Checklist. (Level of) Physical Activity: Sickness Impa ct Profile (SIP) subscale mobility (SIP-MOB) and the Physical Activities Rating Scale. (Functional)
Impairment: impairment in daily life; subscale of activities at home of the SIP. Sense of Control (over Symptoms): selected items of the modified Pain
Cognition List on a specific five-point scale. Causal Attributions: Causal Attributions List (high scores: physical attributions, low scores: psychosocial
attributions).
Fatigue
Impairment
Physical Activity
Sense of
Control over
Symptoms
Intervention
(CBT)
Causal
Attributions
Intervention
(GET)
Focusing on
Symptoms
Precipitating factors
Pathophysiology
Symptoms (clinical expression)
Predisposing factors
Perpetuating factors
Legenda
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pathophysiology that accounts for (c) specific symptoms.
Figure 3 shows a biological model that plausibly explains
'fatigue' and ME/CFS by organic abnormalities and cause
and effect relationships [4]. The model of Harvey and
Wessely [1], however, does not specify (b) biological
pathways that explain and maintain (c) the clinical picture
and that are induced by (a) precipitating factors. Cer-
tainly, Harvey and Wessely [1] consider that a virus may
trigger fatigue; however, their model does not include the
concept that infections can trigger IO&NS pathways that
may explain the consequent symptoms. We label the
IO&NS-induced symptom complex 'fatigue and somatic'
(F&S) symptoms, which encompass a flu-like malaise,
fatigue, pain and muscle aches, cognitive disturbances,
autonomic symptoms and so on [5]. Psychiatrists typi-
cally consider these symptoms to be 'functional' and label
them as 'psychosomatic', 'hysteria' or 'somatisation'.
Patients with specific F&S symptoms are diagnosed as
ME/CFS patients once a number of diagnostic criteria are
fulfilled (for example, as described by Fukuda et al. [6]).
While Harvey and Wessely [1] acknowledge a minor role
for biological factors as maintenance factors of ME/CFS,
the cause and effect relationships of these biological fac-
tors are not specified.
However, there is evidence that IO&NS pathways play a
key role in the pathophysiology of ME/CFS and other
conditions in which F&S symptoms are prevalent. The
findings that IO&NS pathways are involved in the
pathophysiology of ME/CFS are replicated in many stud-
ies as reviewed previously ([4,7-9] and references
therein). Figure 3 shows the pathways that are involved in
F&S symptoms and ME/CFS. The factors involved are
shown in Table 1[10-30].
These, and other previously reviewed findings show
that the F&S symptoms are a clinical expression of dys-
regulated IO&NS pathways [4]. As previously outlined
[4], increased levels of proinflammatory cytokines, oxida-
tive damage, increased cyclo-oxygenase 2 (COX-2) pro-
Figure 3 The inflammatory and oxidative and nitrosative (IO&NS) pathophysiology of myalgic encephalomyelitis/chronic fatigue syn-
drome (ME/CFS). COX-2 = cyclo-oxygenase 2; iNOS = inducible nitric oxide synthase; PUFA = polyunsaturated fatty acids; NFκB = nuclear factor κB.
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duction, increased translocation by Gram-negative
enterobacteria and so on, can generate F&S symptoms,
including fatigue, a flu-like malaise, pain, symptoms of
irritable bowel syndrome, and neurocognitive disorders.
In addition, aberrations in IO&NS pathways are interre-
lated. For example, viral and bacterial infections and gut-
derived inflammation may induce nuclear factor κB
(NFκB) and consequently COX-2, inducible nitric oxide
synthase (iNOS) and increased levels of proinflammatory
cytokines. These inflammatory pathways and persistent
or reactivating infections induce radical oxygen species
(ROS) and radical nitrogen species (RNS), which in turn
may damage membrane fatty acids, proteins, DNA and
mitochondria. As a consequence of IO&NS, some cellu-
lar immune functions may be suppressed, for example,
lowered natural killer cell activity (NKCA) and ex vivo
expression of T cell activation markers, such as CD69.
The aberrations mentioned above can also cause chan-
nelopathy, reduced omega-3 polyunsaturated fatty acid
levels, cell death and apoptosis, and change inactive
autoantigens into neoepitopes, which have acquired
immunogenicity and act as triggers to bypass immuno-
logical tolerance. This process may explain the occur-
rence of an IgM-mediated autoimmune responses
mounted against neoepitopes formed by O&NS damage
to fatty acids, by oxidation, and proteins, by nitration.
The above-mentioned processes may also explain the
development of autoimmune responses against a plethora
of self-antigens, including gangliosides and serotonin
[4,20]. Depletion of antioxidants in patients with ME/
CFS, partially due to inflammation, may further impair
the protection against ROS and RNS, causing more dam-
age to fatty acids, proteins, DNA and mitochondria
[4,20]. Not every patient exhibits the full spectrum of
these IO&NS disorders. In fact, each of the above-men-
tioned aberrations and/or combinations thereof may
induce specific F&S symptoms, whereas ME/CFS is asso-
ciated with the more severe forms of IO&NS aberrations
(for example, severe inflammation, dysregulation of the
RNase L pathway, apoptosis pathways, persistent damage
to membrane lipids, functional proteins, DNA, and mito-
chondria and autoimmune responses [4,20]). For exam-
ple, an initial infection may trigger the production of
NFκB and consequently proinflammatory cytokines.
These in turn may induce active immune-mediated
symptoms (the F&S symptoms). Increased O&NS as a
consequence of inflammatory responses can cause dam-
age to membrane fatty acids, functional proteins, DNA or
mitochondria, which further aggravate the immune-
mediated symptoms. The primary inflammatory reac-
tions can cause gut-derived inflammation that further
aggravates inflammation and O&NS [10]. In some severe
cases the above-mentioned processes may cause autoim-
mune responses against neoepitopes or self-antigens via,
for example, mimicry [4,20].
Table 1: Overview of the different immune, inflammatory,
oxidative and nitrosative stress (IO&NS) aberrations in
myalgic encephalomyelitis/chronic fatigue syndrome (ME/
CFS)
Aberrations in the IO&NS pathways in
ME/CFS
Reference(s)
Increased production of key inflammatory
mediators, such as NFκB, COX-2, iNOS
Maes et al. [10], Maes
et al. [11]
Increased levels of proinflammatory
cytokines
Fletcher et al. [12]
Immune activation, with increased in vivo
expression of activation markers, such as
CD38, and Th 1-like or Th 2-like responses
Klimas et al. [13]
Immunosuppression, for example,
diminished natural killer cell activity (NKCA),
and decreased ex vivo expression of
activation markers, such as CD69
Maher et al. [14],
Mihaylova et al. [8]
Depleted antioxidant levels Maes et al. [15]
Increased levels of radical oxygen (ROS) and
nitrogen species (RNS)
Kennedy et al. [16]
Oxidative damage to membrane fatty acids,
mitochondria, functional proteins and DNA
Maes et al. [17], Behan
et al. [18]
Autoimmune responses against oxidatively
modified fatty acids and nitrated proteins
(neoepitopes)
Maes et al. [9]
Autoimmune reactions Maes (review) [19]
Gut dysbiosis and gut-derived inflammation
with increased bacterial translocation
Maes et al. [20-22],
Sheedy et al. [23]
Mitochondrial dysfunctions with lower
carnitine and coenzyme Q10 levels
Myhill et al. [24],
Plioplys and Plioplys
[25], Maes et al. [7]
Upregulation and dysregulation of the 2'-5'
oligoadenylate synthetase/RNase L
pathway
Nijs and De Meirleir
[26]
Apoptosis pathways Gow et al. [27], Kerr et
al. [28]
Ion channel dysfunction (channelopathy) Broderick et al. [29]
Lowered omega-3 polyunsaturated fatty
acids
Maes et al. [30]
For space considerations, this table only shows a selection of the
relevant references. A more comprehensive listing can be supplied
on request from the authors.
