ME Association October Summary of ME/CFS Published Research | 06 November 2019

November 6, 2019

Charlotte Stephens, Research Correspondent, ME Association.

The Index of Published ME/CFS Research has been updated to take account of the research published during October 2019.

The Index is a convenient way to locate and read the most recent studies and also those that were published previously.

The Index lists studies by subject matter and author, with links to PubMed or the relevant Journal.

It is free to download, comes with an interactive contents table and is an A-Z list of all the most important studies (and selected key documents and articles).

You can also find the index in the Research section of the website together with all the summary research reviews that the ME Association has published.

ME/CFS Research Published in October 2019

1. Barnden LR et al. (2019)
Intra brainstem connectivity is impaired in chronic fatigue syndrome. Neuroimage: Clinical 24.

In myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), abnormal MRI correlations with symptom severity and autonomic measures have suggested impaired nerve signal conduction within the brainstem. Here we analyse fMRI correlations to directly test connectivity within and from the brainstem.

Resting and task functional MRI (fMRI) were acquired for 45 ME/CFS (Fukuda criteria) and 27 healthy controls (HC). We selected limited brainstem reticular activation system (RAS) regions-of-interest (ROIs) based on previous structural MRI findings in a different ME/CFS cohort (bilateral rostral medulla and midbrain cuneiform nucleus), the dorsal Raphe nucleus, and two subcortical ROIs (hippocampus subiculum and thalamus intralaminar nucleus) reported to have rich brainstem connections.

When HC and ME/CFS were analysed separately, significant correlations were detected for both groups during both rest and task, with stronger correlations during task than rest. In ME/CFS, connections were absent between medulla and midbrain nuclei, although hippocampal connections with these nuclei were enhanced. When corresponding correlations from HC and ME/CFS were compared, ME/CFS connectivity deficits were detected within the brainstem between the medulla and cuneiform nucleus and between the brainstem and hippocampus and intralaminar thalamus, but only during task. In CFS/ME, weaker connectivity between some RAS nuclei was associated with increased symptom severity. RAS neuron oscillatory signals facilitate coherence in thalamo-cortical oscillations.

Brainstem RAS connectivity deficits can explain autonomic changes and diminish cortical oscillatory coherence which can impair attention, memory, cognitive function, sleep quality and muscle tone, all symptoms of ME/CFS.

2. Bedree H et al. (2019)
The DePaul Symptom Questionnaire-2: a validation study.
Fatigue: Biomedicine, Health and Behavior 7 (3).

Background: The DePaul Symptom Questionnaire (DSQ) was developed to assess the symptomatology and case definition fulfillment of individuals with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). The questionnaire was recently revised to improve its psychometric properties, increase its diagnostic reliability, and assess symptoms required by case definitions. The resulting instrument was named the DSQ-2.

Purpose: The current study sought to evaluate the utility and reliability of the new and revised items in the DSQ-2.

Results: Descriptive analyses of the DSQ-2 suggest that the new and revised items enhance the instrument’s ability to assess certain symptom domains and evaluate recent case definitions. Additionally, an exploratory factor analysis resulted in an eight-factor solution: post-exertional malaise, cognitive impairment, fever and flu, pain, sleep disruption, orthostatic intolerance, genitourinary issues, and temperature intolerance. The items within each factor demonstrated strong internal consistency reliability (Cronbach’s alphas = .73 – .91).

Conclusion: These analyses indicate that the DSQ-2 offers a more thorough and precise understanding of ME and CFS symptomology and case definition fulfillment.

3. Bransfield RC and Friedman KJ (2019)
Differentiating Psychosomatic, Somatopsychic, Multisystem Illnesses and Medical Uncertainty.
Healthcare 7 (4): 114.

There is often difficulty differentiating between psychosomatic, somatopsychic, multisystem illness, and different degrees of medical uncertainty. Uncommon, complex, and multisystem diseases are commonly misdiagnosed. Two case histories are described, and relevant terms differentiating psychosomatic, somatopsychic, and multisystem illnesses are identified, reviewed, and discussed.

Adequate differentiation requires an understanding of the mind/body connection, which includes knowledge of general medicine, psychiatry, and the systems linking the body and the brain. A psychiatric diagnosis cannot be given solely based upon the absence of physical, laboratory, or pathological findings. Medically unexplained symptoms, somatoform disorder, and compensation neurosis are outdated and/or inaccurate terms.

