An increasing number of young and previously fit and healthy people who did not require hospitalisation continue to have symptoms months after mild cases of COVID-19. Rehabilitation clinics are already offering cognitive behavioural therapy (CBT) as an effective treatment for long COVID and post-COVID-19 fatigue syndrome based on the claims that it is effective for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)—the most common post-infectious syndrome—as no study into the efficacy of CBT for post-COVID-19 fatigue syndrome has been published. Re-analyses of these studies, however, showed that CBT did not lead to objective improvements in heterogeneous groups of ME/CFS patients, nor did it restore the ability to work. The group of patients with long COVID and post-COVID-19 fatigue syndrome, on the other hand, is homogeneous. We therefore analysed the Dutch Qure study, as it studied the efficacy of CBT in a homogeneous group of patients who developed Q-fever fatigue syndrome—which affects up to 30% of patients—after the largest reported outbreak of Q-fever, to see if CBT might potentially be an effective treatment for long-haulers after COVID-19 infection. Our reanalysis found that the Qure study suffered from many serious methodological problems, which included relying on one subjective primary outcome in a study without a control group for the non-blinded CBT treatment group, using a post hoc definition of improvement, waiting 2 years before publishing their objective actometer results and ignoring the null effect of said results. Moreover, only 10% of participants achieved a clinically meaningful subjective improvement in fatigue as a result of CBT according to the study’s own figures. Consequently, CBT has no subjective clinically meaningful effect in nine out of every ten patients that are treated with it. Additionally, the subjective improvement in fatigue was not matched by an improvement in disability, even though the disability was fatigue related according to the researchers. On top of this, CBT did not lead to an objective improvement in physical performance. Therefore, it cannot be said that CBT is an effective treatment for Q-fever fatigue syndrome either. It seems therefore unlikely that CBT will reduce disability or lead to objective improvement in long COVID or in post-COVID-19 fatigue syndrome.
Myalgic encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a multi-system illness characterised by a diverse range of debilitating symptoms including autonomic and cognitive dysfunction. The pathomechanism remains elusive, however, neurological and cognitive aberrations are consistently described. This systematic review is the first to collect and appraise the literature related to the structural and functional neurological changes in ME/CFS patients as measured by neuroimaging techniques and to investigate how these changes may influence onset, symptom presentation and severity of the illness.
A systematic search of databases Pubmed, Embase, MEDLINE (via EBSCOhost) and Web of Science (via Clarivate Analytics) was performed for articles dating between December 1994 and August 2019. Included publications report on neurological differences in ME/CFS patients compared with healthy controls identified using neuroimaging techniques such as magnetic resonance imaging, positron emission tomography and electroencephalography. Article selection was further refined based on specific inclusion and exclusion criteria. A quality assessment of included publications was completed using the Joanna Briggs Institute checklist.
A total of 55 studies were included in this review. All papers assessed neurological or cognitive differences in adult ME/CFS patients compared with healthy controls using neuroimaging techniques. The outcomes from the articles include changes in gray and white matter volumes, cerebral blood flow, brain structure, sleep, EEG activity, functional connectivity and cognitive function. Secondary measures including symptom severity were also reported in most studies.
The results suggest widespread disruption of the autonomic nervous system network including morphological changes, white matter abnormalities and aberrations in functional connectivity. However, these findings are not consistent across studies and the origins of these anomalies remain unknown. Future studies are required confirm the potential neurological contribution to the pathology of ME/CFS.
Care providers use the knowledge gap about ME/CFS as an excuse for indolence. In spite of differences of opinion among researchers on the significance of reported physiological abnormalities, studies support the existence of a severely debilitating syndrome, independent of geography and with a distinct pattern of symptoms. Even though there is no specific treatment; patients need help with diagnosis, symptom relief and support measures. A recent official Swedish report concludes that this is best done at specialist clinics.
When myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) gets media atten-
tion, the lack of knowledge of the underlying pathology and the disagreements within
the medical community are often emphasized.1,2 Care providers use the knowledge gap
as an excuse for indolence.3 It is therefore important to point out that there is much that
the researchers actually agree on and that the care of this neglected group of patients
has to improve.
ME/CFS was first observed as a sequel to certain infections.4,5 The cardinal symptom is
post-exertional malaise (PEM).6 This can be described as a significant fatigability and
symptom exacerbation after physical or cognitive activity, which often sets in with a de-
lay. Other key symptoms are fatigue that is not relieved by rest, unrefreshing sleep, and
neurocognitive impairment (e.g. concentration problems, short-term memory loss, and
difficulty processing information). Most patients also show an array of autonomic, im-
mune, and endocrine symptoms; as well as pain.7 The illness is recognized by the World
Health Organisation (WHO) since 1969.8
ME/CFS is not a socially transmitted illness, nor is it limited to western societies. The
illness has been found in all places where it has been looked for: all social groups, all
ethnic minorities, and all geographical regions.9-14 Studies show that ME/CFS often is
severely debilitating,15-19 which is also acknowledged by clinicians and scientists working
with this group of patients.20 The illness has an alarming tendency to become chronic,21,22
although the prognosis for children and adolescents seems to be better.23,24 In 70–80 per-
cent of the cases, the illness is triggered by an infection.25-28 However, there are other
triggers, and the onset may also be gradual.29 It is well documented that some pathogens
carry a high risk for developing ME/CFS, for example Epstein–Barr virus.30-34
Physiological abnormalities have been reported in a number of studies, but there is a
difference of opinion about the significance of the findings and there is no clear under-
standing of the pathology. Some examples of findings that might provide valuable clues
to what is going on are functional, chemical, and structural abnormalities in brain
scans,35-42 impaired NK cell cytotoxicity,43 signs of autonomic44 and mitochondrial dys-
function,45-47 and an unknown, soluble factor in the blood serum of patients that has
affected the results of several studies.48-52 Physiological abnormalities and impaired cog-
nitive performance have also been observed after exertion, which suggests that PEM is
an objective phenomenon.53-58
The controversy surrounding ME/CFS has mostly been about a treatment model, which
is based on the assumption that the illness is perpetuated by unhelpful beliefs and de-
conditioning. The model has been tested in a number of treatment studies, which have
shown modest improvements in subjective outcomes.59 However, the results are dismis-
sed by many researchers, as no improvement has been demonstrated in objective out-
comes and the treatment effects do not exceed what could be expected from systematic
bias.60-63 A recent review concluded that there is little scientific support for the model.64
There has also been a difference of opinion about the diagnostic criteria. British psychi-
atrists tried to redefine ME/CFS as idiopathic chronic fatigue,65 a proposition that has
been dismissed by other scientists.66 There is some uncertainty about how a distinct clin-
ical entity should best be defined, and several different diagnostic criteria have been
proposed.67 However, this uncertainty does not invalidate the phenomenon ME/CFS.
It is not acceptable to refer patients with ME/CFS to the Swedish primary care, where
many GPs openly question the legitimacy of the diagnosis.3,68 Granted, there is no spe-
cific treatment available, but the patients still need a thorough diagnosis, symptom relief
and supportive care.69-71 A recent report published by the Swedish Agency for Health
Technology Assessment and Assessment of Social Services (SBU) concluded that this can
best be accomplished by specialist clinics,72 which so far only are available in a few pla-
ces. The Swedish Counties must take a greater responsibility for this group of patients
and provide specialized care. ME/CFS exists and the problem will not disappear.