COX-2: cyclo-oxygenase 2; iNOS = inducible nitric oxide synthase;
NFκB = nuclear factor κB; Th = T helper.
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It is often argued that the above-mentioned aberrations
may be 'consequences' rather than the initial cause of the
illness. However, as reviewed previously [4,8,9,20], there
is ample evidence that immune activation and increased
O&NS may induce F&S symptoms and, in specific cases,
ME/CFS, and that treatments that target the IO&NS
pathways may have a clinical efficacy in treating ME/CFS
and F&S symptoms in general [4]. Moreover, these clini-
cal findings are corroborated by observations in animal
models demonstrating that experimentally induced acti-
vation of IO&NS pathways is accompanied by inflamma-
tion-induced 'fatigued' behaviour [31,32]. In this context,
only a few examples are given. In mice, lipopolysaccha-
ride (LPS)-induced peripheral immune activation is
accompanied by fatigue. The severity of fatigue, motor
deficits, coordination problems induced by immune acti-
vation correlate to the levels of the anti-inflammatory
cytokine interleukin 10 [33]. In rats, intraperitoneal injec-
tions of a synthetic double-stranded RNA, polyriboinos-
inic:polyribocytidylic acid (poly I:C) induces profound
fatigue, which is, amongst other things, characterised by
increased levels of interferon-alpha that induces immune
activation [34]. In experimental animals, induction of
O&NS by intensive and exhaustive exercise induces neu-
rocognitive symptoms [35]. Evidence is also provided by
animal models showing that experimentally induced F&S
symptoms are associated with activation of the IO&NS
pathways and that targeting IO&NS may reverse
'fatigued' behaviour [31-35].
It is often argued that 'animal models of ME/CFS' do
not reflect ME/CFS in humans. However, translational
research is of great importance in deciphering the path-
ways that may cause inflammation-mediated behavioural
changes. Only one example is given: the effect of LPS. An
increased immune response against the LPS from Gram-
negative bacteria has been established in patients with
ME/CFS, indicating a higher LPS load in their blood [20].
This may be the result of an increased translocation of
Gram-negative enterobacteria from the gut to the blood
due to increased gut permeability or leaky gut [20]. Ani-
mal experiments have demonstrated that LPS injected
into the rodent may induce specific symptoms, such as
F&S symptoms, through immune activation and neuroin-
flammation [20]. These translational experiments show
that an increased immune response against LPS from
Gram-negative bacteria, as has been detected in ME/CFS
patients, can induce inflammation-mediated F&S symp-
toms [20].
Aetiological factors
In humans, many studies have demonstrated that differ-
ent pathogens can induce and/or maintain F&S and ME/
CFS: viral (for example, Herpes Simplex, cytomegalovi-
rus, Epstein Barr, Human Herpesvirus 6 (HHV-6)), and
bacterial, (for example, Chlamydia pneumoniae, Myco-
plasma species, enterobacteria, and Coxiella burnetii
infections [4]). Psychosocial and physical stressors can be
important precipitating and perpetuating (co)factors for
F&S symptoms and gradual onset ME/CFS as well [4]. As
reviewed previously, even moderate psychological stres-
sors, such as examination stress, can induce the cytokine
network [36] and O&NS pathways [4,37]. There is suffi-
cient evidence that physical stressors activate the IO&NS
pathways [4]. Harvey and Wessely [1] consider viral infec-
tions and stress to be triggers only, and don't consider
their role in the pathophysiology of ME/CFS. Their
model does not specify whether stress indicates physical
or psychological stress. But more importantly, the model
does not embody the important role of infections (viral
and bacterial) and physical or psychological stress as
cofactors. Therefore, we propose to include all above-
mentioned precipitating factors in the biological explana-
tory model, as presented in Figure 3.
As stated by Harvey and Wessely [1], other factors can
instigate ME/CFS symptoms (that is, the 'zebras', the rare
organic causes of ME/CFS such as immune disorders).
This is important because (auto)immune disorders,
including autoimmune thyroid disorders, multiple sclero-
sis and rheumatoid arthritis, can induce F&S symptoms
[19]. Consequently, '(auto)immune disorders' should be
acknowledged as perpetuating factors for ME/CFS and
F&S symptoms in general. In analogy to the diagnostic
classification system in depression one could consider
this concept as 'ME/CFS due to a general medical condi-
tion'. However, as discussed above, it has been demon-
strated that patients with ME/CFS suffer from one or
more IO&NS disorders and thus from an organic condi-
tion that can explain their F&S symptoms. An alternative
view is that all the triggers mentioned above share the
capacity to activate IO&NS pathways that eventually
cause F&S symptomatology.
Harvey and Wessely [1] declare ME/CFS to be medi-
cally unexplained. However as stated above, the core ele-
ments of the organic pathophysiology of ME/CFS are
already likely known: the induction of IO&NS pathways
and its sequelae. As such the F&S symptoms of ME/CFS
are largely explainable in terms of its pathophysiology. Of
course, Harvey and Wessely [1] are correct to state that
the trigger factors often remain unknown even after
'chasing the zebras'. Indeed, in the individual patient it
not always possible to pinpoint the original trigger,
because the trigger may have disappeared when the
patient is examined. For example, a Mycopl asma infec-
tion may contribute to (chronic) activation of the IO&NS
pathways, which eventually cause damage to lipids, pro-
teins and DNA, gut-derived inflammation and autoim-
munity [20]. The latter may persist after the Mycoplasma
infection is eradicated by antibiotics [20]. Therefore, Har-
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vey and Wessely's [1] discussion on whether the triggers
(the zebras, the horses) can be pinpointed is in fact not
really relevant, because ME/CFS can be understood by its
pathophysiology even though sometimes (but not always)
the precipitating factors cannot be pinpointed.
Based on their model, Harvey and Wessely [1] propose
that the initial cause of the fatigue has a limited impact on
the eventual course of the illness. This statement may be
correct in some cases. However, it has been demon-
strated that the severity of the illness and the rate of
recovery of ME/CFS patients whose condition was trig-
gered by specific infections may be determined by the
acute phase of the infection [38,39]. More importantly,
specific pathogens have been shown to cause persistent
infections [40-43]. Whether or not the original trigger is
still present and can be detected, the severity of F&S
symptoms is significantly correlated to pathophysiologi-
cal biomarkers. For example, Maes et al. [9-11,44]
detected significant positive correlations between the
severity of F&S symptoms in ME/CFS and IgM-mediated
immune responses against neoepitopes originating from
damage to O&NS-modified lipids and proteins, and
increased NFκB, COX-2, and iNOS production. This
indicates that even if the initial trigger has a limited
impact on the course of the illness, there still is a signifi-
cant association between the pathophysiological path-
ways induced by that trigger and the clinical
manifestations of aberrations in the IO&NS pathways.
Harvey and Wessely [1] outline that even fatigue associ-
ated with 'apparent medical causes', such as cancer and
HIV infection, is more closely associated with behav-
ioural and psychological factors than with the severity of
the underlying pathophysiology. However, in patients
with autoimmune disorders, 'fatigue' can largely be
explained by activated IO&NS pathways (for example,
increased interleukin 1 (IL-1) [45]). In cancer patients,
there is evidence that cytokines (for example, IL-6) play a
key role in the fatigue [46]. HIV infection is characterised
by fatigue accompanied by clinical signs of inflammation
[47], an impaired quality of life that is related to immune
activation [48], and a dysfunctional carnitine-dependent
energy production [49].