The terms subjective, nonspecific, and vague can be used inaccurately. Conversion disorders, functional disorders, psychogenic illness, factitious disorder imposed upon another (Munchausen’s syndrome by proxy), somatic symptom disorder, psychogenic seizures, psychogenic pain, psychogenic fatigue, and delusional parasitosis can be over-diagnosed. Bodily distress disorder and bodily distress syndrome are scientifically unsupported and inaccurate. Many “all in your head” conditions may be related to the microbiome and the immune system.

Better education concerning the interface between medicine and psychiatry and the associated diagnostic nomenclature as well as utilizing clinical judgment and thorough assessment, exercising humility, and maintaining our roots in traditional medicine will help to improve diagnostic accuracy and patient trust.

4. Cabanas H et al. (2019)
Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients.
Frontiers in Immunology [Epub ahead of print]

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a seriously long-term and debilitating illness of unknown cause hallmarked by chronic pain and fatigue, memory and concentration impairment, and inflammation. ME/CFS hypothesis involves impaired Transient receptor potential melastatin 3 (TRPM3) ion channel function, affecting calcium signaling and Natural killer (NK) cell functions.

Currently, substances called opioids, agonists of mu (μ)-opioid receptors (μOR), are the strongest painkillers clinically available for people suffering from strong or long-lasting pain characteristic of ME/CFS. μOR have been reported to specifically inhibit TRPM3 and to be expressed in immune cells where they play an immunomodulatory and immunosuppressive role. Naltrexone hydrochloride (NTX) acts as an antagonist to the μOR thus negating the inhibitory function of this opioid receptor on TRPM3. Therefore, understanding the mechanism of action for NTX in regulating and modulating TRPM3 channel function in NK cells will provide important information for the development of effective therapeutic interventions for ME/CFS.

Whole-cell patch-clamp technique was used to measure TRPM3 activity in Interleukin-2 (IL-2) stimulated and NTX-treated NK cells for 24 h on eight ME/CFS patients and 8 age- and sex-matched healthy controls, after modulation with a TRPM3-agonist, pregnenolone sulfate (PregS), NTX and a TRPM3-antagonist, ononetin.

We confirmed impaired TRPM3 function in ME/CFS patients through electrophysiological investigations in IL-2 stimulated NK cells after modulation with PregS and ononetin. Importantly, TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 h with NTX. Moreover, we demonstrated that NTX does not act as an agonist by directly coupling on the TRPM3 ion channel gating.

The opioid antagonist NTX has the potential to negate the inhibitory function of opioid receptors on TRPM3 in NK cells from ME/CFS patients, resulting in calcium signals remodeling, which will in turn affect cell functions, supporting the hypothesis that NTX may have potential for use as a treatment for ME/CFS.

Our results demonstrate, for the first time, and based on novel patch clamp electrophysiology, potential pharmaco-therapeutic interventions in ME/CFS.

5. Campen CL et al. (2019)
Open Trial of Vitamin B12 Nasal Drops in Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Comparison of Responders and Non-Responders.
Frontiers in Pharmacology [Epub ahead of print].

Introduction: A recent study reported a favorable effect of vitamin B12 injections/oral folic acid support in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients. Recently, vitamin B12 nasal drops were developed as an alternative to the vitamin B12 injections. As no data are available on efficacy of this formulation, we studied vitamin B12 serum levels, the physical activity scale of the RAND-36, the number of steps on an activity meter, and the fatigue and concentration scales of the CIS20r questionnaires, before and after 3 months of treatment in ME/CFS patients.

Methods and Results: Fifty-one patients completed all measurements. Forty-four were female. Mean age was 42 years, and mean disease duration was 16 years. Median vitamin B12 levels before treatment were 328 (244–429) pmol/l, and 973 (476–1,476) pmol/l after treatment. Thirty-four patients reported a favorable response to treatment. In the non-responders, only a small but significant increase in vitamin B12 levels was observed. In contrast, in responders, the number of steps, the physical activity scale of the RAND-36, and the vitamin B12 serum levels increased significantly. The CIS20r fatigue scale decreased significantly, and the CIS20r concentration scale was unchanged.

Conclusions: Nasal drop vitamin B12 administration resulted in a significant increase in vitamin B12 serum levels and therefore may be effective. This pilot study suggest that the nasal drops may be used as an alternative to injections because two thirds of ME/CFS patients reported a positive effect, accompanied by an increased number of steps, improvement of the RAND-36 physical functioning scale and the CIS20r fatigue scale, and a significant increase in serum vitamin B12 levels.

