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Fatigue and inflammation: A psychoneuroimmunological approach to chronic fatigue


Senior Member
via Dr. Marc-Alexander Fluks
Source: University of London
Date: July 17, 2017
URL: https://kclpure.kcl.ac.uk/portal/en...on(f592a66f-ddd9-4a29-a375-2295953a86d6).html

Fatigue and inflammation: A psychoneuroimmunological approach to chronic fatigue
Alice Elizabeth Russell
- King's College London, University of London


Chronic Fatigue Syndrome (CFS) is characterised by severe fatigue, endured for at least six months, together with symptoms including impaired cognitive function, sleep disturbance, and musculoskeletal pain. The pathogenesis is still unknown, resulting in a lack of treatment options and the stigmatization of patients. Both psychological and biological factors have been implicated in the development of CFS. To date, evidence has come largely from cross-sectional studies, and there have been a paucity of longitudinal studies.

The aim of this study was to explore interferon-alpha (IFN-alpha) induced persistent fatigue as a proxy model of CFS. IFN-alpha is an immunotherapy for chronic Hepatitis C Virus (HCV) infection. It induces a range of side effects including fatigue, which in some patients persists post-treatment. This model allows for the identification of risk factors and monitoring of biological and behavioural changes from the perspective of the trigger, to determine factors relevant to the persistence of fatigue after the original stimulus is no longer present. Fifty-five patients undergoing IFN-alpha treatment for chronic HCV were assessed at baseline, during treatment, and six-months post-treatment. Clinical, inflammatory and cortisol measures were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment measures from HCV persistent and resolved fatigue patients.

IFN-alpha induced persistent fatigue was associated with an exaggerated response to IFN-alpha, with increased fatigue, depressive symptoms, and perceived stress, a greater decline in health status, and higher inflammation. This higher symptomatology during treatment put these patients at a disadvantage for their subsequent recovery. Neither IFN-alpha induced persistent fatigue nor CFS was associated with continued peripheral inflammation, emphasising the importance of the response to the initial trigger. Future studies are needed to elucidate the mechanisms behind the exaggerated response, and the 'conversion' to chronic illness in the absence of peripheral immune activation.


Senior Member
Interferon alpha-induced persistent fatigue may be a better model of ME/CFS than the forced swim murine model of ME/CFS, which I have seen several studies use. In the forced swim model, they force mice to swim for a long time until they are totally exhausted, and then equate that exhaustion to ME/CFS. But I should think normal physical exhaustion in healthy animals or humans has little to do with the pathophysiology of ME/CFS.

So this interferon model may be an improvement on the forced swim model.
Thanks. I had a very quick skim (it's 445 pages) and thought that there could be some interesting info in there, but there was a lot of annoying credulous citing of poor quality psychosocial research, and I kept getting the impression that the author wanted results to fit his narrative. There seemed to be lots of faith that questionnaires were measuring what they were supposed to, rather than being biased by other differences between participants.

eg of review of psychosocial stuff:

Also important are illness and treatment perceptions, which have been shown to
be associated with the onset of chronic fatigue following infectious diseases.
For example, a study by Candy and colleagues found perceptions about
the expected illness duration and long-term impact to be predictive of poorer
outcomes up to six-months after onset of Infectious Mononucleosis (IM)
(Candy et al., 2003). A later, larger study of predictors of CFS following IM found that
negative illness perceptions -including believing the condition to be serious and
distressing, that it would last a long time, and was incontrollable- predicted a
subsequent diagnosis. Of the cognitive and behavioural responses to symptoms
examined, ‘all or nothing’ behaviour, defined as bursts of activity with a need to
rest afterwards, also predicted a subsequent diagnosis, and in fact was the
strongest predictor (Moss-Morris et al., 2011). Moreover, in a study comparing
patients already diagnosed with CFS with those suffering from rheumatoid
arthritis- a more clearly defined condition with overlapping symptoms- CFS
patients held more negative illness perceptions. Physical disability was
comparable across the two groups. However, CFS patients reported greater
problems with social functioning and limitations to everyday activities as
a result of their symptoms (Moss-Morris & Chalder, 2003).

Illness or symptom attributions, related to the factors which patients or
individuals feel have caused their condition or made it worse, may also be
relevant. There are three overarching categories: somatic (i.e. a physical
abnormality), psychological (e.g. emotional upset) and normalising (external
events, e.g. a change in environment or behaviour) (Moss-Morris, 2005). A
study of PVFS found that tendency to attribute symptoms to somatic factors
was the strongest risk factor for subsequent chronic fatigue (Cope et al., 1994).
CFS patients have been shown to be less likely to make psychological
attributions, and to make similar physical attributions to Multiple Sclerosis
patients (Dendy et al., 2001). A community study of fatigued individuals found
that those attributing their fatigue to social factors were more ‘protected’ than
those making biological attributions from later fatigue and disability (Chalder et
al., 1996). Findings concerning the effect on outcome following treatment for
CFS have been mixed. One study in primary carefound that physical illness
attributions predicted a worse outcome (Chalder et al., 2003). Studies of tertiary
care services, however, found no link (Deale et al., 1998; Kempke et al., 2010).

Another concept that has been examined in CFS patients is ‘willingness’. In this
case, ‘willingness’ can be defined as the appreciation that avoidance and
control of symptoms are not always possible. A lack of ‘willingness’ indicates a
lack of acceptance of fatigue, which has been linked to increased disability.
However, it has also been shown to be modifiable following cognitive
behavioural therapy interventions(Brooks et al., 2011).

In this thesis, I will explore the relevance of illness perceptions and cognitive
and behavioural responses to fatigue to the persistence of fatigue following
another immune trigger not yet studied in this context. Specifically, in patients
who have been treated with IFN-α, to be described in the next section. I will also
compare attributions made, and levels of acceptance of fatigue in the IFN-α
treated patients, healthy volunteers and patients with CFS.

Couple of paragraphs on results I pulled out:

In support of my hypothesis that negative baseline illness perceptions would
predict worse acute fatigue, I found an association with all but one of the
measures of pre-treatment illness perceptions. Beliefs not associated with the
severity of acute fatigue related to the potential success of treatment in
controlling/managing symptoms.

Understudied in the context of IFN-α induced side effects, I found that baseline
illness perceptions were predictive of subsequent acute fatigue. However,
unlike has been seen in post-viral fatigue, they were not associated with the
persistence of fatigue post-treatment. Indeed, few characteristics or baseline
risk factors were evident, which may have otherwise identified patients at
greater risk of persistent fatigue, or indeed more severe fatigue post-treatment.

For example, I did not find the expected association with past experience of
childhood trauma, though traumatic events across the lifespan were to some
extent associated with the persistence of fatigue. Although baseline
inflammatory markers were in general not associated with persistent fatigue,
there was a trend towards higher levels of IL-6 and IFN-γ, which warrant further
investigation as predictors in other disease models.

@Dx Revision Watch might be interested in this, as she seems familiar with him:

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