Predisposing factors
Harvey and Wessely's [1] model incorporates the
assumption that some individuals are predisposed to
develop fatigue and ME/CFS. They propose that person-
ality factors, periodic overactivity, deconditioning,
increased use of doctors, early childhood illness and so
on, may predispose towards ME/CFS. However, central
elements of their psychosocial model and the Vercoulen
et al. model [2], including kinesiophobia and personality
traits, have been disproved by various studies [50,51]. A
recent study by Wiborg et al. [52], for example, invali-
dates the cause and effect relationship between physical
activity and 'fatigue': improvement in the subjective feel-
ing of 'fatigue' is not reflected by an increase in physical
activity. The Vercoulen et al. model [2] as a whole has
been invalidated by Song and Jason [50]. It is also inter-
esting to note that in some studies, but not all, personality
traits, coping mechanisms and psychiatric history do not
seem to affect the outcome of CBT/GET, while immuno-
logical and related endocrinological variables do
[51,53,54]. In addition, Harvey and Wessely [1] do not
mention the immunological predisposing factors, such as
polymorphisms in immune genes associated with ME/
CFS [55-57], and deficiencies in immunoglobulins, such
as IgG1, IgG2 and IgG3 [20,58].
Maintaining factors
In the Harvey and Wessely model [1] biological factors
are mentioned as maintaining factors. Harvey and Wes-
sely [1], however, do not specify these 'biological factors'.
There is no rationale to locate these pathophysiological
maintaining factors between fatigue and CFS as Harvey
and Wessely do. In our model, however, IO&NS abnor-
malities such as chronic inflammation, damage caused by
IO&NS, and autoimmune disorders may persist, thereby
becoming maintaining factors. The activated IO&NS
pathways not only determine the expression of F&S
symptoms, but can also determine the duration of those
symptoms directly.
Other important maintaining factors in Harvey and
Wessely's model are prolonged bed rest and boom and
bust activity. Prolonged bed rest cannot be considered to
be a maintaining factor, since often it is a dependent vari-
able (not cause, but effect). As an illustration we refer to a
case study [20]. This was a patient who suffered from
ME/CFS, but was considered to be hysteric (la belle indif-
ference) or psychosomatic by psychiatrists, the usual 'psy-
chiatric' explanation. In this patient, a Mycop lasma
infection induced an inflammatory cascade accompanied
by O&NS-induced damage, a deficiency in specific anti-
oxidants, gut-derived inflammation, autoimmunity to
serotonin and gangliosides, resulting in paralysis and
'prolonged bed rest' [20]. In this case, one might expect
the physician to conclude that the Mycoplasma infection
is an important propulsive trigger factor for an IO&NS-
driven pathophysiology, including severe inflammation
and autoimmune responses, such as Guillain-Barre syn-
drome, with paralysis and, thus, prolonged bed rest [20].
It is, therefore, incomprehensible that Harvey and Wes-
sely [1] consider a dependent variable to be an explana-
tory variable in their model, while the real explanatory
variables (for example, the aberrations in the IO&NS
pathways and their sequelae), and the bacterial infections,
are not included.
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How boom and bust activity may act as a maintaining
factor in ME/CFS is not clear to us. Even if boom and
bust activity would be relevant, its exact role in the model
has yet to be determined and we would propose that this
needs to be further verified by applying pathway analysis
or other multivariate techniques in order to ascertain the
significant cause and effect relationships between boom
and bust activity and the IO&NS variables.
In addition, psychological stressors can be important
maintaining factors for ME/CFS, as indicated by observa-
tions that acute and chronic psychological stress ampli-
fies inflammation [16] and O&NS [37,59,60], which are
already present in ME/CFS. Physical stressors can act as
perpetuating factors for ME/CFS. This is substantiated by
observations that exercise intensifies the pre-existing bio-
logical pathophysiology in many patients with ME/CFS
[51].
Symptomatology
In accordance with Jones et al. [61], Harvey and Wessely
[1] propose to extend the definition of CFS by relaxing
the exclusion criteria of the case definition of Fukuda [6].
Whether this is appropriate or not needs further investi-
gation, we suggest by pattern recognition methods to
determine whether specific patient clusters can be
retrieved in a 'fatigued' population and to unravel the fac-
tor structure of F&S symptomatology. Unfortunately, in
contrast to research in depression, to date not much
effort has been put into multivariate studies in ME/CFS
and fatigue in general. In some of our studies we have
considered the differences in IO&NS pathways between
patients fulfilling Fukuda's ME/CFS criteria and patients
with chronic fatigue not fulfilling Fukuda's criteria. A dis-
tinction between ME/CFS and chronic fatigue is reflected
by the type and severity of F&S symptoms, and by the
biological abnormalities that are more prevalent in ME/
CFS. Analyses of IgA responses against enterobacteria
showed that these biological disorders are significantly
more pronounced in ME/CFS than in chronic fatigue
[21]. This situation is comparable to 'melancholic' depres-
sion, which is within the group of depressed patients
(including minor and major depression) a qualitatively
different category with regard to the severity and type of
depressive symptoms and biological abnormalities [5].
Harvey and Wessely [1] suggest that the most common
'comorbid' condition in ME/CFS is depression, and they
seem to suggest that if depression is present a mental
state examination remains the best investigation. Depres-
sion frequently co-occurs with ME/CFS [62]. Because
many patients with ME/CFS and related conditions have
comorbid mood or anxiety disorders, it has been sug-
gested that chronic fatigue is a 'form fruste' of depression
[63]. Recently, we have shown that F&S symptoms are
also key symptoms of (melancholic) depression. F&S
symptoms observed in depression even seem to predict
the severity and chronicity of depression [5]. Some
patients presenting to physicians for evaluation of their
symptoms concentrate on fatigue and are depressed. A
mental state examination to identify patients with
'comorbid' depression is certainly warranted and treat-
ment of depression, when present, is recommendable.
The proposal of Harvey and Wessely [1] that a 'mental
state examination' remains the best investigation in per-
sons with 'unexplained fatigue' is not correct. First, as jus-
tified above, we would propose that analysing the
aberrations in the IO&NS pathways is more important
for unravelling the pathophysiology of ME/CFS and F&S
symptoms in general than a mental state examination.
Second, ME/CFS can be discriminated with a 100% accu-
racy from depression using percentage of time fatigue
reported, severity of post-exertional malaise and short-
ness of breath, unrefreshing sleep severity, confusion/dis-
orientation severity, and self-reproach [64]. In addition, a
biological distinction between ME/CFS and depression
has recently been confirmed by differential gene expres-
sion [65].
Further, we would suggest that the co-occurrence of
depression, F&S symptoms and ME/CFS is more complex
than suggested by Harvey and Wessely [1]. There is evi-
dence that partially overlapping IO&NS pathways can
induce two typical symptom clusters (that is, F&S symp-
toms such as pain, muscle tension, a flu-like malaise, neu-
rocognitive complaints, and sleep disorders; and
depressive complaints, such as sadness, loss of interest,
psychomotor retardation, anorexia, weight loss and anhe-
donia [4,66,67]). For example, cytokine-based immuno-
therapy (with interferon-α) in patients infected with the
hepatitis C virus induces two potentially coexistent
symptom profiles: (a) F&S symptoms appearing early
after starting treatment and occurring in almost all
patients, and (b) depressive symptoms, occurring some
weeks later in a subgroup of the patients [68,69]. Impor-
tantly, the severity of depression is even predicted by the
severity of the F&S symptoms some weeks earlier [68]. In
animal models, the above-mentioned F&S symptoms and
depressive symptoms are induced by peripheral and cen-
tral (neuro)inflammation, for example by interleukin 1β
and tumour necrosis factor α (TNFα) [70,71]. This
implies that depression and ME/CFS can be regarded as
clinical manifestations of aberrations in shared IO&NS
pathways. They can be distinguished by differences in
other biological pathways (for example, the turnover of
serotonin, neurodegeneration, decreased neurogenesis,
and hypercortisolism, distinctive for depression [67]),
and, for example, RNase L fragmentation [26,72] and
hypocortisolism [73], characteristic for ME/CFS.
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Whether ME/CFS and depression are co-occurrent man-
ifestations of shared IO&NS pathways requires further
investigation.