6. Comhaire F and Deslypere JP et al. (2019)
News and views in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): The role of co-morbidity and novel treatments.
Medical Hypotheses 134.

Though affecting many thousands of patients, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) should be considered an orphan disease, since the cause remains elusive and no treatment is available that can provide complete cure.

There is reasonable insight into the pathogenesis of signs and symptoms, and treatments specifically directed to immunological, inflammatory and metabolic processes offer relief to an increasing number of patients. Particular attention is given to the importance of co-morbidity requiring appropriate therapy.

Promising results are obtained by treatment with Metformin, or possibly Momordica charantia extract, which will correct insulin resistance, with Meldonium improving the transportation of glucose into the mitochondria, with sodium dichloroacetate activating pyruvate dehydrogenase, and with nutraceutical support reducing oxidative and inflammatory impairment.

7. Chalder T et al. (2019)
Persistent physical symptoms reduction intervention: a system change and evaluation in secondary care (PRINCE secondary) – a CBT-based transdiagnostic approach: study protocol for a randomised controlled trial.
BMC Psychiatry 19 (1): 307.

Background: Persistent physical symptoms (PPS), also known as medically unexplained symptoms (MUS), affect approximately 50% of patients in secondary care and are often associated with disability, psychological distress and increased health care costs.

Cognitive behavioural therapy (CBT) has demonstrated both short- and long-term efficacy with small to medium effect sizes for PPS, with larger treatment effects for specific PPS syndromes, including non-cardiac chest pain, irritable bowel syndrome (IBS) and chronic fatigue syndrome (CFS).

Research indicates that PPS conditions share similar cognitive and behavioural responses to symptoms, such as avoidance and unhelpful beliefs. This suggests that a transdiagnostic approach may be beneficial for patients with PPS.

Methods: A randomised controlled trial (RCT) will be conducted to evaluate the efficacy and cost-effectiveness of a transdiagnostic CBT-based intervention for PPS. 322 participants with PPS will be recruited from secondary care clinics. Participants stratified by clinic and disability level will be randomised to CBT plus standard medical care (SMC) versus SMC alone.

The intervention consists of 8 CBT sessions delivered by a qualified therapist over a period of 20 weeks. Outcomes will be assessed at 9, 20, 40- and 52-weeks post randomisation.

  • Efficacy will be assessed by examining the difference between arms in the primary outcome Work and Social Adjustment Scale (WSAS) at 52 weeks after randomisation.
  • Secondary outcomes will include mood, symptom severity and clinical global impression at 9, 20, 40 and 52 weeks.
  • Cost-effectiveness will be evaluated by combining measures of health service use, informal care, loss of working hours and financial benefits at 52 weeks.

Discussion: This trial will provide a powered evaluation of the efficacy and cost-effectiveness of a transdiagnostic CBT approach versus SMC for patients with PPS. It will also provide valuable information about potential healthcare pathways for patients with PPS within the National Health Service (NHS).

8. Friedberg F et al. (2019)
Rethinking the Standard of Care for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Journal of General Internal Medicine pp 1-4.

For over two decades, the standard of care for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been cognitive behavior therapy (CBT) and graded exercise therapy (GET). Both interventions had been recommended by the US Centers for Disease Control and the UK NICE guidelines.

Behavioral intervention as the clinical standard was given a considerable boost by the 5 million–pound PACE trial, a large multi-arm randomized trial of CBT and GET launched in 2007. This British government–funded trial was intended to definitively answer whether such interventions were beneficial in ME/CFS. In their 2011 and 2013 publications, the PACE trial authors announced with widespread publicity that 22% of their patients had “recovered” and 59–61% had clinically improved across the CBT and GET interventions.

More generally, multiple literature reviews have reported that these therapies are not only effective at improving fatigue and, to a lesser extent, physical function in ME/CFS but also safe. It would seem obvious then that good clinical care of these patients would include these behavioral interventions.

But, a closer look at these trials has generated many concerns about their applicability to these patients. This perspective critically examines their findings and more generally discusses the behavioral intervention literature in ME/CFS. Finally, we briefly describe a pragmatic clinical approach for these often-marginalized patients.