Therapy
When looking at the evidence base, it is not clear that the
effectiveness of CBT/GET is significant in CFS/ME. The
effectiveness of CBT/GET (20% to 40%), compared to
support groups, natural course, standard medical care
and so on (20% to 30%), is at best marginal [3]. If one
takes into consideration the fact that self-rated fatigue
was the only measure in most studies, 'fatigue' is a subjec-
tive measure that we suggest is largely insufficient to
diagnose ME/CFS and has no correlation with objective
measures, such as cardiopulmonary capacity [74] or
physical activity [51]. Moreover, of the few randomised
controlled trials considered to be relevant, almost all
explicitly excluded large groups of ME/CFS patients and/
or included non-ME/CFS patients, due to the selection
criteria [51].
Previous papers have reported favourable effects for
improvement in functional work capacity and fatigue by
GET, irrespective of depression [75]. This could be
explained by the fact that habitual exercise can improve
autonomic nervous system adaptation and induce pulmo-
nary and cardiovascular conditioning in a subset of
chronic fatigued patients. However, in patients with ME/
CFS, CBT/GET has been shown to be counterproductive
in many patients. Based on the evaluation of the Belgian
Reference Centres, the Belgian Minister of Health offi-
cially declared that CBT/GET should not be regarded as a
curative therapy for ME/CFS [51,74]. This evaluation
revealed that the exercise capacity/condition of the
patients treated had not improved and that the occupa-
tional participation had even decreased after CBT/GET
[51]. Two large-scale patient surveys in the UK and Nor-
way, and two smaller surveys in Scotland and The Neth-
erlands indicate that CBT/GET aggravates the condition
of many ME/CFS patients [51]. It could be argued that
GET may result in a 'late improvement' following 'initial
worsening'. However, we have reviewed elsewhere that
rehabilitation programmes, like CBT/GET, intensify
characteristic F&S complaints, such as fatigue, pain, neu-
rocognitive problems and so on [51]. This negative
impact on the symptomatology of ME/CFS can be
explained by the fact that exertion and GET may amplify
the pre-existing pathophysiological aberrations, such as
inflammation, O&NS; damage caused by O&NS, and
sequelae such as mitochondrial dysfunctions and so on
[51]. This suggests that the IO&NS pathways should be
normalised before starting GET-like rehabilitation pro-
grammes. GET should, in our view, be accompanied by
frequent assessment for IO&NS abnormalities. If present,
they would strongly indicate that CBT/GET likely has no
significant or even possibly negative effects. It could be
argued, however, that the harm induced by CBT/GET
will most likely occur in misdiagnosed patients, and it
cannot be excluded that CBT may be a useful therapy for
ME/CFS in some cases even in patients without major
depression.
Conclusions emerging from the IO&NS model
presented here
Our comparison of Harvey and Wessely's model with a
model more biologically based suggests that a biological
model based upon IO&NS pathways is more appropriate
to describe this complex organic disorder. Activation of
the IO&NS pathways induces important characteristic
ME/CFS symptoms, forms of chronic fatigue and F&S
symptoms in general. The IO&NS pathways can be insti-
gated by infections, viral and bacterial, psychosocial and
physical stressors as well as medical disorders such as
(auto)immune disorders, which all function as precipitat-
ing and/or maintaining factors for ME/CFS.
The IO&NS model presented here may explain the
spontaneous improvement or resolution of illness that
occurs in those with an acute onset and particularly in
adolescents with an infectious onset. Spontaneous reso-
lution of the symptoms may occur when these IO&NS
responses are diminished once the initial infection is
eradicated. However, in predisposed persons, the initial
infection may induce extensive and long-term sequelae in
the IO&NS pathways. Our pathophysiological model
could also explain why F&S symptoms may persist in the
absence of increased cytokine levels as is documented in
post-infection fatigue studies [76]. The primary infec-
tions and subsequent responses in some specific cytok-
ines might have resolved while the damage caused by
O&NS to lipids, proteins or DNA and consequent auto-
immune responses may persist and disable the patients,
thus explaining residual F&S symptoms [19,20]. More-
over, it is always possible that neuroinflammation, other
cytokines or proinflammatory products are involved
which had not been measured in these studies.
It is important to note that the above-mentioned
IO&NS pathways also offer a plausible explanation for the
earlier mortality due to cardiovascular disorder in ME/
CFS, which is described in detail elsewhere [77,78].
Based on their model, Harvey and Wessely [1] recom-
mend clinicians to avoid spending too much time chasing
'rare or unlikely diagnoses', or in their own words: 'not to
spend too much time looking for zebras among the
horses', and they propose to limit the organic investiga-
tions to a small set of blood tests. In contrast, we suggest
that clinicians should examine the IO&NS pathophysiol-
ogy, their sequelae, and the possible precipitating and
maintaining factors (for example, infections) in any given
patient. In our opinion, not investigating the IO&NS
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pathways could lead to inappropriate diagnosis of the
underlying pathophysiology and thus possible inappro-
priate treatment for the patient.
The set of blood tests proposed by Harvey and Wessely
[1] includes some widely accepted tests for inflammatory
diseases, such as C reactive protein and antibody assays
for bacterial and viral infections and, in our opinion,
should be conducted when assessing patients with ME/
CFS. In addition, we suggest additional tests (outlined in
Appendix 1) that are also good candidates and that can be
performed as part of routine laboratory investigations;
some of these are already approved by regulatory agen-
cies. We think that regulatory agencies should objectively
evaluate and approve the other tests, so that ME/CFS
patients are reimbursed and these assays can be used on a
regular basis in these patients.
Further, to identify the most accurate therapeutical
approach it is likely necessary to define subtypes accord-
ing to the IO&NS pathophysiology and the precipitating
and predisposing factors [4,74]. Thus, a distinction
should be made between the type of IO&NS disorders the
patients suffer from. Does the individual patient suffer
from gut-derived inflammation, T helper (Th) 1-like or
Th 2-like immune responses, monocytic activation, dys-
regulation of RNase L pathway, channelopathy, mito-
chondrial dysfunction, a low coenzyme Q10 syndrome,
damage to fatty acids, functional proteins or DNA, auto-
immunity, and so on, or combinations of these aberra-
tions? It is also important to uncover potential triggers
and maintaining factors, such as bacterial and viral infec-
tions, psychological stressors, overexertion, and the rare
'zebras', such as (auto)immune disorders, that may
explain the IO&NS pathophysiology of F&S symptoms
and ME/CFS. Finally, it is important to pinpoint the pre-
disposing and maintaining factors, such as IgG subclass
deficiencies and immunosuppression with recurrent
infections, respectively. When bacterial or viral infections
have been shown to be important maintaining factors,
antibiotics and antiviral medications are essential [4,74].
Intravenous immunoglobulins are an evidence-based
treatment option for ME/CFS accompanied by common
variable hypo-γ-globulinaemia or IgG subclass deficien-
cies, and recurrent infections or autoimmunity [20].
Treatment with carnitine, coenzyme Q10, and so on, may
be advised in subjects with depleted mitochondrial func-
tions [7,79]. Gut-derived inflammation responds favour-
ably to treatment with glutamine [22]. Mouse models of
ME/CFS demonstrate that F&S symptoms can be
induced by peripheral and central IO&NS pathways,
including lipid peroxidation and depleted antioxidant
defences, and that those symptoms may be reversed by
specific anti-inflammatory and antioxidant therapies tar-
geting the IO&NS pathways [31,32]. Needless to say that
there are still many IO&NS pathways in ME/CFS for
which no adequate treatment exists, such as severe dam-
age to lipids and proteins, and autoimmune responses.
We do not agree with the statement of Harvey and
Wessely [1] that a mental state examination remains the
best investigation in persons with 'unexplained fatigue'
because the 'fatigue' could be explained by a mental con-
dition, such as depression. First, because we would pro-
pose that a biological investigation is likely to be a better
indication of the underlying causes that may account for
many F&S complaints. Second, patients with ME/CFS
can be discriminated from those with depression by using
a characteristic symptom profile [64] or biological mark-
ers [72,73]. Third, as described above, the co-occurrence
between depression, F&S symptoms and ME/CFS is com-
plex. It appears that ME/CFS and major depression are
symptomatic manifestations of shared IO&NS pathways.