9. Maes M et al. (2019)
Is a diagnostic blood test for chronic fatigue syndrome on the horizon?
Expert Review of Molecular Diagnostics [Epub ahead of print].


10. Miwa K (2019)
Paradigme shift to disequilibrium in the genesis of orthostatic intolerance in patients with chronic fatigue syndrome.
European Heart Journal 40 (1).

Background: Chronic fatigue syndrome (CFS) characterized by severe disabling fatigue and prolonging post-exertional malaise. The dysfunction of the central nervous system associated with myalgic encephalomyelitis (ME) has been postulated as the main cause of CFS.

Orthostatic intolerance (OI) causes a marked reduction in the activities of daily living and impairs the quality of life in patients with ME/CFS. OI has been surmised to be a cardiovascular symptom with cerebral hypo-perfusion and exaggerated sympathetic nervous activation.

Purpose: Postural instability or disequilibrium may be involved in the etiology of OI because postural stability is an essential element for static balance.

Methods: The study comprised 72 patients with ME/CFS (18 men and 54 women; mean age, 37±10 years), who underwent neurological examinations and the active 10-min standing test.

Results: Disequilibrium defined as instability on standing with their feet together and eyes shut, was detected in 23 (32%) patients while postural orthostatic tachycardia in 16 (22%).

  • Compared with 49 patients without disequilibrium, patients with disequilibrium more prevalently failed to complete the 10-min standing test (74% vs. 4%, p<0.01) and body sway was significantly more prevalently observed during the test (100% vs. 12%, p<0.01).
  • The performance status score was significantly higher in patients with disequilibrium than those without it (median: 7 vs. 5, p<0.01), suggesting more severely restricted activity of daily living in the former.
  • The prevalence of postural orthostatic tachycardia during the standing test was comparable between the patients with disequilibrium (23%) and those without it (22%, p=1.00).
  • The 19 (26%) patients who failed to complete the 10-min standing test had disequilibrium more prevalently than those who completed it (89% vs. 11%, p<0.01).
  • Performance status score was significantly higher in patients who failed to complete it than those who completed it (median: 6 vs. 5, p<0.01), suggesting more severe restriction of activity of daily living in the former.
  • Significantly higher rates of disequilibrium (89% vs. 11%, p<0.01), unstable standing on one leg (84% vs. 17%, p<0.01) as well as abnormal tandem gait (79% vs. 11%, p<0.01) were noted in patients who failed to complete it than those who completed it.
  • Body sway during the standing test was significantly more prevalently observed in the patients who failed to complete it than those who completed it (89% vs. 23%, p<0.01).
  • The prevalence of postural orthostatic tachycardia during the standing test was comparable between the patients who failed to complete it and those who completed it (21% vs. 23%, p=1.00).
  • Among the patients who failed to complete it 8 had the previous study records which revealed that 6 of them had completed it 6–24 months before when all the 6 patients had had no disequilibrium.

Conclusion: Disequilibrium should be recognized as an important cause of OI in patients with ME/CFS.

11. Natelson BH et al. (2019)
The Effect of Comorbid Medical and Psychiatric Diagnoses on Chronic Fatigue Syndrome.
Annuals in Medicine [Epub ahead of print].

Objective: To determine if presence of co-existing medically unexplained syndromes or psychiatric diagnoses affect symptom frequency, severity or activity impairment in Chronic Fatigue Syndrome.

Results: Current and lifetime psychiatric diagnosis was common (68%) increasing mental fatigue/health but not other illness variables and not with diagnosis of other medically unexplained syndromes. 81% of patients had at least one of these conditions with about a third having all three co-existing syndromes. Psychiatric diagnosis was not associated with their diagnosis. Increasing the number of these unexplained conditions was associated with increasing impairment in physical function, pain and rates of being unable to work.

Conclusions: Patients with Chronic Fatigue Syndrome should be evaluated for current psychiatric conditions because of their impact on patient quality of life, but they do not act as a symptom multiplier for the illness.

Other co-existing medically unexplained syndromes are more common than psychiatric co-morbidities in patients presenting for evaluation of medically unexplained fatigue and are also more associated with increased disability and the number and severity of symptoms.