Based on the above, we propose that the F&S symptoms
of ME/CFS are not caused by depression and that ME/
CFS does not cause depression. This implies also that
both disorders are distinct diagnostic categories that
should be treated differently.
We propose that future research should use high
throughput, high quality screening, as made possible by
translational research employing genotyping microarrays
and functional genomics (assays of IO&NS genes), novel
IO&NS animal models of ME/CFS, including transgenic
mouse models (IO&NS overexpression or knockouts),
and promoter induction based indicator cell lines that are
specific to the brain (for example, neuroinflammation,
damage by O&NS), muscles (for example, damage by
O&NS, mitochondrial dysfunctions) and the gut (for
example, gut inflammation and gut-derived inflamma-
tion) in order to further delineate novel drug targets in
the IO&NS pathways and develop new drugs to treat this
complex medical disorder. Multivariate pattern recogni-
tion studies should be carried out in order to (a) define
clinical subtypes of ME/CFS and chronic fatigue and
their associations with co-occurrent depression, and (b)
examine the shared IO&NS pathways versus those that
discriminate both disorders. Finally, interventional stud-
ies should be carried out to test the clinical efficacy of
(novel) drugs in treating the biological causes of ME/CFS
subgroups, defined by biomarkers such as inflammatory
profiles or gene expression.
Appendix 1
List of specific tests by category that should be carried
out on a regular basis to investigate IO&NS abnormalities
in ME/CFS.
Inflammation
Proinflammatory cytokine tests: interleukin 1β (IL-1β),
IL-6, and tumour necrosis factor α (TNFα).
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T cell activation marker measurement by means of flow
cytometry (for example, CD38+ T cells).
Anti-nuclear factor antibody tests.
Serotonin and ganglioside antibody tests.
Protein electrophoresis.
Oxidative and nitrosative stress
IgM response tests against neoepitopes formed by O&NS
damage to lipids and proteins.
Plasma carnitine tests (free, total and so on).
Plasma malondealdehyde (thiobarbituric acid reactive
substances (TBARS)) test.
Gut-derived inflammation
Tests to detect increased gut permeability.
Predisposing factors
IgG subclass deficiency tests (IgG3 and so on).
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
Both authors contributed equally to this review and reanalysis. The authors
read and approved the final manuscript.
Author Details
1Maes Clinics @ TRIA, Piyavate Hospital, Bangkok, Thailand and 2ME-de-
patiënten Foundation, Limmen, The Netherlands
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Received: 4 December 2009 Accepted: 15 June 2010
Published: 15 June 2010
This article is available from: http://www.biomedcentral.com/1741-7015/8/35© 2010 Maes and Twisk; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.BMC Medicine 2010, 8:35
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Pre-publication history
The pre-publication history for this paper can be accessed here:
http://www.biomedcentral.com/1741-7015/8/35/prepub
doi: 10.1186/1741-7015-8-35
Cite this article as: Maes and Twisk, Chronic fatigue syndrome: Harvey and
Wessely's (bio)psychosocial model versus a bio(psychosocial) model based
on inflammatory and oxidative and nitrosative stress pathways BMC Medicine
2010, 8:35
... These different approaches, sometimes even competing, comprise folk psychology (the culprit of CFAS-D is a psychological problem) and the medical approach (the culprit is one specific virus or different viruses or bacteria). The dominant view, especially in Europe, is that of the cognitive-behavioral and the biopsychosocial schools (1). This view entails that CFAS-Ds, even when due to medical disease (e.g., cancer), are the consequence of psychosocial and biological factors and negative cognitions (1)(2)(3)(4). ...
... The dominant view, especially in Europe, is that of the cognitive-behavioral and the biopsychosocial schools (1). This view entails that CFAS-Ds, even when due to medical disease (e.g., cancer), are the consequence of psychosocial and biological factors and negative cognitions (1)(2)(3)(4). The Wessely model, for example, conceptualizes that the effects of a trigger factor, which may be a virus, are mediated by boom and bust activity and bed rest and the Vercoulen model considers that CFAS-D symptoms are aggravated by causal attributions and reduced physical activity (1). ...
... This view entails that CFAS-Ds, even when due to medical disease (e.g., cancer), are the consequence of psychosocial and biological factors and negative cognitions (1)(2)(3)(4). The Wessely model, for example, conceptualizes that the effects of a trigger factor, which may be a virus, are mediated by boom and bust activity and bed rest and the Vercoulen model considers that CFAS-D symptoms are aggravated by causal attributions and reduced physical activity (1). Nevertheless, it appears that the label "biopsychosocial" is more window dressing than the actual approach because, in fact, folk psychology statements abound in their publications, as, for example, "it is in the mind, " "they think themselves ill, " and "it is a disorder of perception, whereby patients think those symptoms are the consequence of a virus" [review : 2]. ...
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There is evidence that chronic fatigue spectrum disorders (CFAS-Ds), including myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and chronic fatigue with physiosomatic symptoms including when due to comorbid medical disease, are characterized by neuroimmune and neuro-oxidative biomarkers. This study was performed to delineate the protein-protein interaction (PPI) network of CFAS-D and to discover the pathways, molecular patterns, and domains enriched in their PPI network. We performed network, enrichment, and annotation analyses using differentially expressed proteins and metabolics, which were established in patients with CFAS-D. The PPI network analysis revealed that the backbone of the highly connective CFAS-D network comprises NFKB1, CTNNB1, ALB, peroxides, NOS2, tumor necrosis factor (TNF), and interleukin-6 (IL-6) and that the network comprises interconnected immune-oxidative-nitrosative and Wnt/β-catenin subnetworks. Multiomics enrichment analysis shows that the CFAS-D network is highly significantly associated with cellular (antioxidant) detoxification, hydrogen peroxide metabolic process, peroxidase and oxidoreductase activity, interleukin-10 (IL-10) anti-inflammatory signaling and neurodegenerative canonical Wnt, the β-catenin complex, cadherin domains, cell-cell junctions and TLR2/4 pathways, and the transcription factors nuclear factor kappa B (NF-κB) and RELA. The top 10 DOID annotations of the CFAS-D network include four intestinal, three immune system disorders, cancer, and infectious disease. The custom Gene Ontology (GO) term annotation analysis revealed that the CFAS-D network is associated with a response to a toxic substance, lipopolysaccharides, bacterium, or virus. In conclusion, CFAS-D may be triggered by a variety of stimuli and their effects are mediated by aberrations in the cross-talks between redox, NF-κB, and Wnt/β-catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes.
... Myalgic Encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a disorder characterized by symptoms that also occur in ESRD, including depression, fatigue, fibromyalgialike symptoms, muscular pain, insomnia, headache, and cognitive impairments [18,19]. There is evidence that ESRD and ME/CFS are both characterized by a multitude of intertwined pathways, including activation of immune-inflammatory and nitro-oxidative stress pathways. ...
... Finally, malfunctions of electrolyte channels and transporters in the injured kidneys may cause abnormalities in sodium, potassium, chloride, and phosphate [33][34][35]. ME/CFS is an immune-inflammatory and oxidative stress disorder which is characterized by increased levels of pro-inflammatory cytokines, an acute phase response with lowered levels of negative acute phase reactants such as albumin and zinc, and increased oxidative stress [18,19,36]. In addition, the severity of ME/CFS, as assessed with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale [37], is associated with signs of activated immune-inflammatory and oxidative pathways [38]. ...
... In addition, the severity of ME/CFS, as assessed with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale [37], is associated with signs of activated immune-inflammatory and oxidative pathways [38]. Previously, it was discussed that these pathways might cause symptoms of mental and physical fatigue and physio-somatic symptoms, including muscle fatigue and pain, insomnia, hyperesthesia, gastro-intestinal (GI) symptoms, cognitive impairments and affective symptoms as well [18,19,36,39,40]. ...
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Background End-stage renal disease (ESRD) is associated with fatigue and physio-somatic symptoms. Objective To delineate the associations between severity of fatigue and physio-somatic symptoms and glomerular filtration rate, inflammatory biomarkers, and Wnt/catenin-pathway proteins. Methods The Wnt-pathway related proteins β-catenin, Dickkopf-related protein 1 (DKK1), R-spondin-1, and sclerostin were measured by ELISA technique in 60 ESRD patients and 30 controls. The Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale was used to assess the severity of FF symptoms. Results ESRD is characterized by a significant increase in the total FF score, muscle tension, fatigue, sadness, sleep disorders, gastro-intestinal (GI) symptoms, and a flu-like malaise. The total-FF score was significantly correlated with serum levels of urea, creatinine, and copper (positively), and β-catenin, eGFR, hemoglobin, albumin, and zinc (inversely). The total-FF score was associated with the number of total dialysis and weekly dialysis sessions, and these dialysis characteristics were more important in predicting FF scores than eGFR measurements. Partial Least Squares analysis showed that the FF score comprised two factors that are differently associated with biomarkers: a) 43.0% of the variance in fatigue, GI symptoms, muscle tension, sadness, and insomnia is explained by hemoglobin, albumin, zinc, β-catenin, and R-spondin-1; and b) 22.3% of the variance in irritability, concentration and memory impairments by increased copper and cations/chloride ratio, and male sex. Conclusion ESRD patients show high levels of fatigue and physio-somatic symptoms, which are associated with hemodialysis and mediated by dialysis-induced changes in inflammatory pathways, the Wnt/catenin pathway, and copper.
... Cytokine alterations are correlated with duration of illness, suggesting that CFS immunopathology is "not static" [13]. Abnormal cytokine profiles such as increased production of interferon (IFN) γ were observed in patients with CFS [14] and latent MTI [15]. Other immune activation markers of CFS include higher levels of the proinflammatory cytokines, tumour necrosis factor (TNF) α, interleukin (IL) 6, and IL-1β. ...
... Our current findings suggest that TB is correlated with CFS. Studies have proposed possible mechanisms of disease, including immunoinflammatory pathways [14,16], neuroimmune dysfunction [16], oxidative and nitrosative stress (O&NS) pathways [24,25], and bacterial translocation [26]. Immunoinflammatory pathway activation is one of the most researched topics related to CFS [14,16]. ...
... Studies have proposed possible mechanisms of disease, including immunoinflammatory pathways [14,16], neuroimmune dysfunction [16], oxidative and nitrosative stress (O&NS) pathways [24,25], and bacterial translocation [26]. Immunoinflammatory pathway activation is one of the most researched topics related to CFS [14,16]. Immune activation markers in CFS include increased levels of proinflammatory cytokines such as TNF-α, IL-6, and IL-1β [27,28]. ...
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Background Chronic fatigue syndrome (CFS) has been shown to be associated with infections. Tuberculosis (TB) is a highly prevalent infectious disease. Patients with chronic fatigue syndrome and post-tuberculosis experience similar symptoms. Furthermore, chronic fatigue syndrome and tuberculosis share similar plasma immunosignatures. This study aimed to clarify the risk of chronic fatigue syndrome following the diagnosis of Mycobacterium tuberculosis infection (MTI), by analyzing the National Health Insurance Research Database of Taiwan. Methods 7666 patients aged 20 years or older with newly diagnosed Mycobacterium tuberculosis infection during 2000–2011 and 30,663 participants without Mycobacterium tuberculosis infection were identified. Both groups were followed up until the diagnoses of chronic fatigue syndrome were made at the end of 2011. Results The relationship between Mycobacterium tuberculosis infection and the subsequent risk of chronic fatigue syndrome was estimated through Cox proportional hazards regression analysis, with the incidence density rates being 3.04 and 3.69 per 1000 person‐years among the non‐Mycobacterium tuberculosis infection and Mycobacterium tuberculosis infection populations, respectively (adjusted hazard ratio [HR] = 1.23, with 95% confidence interval [CI] 1.03–1.47). In the stratified analysis, the Mycobacterium tuberculosis infection group were consistently associated with a higher risk of chronic fatigue syndrome in the male sex (HR = 1.27, 95% CI 1.02–1.58) and age group of ≥ 65 years old (HR = 2.50, 95% CI 1.86–3.38). Conclusions The data from this population‐based retrospective cohort study revealed that Mycobacterium tuberculosis infection is associated with an elevated risk of subsequent chronic fatigue syndrome.
... That is, stigma, epistemic injustice and psycho-emotional disablism may become embodied (see Hughes and Paterson 1997). In the field of ME/CFS, a bio(psychosocial) model has been forwarded drawing upon immune, inflammatory, oxidative and nitrosative pathways that may be precipitated or perpetuated by biological and psychosocial stressors (Maes and Twisk 2010). It is reasonable to suggest that stigma and epistemic injustice -alternatively understood as psycho-emotional disablism -represent a stressor in such a model. ...
Article
A particular application of the biopsychosocial model is associated in peer-reviewed literature and patient testimony with harms done to chronically ill and disabled people. These harms derive from an empirically unsubstantiated, neoliberal narrative emphasising the role of personal responsibility and effort in ‘recovery’ from ill-health, ignoring socio-structural contributors to chronic illness and disability. Notably, this biopsychosocial model ignores the health-related impact of welfare and disability insurance reforms which the model has been employed to justify. The model and associated interests can thus be recognised as socio-structural phenomena that should be acknowledged in any truly holistic biopsychosocial approach to chronic illness and disability. A critically informed and reflexive approach to biopsychosocial theorising would allow a more holistic and nuanced understanding of chronic illness and disability, with implications for health and social policy that underline and address what ails society as opposed to what is ‘wrong’ with the individual.
... The World Health Organization Page 2 of 19 Leong et al. Journal of Translational Medicine (2022) 20:268 immunoinflammatory pathways [6], neuroimmune dysfunctions [7], and oxidative and nitrosative stress pathways, such as those induced by burn injury [8,9]. It also shares some features of autoimmune disease. ...
Full-text available
Article
Background This study aims to provide 12-year nationwide epidemiology data to investigate the epidemiology and comorbidities of and therapeutic options for chronic fatigue syndrome (CFS) by analyzing the National Health Insurance Research Database. Methods 6306 patients identified as having CFS during the 2000–2012 period and 6306 controls (with similar distributions of age and sex) were analyzed. Result The patients with CFS were predominantly female and aged 35–64 years in Taiwan and presented a higher proportion of depression, anxiety disorder, insomnia, Crohn’s disease, ulcerative colitis, renal disease, type 2 diabetes, gout, dyslipidemia, rheumatoid arthritis, Sjogren syndrome, and herpes zoster. The use of selective serotonin receptor inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), Serotonin antagonist and reuptake inhibitors (SARIs), Tricyclic antidepressants (TCAs), benzodiazepine (BZD), Norepinephrine-dopamine reuptake inhibitors (NDRIs), muscle relaxants, analgesic drugs, psychotherapies, and exercise therapies was prescribed significantly more frequently in the CFS cohort than in the control group. Conclusion This large national study shared the mainstream therapies of CFS in Taiwan, we noticed these treatments reported effective to relieve symptoms in previous studies. Furthermore, our findings indicate that clinicians should have a heightened awareness of the comorbidities of CFS, especially in psychiatric problems.
... The activated immune-inflammatory and nitro-oxidative pathways in that disorder may explain this high incidence of affective and CFS-like symptoms in RA [36]. Affective disorders including major depressive disorder (MDD) and generalized anxiety disorder, and CFS are neuro-immune and neuro-oxidative disorders characterized by immune activation (increased IFN-γ and IL-10), chronic low-grade inflammation (increased IL-1β, IL-6, and TNF-α), and increased nitro-oxidative stress (lipid peroxidation, protein oxidation) [37][38][39][40][41][42][43]. In RA, depressive symptoms are significantly associated with disease activity and immune activation markers, such as increased levels of IL-6 and IL-17 [34]. ...