Key Messages:

  • When physicians see patients with medically unexplained fatigue, they often infer that this illness is due to an underlying psychiatric problem.
  • This paper shows that the presence of co-existing psychiatric diagnoses does not impact on any aspect of the phenomenology of medically unexplained fatigue also known as chronic fatigue syndrome.
  • Therefore, psychiatric status is not an important causal contributor to CFS.
  • In contrast, the presence of other medically unexplained syndromes do impact on the illness such that the more of these that co-exist the more health-related burdens the patient has.

12. Nelson MJ et al. (2019)
Evidence of altered cardiac autonomic regulation in myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review and meta-analysis.
Medicine (Baltimore) 98 (43).


Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition with no reliable diagnostic biomarkers.

Studies have shown evidence of autonomic dysfunction in patients with ME/CFS, but results have been equivocal.

Heart rate (HR) parameters can reflect changes in autonomic function in healthy individuals; however, this has not been thoroughly evaluated in ME/CFS.

Methods: A systematic database search for case-control literature was performed. Meta-analysis was performed to determine differences in HR parameters between ME/CFS patients and controls.

Results: Sixty-four articles were included in the systematic review. HR parameters assessed in ME/CFS patients and controls were grouped into ten categories: resting HR (RHR), maximal HR (HRmax), HR during submaximal exercise, HR response to head-up tilt testing (HRtilt), resting HR variability (HRVrest), HR variability during head-up tilt testing (HRVtilt), orthostatic HR response (HROR), HR during mental task(s) (HRmentaltask), daily average HR (HRdailyaverage), and HR recovery (HRR).

Meta-analysis revealed RHR (MD ± 95% CI = 4.14 ± 1.38, P < .001), HRtilt (SMD ± 95% CI = 0.92 ± 0.24, P < .001), HROR (0.50 ± 0.27, P < .001), and the ratio of low frequency power to high frequency power of HRVrest (0.39 ± 0.22, P < .001) were higher in ME/CFS patients compared to controls, while HRmax (MD ± 95% CI = -13.81 ± 4.15, P < .001), HR at anaerobic threshold (SMD ± 95% CI = -0.44 ± 0.30, P = 0.005) and the high frequency portion of HRVrest (-0.34 ± 0.22, P = .002) were lower in ME/CFS patients.

Conclusions: The differences in HR parameters identified by the meta-analysis indicate that ME/CFS patients have altered autonomic cardiac regulation when compared to healthy controls. These alterations in HR parameters may be symptomatic of the condition.

13.  O’Callaghan JP and Miller DB (2019)
Neuroinflammation disorders exacerbated by environmental stressors.
Metabolism Clinical and Experimental 100: 153951.


Neuroinflammation is a condition characterized by the elaboration of proinflammatory mediators within the central nervous system.

Neuroinflammation has emerged as a dominant theme in contemporary neuroscience due to its association with neurodegenerative disease states such as Alzheimer's disease, Parkinson's disease and Huntington's disease.

While neuroinflammation often is associated with damage to the CNS, it also can occur in the absence of neurodegeneration, e.g., in association with systemic infection.

The “acute phase” inflammatory response to tissue injury or infections instigates neuroinflammation-driven “sickness behavior,” i.e. a constellation of symptoms characterized by loss of appetite, fever, muscle pain, fatigue and cognitive problems.

Typically, sickness behavior accompanies an inflammatory response that resolves quickly and serves to restore the body to homeostasis. However, recurring and sometimes chronic sickness behavior disorders can occur in the absence of an underlying cause or attendant neuropathology.

Here, we review myalgic enchepalomyelitis/chronic fatigue syndrome (ME/CFS), Gulf War Illness (GWI), and chemobrain as examples of such disorders and propose that they can be exacerbated and perhaps initiated by a variety of environmental stressors.

Diverse environmental stressors may disrupt the hypothalamic pituitary adrenal (HPA) axis and contribute to the degree and duration of a variety of neuroinflammation-driven diseases.

14. Ryabkova VA et al. (2019)
Neuroimmunology: What Role for Autoimmunity, Neuroinflammation, and Small Fiber Neuropathy in Fibromyalgia, Chronic Fatigue Syndrome, and Adverse Events after Human Papillomavirus Vaccination?
International Journal of Molecular Science 20 (20) 5164.

Fibromyalgia is a disorder characterized by chronic widespread pain and non-pain symptoms, such as fatigue, dysautonomia, and cognitive and sleep disturbances. Its pathogenesis and treatment continue to be the subject of debate.

We highlight the role of three mechanisms—autoimmunity, neuroinflammation, and small fiber neuropathy—in the pathogenesis of the disease. These mechanisms are shown to be closely interlinked (also on a molecular level), and the review considers the implementation of this relationship in the search for therapeutic options.

We also pay attention to chronic fatigue syndrome, which overlaps with fibromyalgia, and propose a concept of “autoimmune hypothalamopathy” for its pathogenesis.

Finally, we analyze the molecular mechanisms underlying the neuroinflammatory background in the development of adverse events following HPV vaccination and suggesting neuroinflammation, which could exacerbate the development of symptoms following HPV vaccination (though this is hotly debated), as a model for fibromyalgia pathogenesis.

15. Terman JM et al. (2019)
How Psychiatric Referrals Influence Stigmatization in Patients with Myalgic Encephalomyelitis and Chronic Fatigue Syndrome: an examination of American and British Models.
Community Psychology in Global Perspective 5 (2): 19-29.

Myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are controversial chronic illnesses with a myriad of debilitating symptoms. This study aimed to explore physician referrals to psychiatrists or psychologists, perceived stigma, and estrangement for patients with ME and CFS.

Findings indicate that patients who have been referred to psychiatrists are likely to perceive illness stigma and feel estranged from others due to their illness. These relationships are moderated by the country of residence, the United States and the United Kingdom. The implications of physician referrals for people with ME and CFS are discussed.

16. Worm-Smeitink M et al. (2019)
Internet-Based Cognitive Behavioral Therapy for Chronic Fatigue Syndrome Integrated in Routine Clinical Care: Implementation Study.
Journal of Medical Internet Research 21 (10).

Background: In a clinical trial, internet-based cognitive behavioral therapy (I-CBT) embedded in stepped care was established as noninferior to face-to-face cognitive behavioral therapy (CBT) for chronic fatigue syndrome (CFS). However, treatment effects observed in clinical trials may not necessarily be retained after implementation.

Objective: This study aimed to investigate whether stepped care for CFS starting with I-CBT, followed by face-to-face CBT, if needed, was also effective in routine clinical care. Another objective was to explore the role of therapists' attitudes toward electronic health (eHealth) and manualized treatment on treatment outcome.

Methods: I-CBT was implemented in five mental health care centers (MHCs) with nine treatment sites throughout the Netherlands. All patients with CFS were offered I-CBT, followed by face-to-face CBT if still severely fatigued or disabled after I-CBT.

Outcomes were the Checklist Individual Strength, physical and social functioning (Short-Form 36), and limitations in daily functioning according to the Work and Social Adjustment Scale.

  • The change scores (pre to post stepped care) were compared with a benchmark: stepped care from a randomized controlled trial (RCT) testing this treatment format.
  • We calculated correlations of therapists' attitudes toward manualized treatment and eHealth with reduction of fatigue severity.

Results: Overall, 100 CFS patients were referred to the centers. Of them, 79 started with I-CBT, 20 commenced directly with face-to-face CBT, and one did not start at all. After I-CBT, 48 patients met step-up criteria; of them, 11 stepped up to face-to-face CBT.

  • Increase in physical functioning (score of 13.4), social functioning (20.4), and reduction of limitations (10.3) after stepped care delivered in routine clinical care fell within the benchmarks of the RCT (95% CIs: 12.8-17.6; 25.2-7.8; and 7.4-9.8, respectively).
  • Reduction of fatigue severity in the MHCs was smaller (12.6) than in the RCT (95% CI 13.2-16.5). After I-CBT only, reduction of fatigue severity (13.2) fell within the benchmark of I-CBT alone (95% CI 11.1-14.2).
  • Twenty therapists treated between one and 18 patients. Therapists were divided into two groups: one with the largest median reduction of fatigue and one with the smallest.
  • Patients treated by the first group had a significantly larger reduction of fatigue severity (15.7 vs 9.0; t=2.42; P=.02).
  • There were no (statistically significant) correlations between therapists' attitudes and reduction in fatigue.

Conclusions: This study is one of the first to evaluate stepped care with I-CBT as a first step in routine clinical care. Although fatigue severity and disabilities were reduced, reduction of fatigue severity appeared smaller than in the clinical trial. Further development of the treatment should aim at avoiding dropout and encouraging stepping up after I-CBT with limited results. Median reduction of fatigue severity varied largely between therapists. Further research will help understand the role of therapists' attitudes in treatment outcome.

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