Full-text available
Article
Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disorder which affects the joints in the wrists, fingers, and knees. RA is often associated with depressive and anxiety symptoms as well as chronic fatigue syndrome (CFS)-like symptoms. This paper examines the association between depressive symptoms (measured with the Beck Depression Inventory, BDI), anxiety (Hamilton Anxiety Rating Scale, HAMA), CFS-like (Fibro-fatigue Scale) symptoms and immune -inflammatory, autoimmune, and endogenous opioid system (EOS) markers, and lactosylcer-amide (CD17) in RA. The serum biomarkers were assayed in 118 RA and 50 healthy controls. Results were analyzed using the new precision nomothetic psychiatry approach. We found significant correlations between the BDI, FF, and HAMA scores and severity of RA, as assessed with the DAS28-4, clinical and disease activity indices, the number of tender and swollen joints, and patient and evaluator global assessment scores. Partial least squares analysis showed that 69.7% of the variance in this common core underpinning psychopathology and RA symptoms was explained by immune-inflammatory pathways, rheumatoid factor, anti-citrullinated protein antibodies, CD17, and mu-opioid receptor levels. We constructed a new endophenotype class comprising patients with very high immune-inflammatory markers, CD17, RA, affective and CF-like symptoms, and tobacco use disorder. We extracted a reliable and replicable latent vector (pathway phenotype) from immune data, psychopathology, and RA-severity scales. Depression, anxiety, and CFS-like symptoms due to RA are manifestations of the phenome of RA and are mediated by the effects of the same immune -inflammatory, autoimmune, and other pathways that underpin the pathophysiology of RA.
... 1042 1043 Abnormalities of inflammatory, immune, oxidative and nitrosative pathways are involved in the pathophysiology of chronic fatigue syndrome, thus contradicting psychiatric theories which ignore medical factors. 1044 14. Stress from ELF exposure increases BAG3 protein and melanoma cell survival. ...
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Electromagnetic Hypersensitivity is categorised as a multisymptomatic 'el-allergy' in the Nordic classification of 2000 (R.68.8). Its symptoms are 'certainly real' and it can be a 'disabling condition' (W.H.O., 2005). It was first recorded in the mid 20th century as an occupational illness, but it has now spread into the general population through environmental exposure from increasing levels of electromagnetic fields and radiation. This Summary covers current research on this syndrome, covering EM Sensitivity and EM Hypersensitivity. It includes tables of symptoms, EMF sources and exposure guidelines, along with references to scientific studies. This New Edition adds updates, international doctors' protocols, aspects of quantum biology, evidence for sensitivity in animals and plants, case studies, disability issues and human rights.
... Therefore, it is appropriate to posit that mood symptoms due to COVID-19 are mediated at least in part by neuroimmune pathways. People with COVID-19 also frequently suffer from mental fatigue, physical fatigue, mild loss of concentration, neurocognitive deficits, headache and myalgia (Borges do Nascimento et al., 2020;Liu et al., 2020b;Zhang et al., 2020c;Zhu et al., 2020), symptoms which are reminiscent of Myalgic Encephalomyelitis / chronic fatigue syndrome (ME/CFS) (Maes and Twisk, 2010). As with mood disorders, patients with ME/CFS show activated neuro-immune pathways with increased levels of pro-and anti-inflammatory cytokines, an acute phase response and multiple signs of nitro-oxidative damage (Bjørklund et al., 2020b;Morris and Maes, 2013). ...
Article
Background : COVID-19 is associated with neuropsychiatric symptoms including increased depressive, anxiety and chronic fatigue-syndrome (CFS)-like and physiosomatic symptoms. Aims : To delineate the associations between affective and CFS-like symptoms in COVID-19 and chest computed tomography scan anomalies (CCTAs), oxygen saturation (SpO2), interleukin (IL)-6, IL-10, C-Reactive Protein (CRP), albumin, calcium, magnesium, soluble angiotensin converting enzyme (ACE2) and soluble advanced glycation products (sRAGEs). Method : The above biomarkers were assessed in 60 COVID-19 patients and 30 heathy controls who had measurements of the Hamilton Depression (HDRS) and Anxiety (HAM-A) and the Fibromyalgia and Chronic Fatigue (FF) Rating Scales. Results : Partial Least Squares-SEM analysis showed that reliable latent vectors could be extracted from a) key depressive and anxiety and physiosomatic symptoms (the physio-affective or PA-core), b) IL-6, IL-10, CRP, albumin, calcium, and sRAGEs (the immune response core); and c) different CCTAs (including ground glass opacities, consolidation, and crazy paving) and lowered SpO2% (lung lesions). PLS showed that 70.0% of the variance in the PA-core was explained by the regression on the immune response and lung lesions latent vectors. One common “infection-immune-inflammatory (III) core” underpins pneumonia-associated CCTAs, lowered SpO2 and immune activation, and this III core explains 70% of the variance in the PA core, and a relevant part of the variance in melancholia, insomnia, and neurocognitive symptoms. Discussion : Acute SARS-CoV-2 infection is accompanied by lung lesions and lowered SpO2 which may cause activated immune-inflammatory pathways, which mediate the effects of the former on the PA-core and other neuropsychiatric symptoms due to SARS-CoV-2 infection.
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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) commonly associated with cognitive complaints. To bring out the neuropsychological symptomatology inherent to ME/CFS, we conducted a systematic review according to PRISMA and MOOSE guidelines of the literature through the analysis of 764 studies published between 1988 and 2019 by using PubMed Central website and Clarivate analytics platform. We performed a meta-analysis to delineate an idea of the neuropsychological profile inherent in ME/CFS. The clinical picture typically affects visuo-spatial immediate memory (g= -0.55, p = 0.007), reaction time (g = 0.66, p = 0.0001), reading speed (g = -0.82, p = 0.0001) and graphics gesture (g = -0.59, p = 0.0001). Analysis also revealed difficulties in several processes inherent in episodic verbal memory (storage, retrieval, recognition) and visual memory (recovery) and a low efficiency in attentional abilities. Executive functions seemed to be little or not affected and instrumental functions appeared constantly preserved. With regard to the complexity and heterogeneity of the cognitive phenotype, it turns out that determining a sound clinical picture of ME/CFS cognitive profile must go through a neuropsychological examination allowing a complete evaluation integrating the notion of agreement between the choice and the number of tests and the complexity intrinsic to the pathology
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To investigate whether cytokine responses may have a bearing on the symptoms and outcome of parvovirus B19 infection, circulating cytokines were measured during acute infection (n l 51), follow-up of acute infection (n l 39) and in normal healthy controls (n l 50). At acute B19 virus infection (serum anti-B19 IgM-positive), patients ranged in age from 4 to 54 years, with a mean age of 28n2 years. The male : female ratio was 1 : 4n1 and symptoms were rash (n l 15), arthralgia (n l 31), fatigue (n l 8), lymphadenopathy (n l 4), foetal hydrops (n l 3), transient aplastic crisis (n l 2), neutropenia (n l 2), myelodysplasia (n l 1), thrombocytopenia (n l 1) and pancytopenia (n l 1). Of these patients, 39 were contacted after a follow-up period of 2–37 months (mean of 22n5 months). In comparison with normal controls, detectable IL-6 was associated with acute B19 virus infection (26 % ; P l 0n0003), but not with follow-up (6 % ; P l 0n16). Detection of interferon (IFN)-γ was associated with acute B19 virus infection (67 % ; P 0n0001) and follow-up (67 % ; P 0n0001). Detection of tumour necrosis factor (TNF)-α was associated with acute B19 virus infection (49 % ; P 0n0001) and follow-up (56 % ; P 0n0001). IL-1β was detected in acute infection (20 %), but not at follow-up. At acute B19 virus infection, detection of serum/plasma IL-6 was associated with rheumatoid factor (P l 0n038) and IFN-γ (7 pg/ml) was associated with fatigue in those patients of 15 years of age (P l 0n022). At follow-up, fatigue was associated with IFN-γ (7 pg/ml) and/or TNF-α (40 pg/ml) (P l 0n0275). Prolonged upregulation of serum IFN-γ and TNF-α appears to represent a consistent host response to symptomatic B19 virus infection.
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Article
Patterns of immune dysfunction have emerged in chronic fatigue syndrome (CFS) that include an immune activation state (evidenced by increased activated T lymphocytes and circulating cytokines) and poor cellular function (low natural killer (NK) cell cytotoxicity and impaired T lymphocyte response to mitogens). Therefore, the aim of the current study was to examine the relationship between clinical and functional characteristics, immune abnormalities and status of the RNase L pathway in CFS compared with healthy control and depression control populations. All study participants were assessed with respect to their general health, functional status, blood count and chemistry, biochemical and immune parameters. The CFS group (N = 66) demonstrated clinical, functional and biochemical abnormalities distinct from the healthy (N = 62) and depression (N = 51) control groups. The CFS group showed marked functional impairment compared with both control groups (P
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Background The Joint Working Group of the Royal Colleges of Physicians, Psychiatrists and General Practitioners (1996) recommended graded exercise and antidepressants for patients with chronic fatigue syndrome. We assessed efficacy and acceptability of these treatments. Method Six-month prospective randomised placebo and therapist contact time controlled trial with allocation to one of four treatment cells: exercise and 20 mg fluoxetine, exercise and placebo drug, appointments only and 20 mg fluoxetine, appointments and placebo drug. Drug treatment was double blind and patients were blind to assignment to exercise or appointments. Results Ninety-six (71%) of 136 patients completed the trial. Patients were more likely to drop out of exercise than non-exercise treatment ( P =0.05). In an intention to treat analysis, exercise resulted in fewer patients with case level fatigue than appointments only at 26 weeks (12 (18%) v . 4 (6%) respectively P =0.025) and improvement in functional work capacity at 12( P =0.005) and 26 weeks ( P =0.03). Fluoxetine had a significant effect on depression at week 12 only ( P =0.04). Exercise significantly improved health perception ( P =0.012) and fatigue ( P =0.028) at 28 weeks. Conclusions Graded exercise produced improvements in functional work capacity and fatigue, while fluoxetine improved depression only.
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Article
Background. The vegetative symptoms of depression resemble the symptoms of malaise associated with activation of the inflammatory response system (IRS), and can be regarded as an expression of a central motivational state that resets the organism's priorities to promote recovery from infection. Early vegetative symptoms, however, may also contribute to the high rates of depression seen later in the course of immune activation. We hypothesized that the onset of vegetative-depressive symptoms early in the treatment with the pro-inflammatory cytokine IFN-α in chronic hepatitis C patients would increase the risk for subsequent depressive cognitions. Method. Sixteen patients eligible for IFN-α treatment and free of psychiatric disorders were recruited. The DSM-IV, the Multidimensional Fatigue Inventory, and the Montgomery–Asberg Depression Rating Scale (MADRS) were administered at baseline and 1, 2, 4, 8, 12 and 24 weeks after treatment was initiated. Cognitive-depressive and vegetative-depressive symptom clusters were constructed. Results. Fatigue and depression scores increased significantly during IFN-α treatment. Depression scores were highest at week 8 of treatment. First week increase in vegetative-depressive symptom score predicted cognitive-depressive symptom score at week 8 and at week 24. Conclusions. During IFN-α treatment, vegetative symptoms of depression appear earlier than, and are predictive of, their cognitive counterparts. This finding suggests that low mood state may in part be driven by the increase in early vegetative-depressive symptoms in the course of IFN-α-induced immune activation.
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Article
The purpose of this study was to evaluate predictors of change in physical function in individuals diagnosed with chronic fatigue syndrome (CFS) following participation in nurse delivered, non-pharmacologic interventions. Participants diagnosed with CFS were randomly assigned to one of four, 6-month interventions including cognitive behavior therapy, cognitive therapy, anaerobic exercise, or a relaxation control group. Baseline measures including immune function, actigraphy, time logs, sleep status, and past psychiatric diagnosis significantly differentiated those participants who demonstrated positive change over time from those who did not. Understanding how patient subgroups differentially respond to non-pharmacologic interventions might provide insights into the pathophysiology of this illness.
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Article
Background: Vercoulen et al.'s (1998) model characterizes patients with chronic fatigue syndrome (CFS) as having insufficient motivation for physical activity or recovery, lacking an internal locus of control, and maintaining a self-defeating preoccupation with symptoms. However, this model has only been tested in a poorly specified group using a single comparison sample. Aims: To investigate whether Vercoulen et al.'s model provides an adequate description of CFS in a community-based sample. Method: A community-based sample recruited through telephone interviewing (N = 28,763) produced five groups (CFS, CF-psychiatrically-explained symptoms, CF-medically-unexplained symptoms, CF-substance misuse, and idiopathic CF). The data were analysed using path analysis with the endogenous (dependent) variables, fatigue severity, physical activity, and impairment, were ratio-level measurements and consisted of at least four values. The exogenous (independent) variables except for causal attribution of fatigue were also ratio-level measurements. Results: The current investigation found that the Vercoulen et al. model adequately represented chronic fatigue secondary to psychiatric conditions but not CFS. Conclusions: This finding points to important differences between CFS and psychiatrically-explained chronic fatigue which may have an impact on the development of therapy as well as explanatory models.
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Chapter
Understanding of mitochondrial dysfunction in CFS will clearly benefit from more study. Our findings warrant detailed studies on larger patient and control populations. The siting of mitochondrial impairment may lead to approaches for alleviating some of the symptoms of CFS. Studies on the effects of cytokines on cellular and mitochondrial bioenergetics are important to see whether cytokines or similar molecules are involved in linking CFS immune disturbances to mitochondrial dysfunction, and to better understand the consequences of cytokine therapies for cancer and viral infection.
Article
Chronic fatigue syndrome (CFS) patients show evidence of immune activation, as demonstrated by increased numbers of activated T lymphocytes, including cytotoxic T cells, as well as elevated levels of circulating cytokines. Nevertheless, immune cell function of CFS patients is poor, with low natural killer cell cytotoxicity (NKCC), poor lymphocyte response to mitogens in culture, and frequent immunoglobulin deficiencies, most often IgG1 and IgG3. Immune dysfunction in CFS, with predominance of so-called T-helper type 2 and proinflammatory cytokines, can be episodic and associated with either cause or effect of the physiological and psychological function derangement and/or activation of latent viruses or other pathogens. The interplay of these factors can account for the perpetuation of disease with remission/exacerbation cycles. A T-helper type 2 predominance has been seen among Gulf War syndrome patients and this feature may also be present in other related disorders, such as multiple chemical sensitivity. Therapeutic intervention aimed at induction of a more favorable cytokine expression pattern and immune status appears promising.
Article
Stress may contribute to aging acceleration and age-related degenerative diseases. Stress and adaptation to stress require numerous homeostatic adjustments including hormones, neurotransmitters, oxidants, and other mediators. The stress-induced hormones, neurotransmitters, and oxidants all have beneficial, but also harmful effects if out of balance. Therefore, the homeostasis of stress and adaptation should be governed by the hormone balance, neurotransmitter balance, and oxidant balance, as well as the interactions among these substances. The imbalance and the over-interaction of these balances may ultimately cause increased oxidant generation and oxidative damage to biomolecules. This increased oxidative damage may add to the oxidant burden associated with normal aerobic metabolism, which in itself, generates oxidants, causes accumulation of oxidative damage in mitochondria, and contributes to normal aging. Therefore, the stress-associated increase of oxidative damage may, in part, contribute to stress-associated aging acceleration and age-related neurodegenerative diseases.