Research abstract:

Surveys over the past two decades found that patients, advocates, and researchers want the name chronic fatigue syndrome (CFS) to be changed because this label minimizes the severity of the illness (Taylor, Friedberg, & Jason, 2001). The present study sought to qualitatively investigate patient views on the illness label CFS and healthcare providers’ knowledge of CFS. A patient-research organization asked members two open-ended questions regarding preferences for specific illness labels and educational suggestions for healthcare providers.

Responses to both questions were coded thematically by multiple, trained research assistants. Findings suggested that 96% of participants disliked/strongly disliked CFS. Myalgic encephalomyelitis (ME) was the majority’s first preference (55%) and was chosen four times more than any other name given.

Four themes emerged for educational concerns:

• attitudes of healthcare providers,
• symptomatology,
• research, and
• implications of inadequate education.

The most frequent subtheme (37%) was patients wanting healthcare providers to acknowledge that this is a real/serious illness.

Diagnostic labels can influence providers’ perceptions of diseases and affect quality of care and communication between providers and patients. Therefore patients should be stakeholders in the process of name change. Understanding patient perspectives on educational priorities and illness labels will facilitate improved communication between providers and patients.

Educational Priorities for Healthcare Providers and Name Suggestions for Chronic Fatigue Syndrome: Including the Patient Voice, by Laura Nicholson, Abigail Brown, Leonard A Jason, Diana Ohanian, and Kelly O’Connor in Schiforschen Clinical Research 2:1, 12 Jan 2016

Comment in Pub Med: Exploring changes to PACE trial outcome measures using anonymised data from the FINE trial, by Sam Carter, Feb 15 2016

When the results of the PACE trial were published (1, 2) it was noted that the primary outcome measures and the definition of “recovery” described in the trial’s published protocol (3) had been abandoned and replaced with markedly less stringent criteria.

The fully anonymised data set from the FINE trial(4), considered to be the PACE trial’s “sister” study, makes it possible to explore how these changes may have affected the reported efficacy of the PACE trial’s interventions.

At week 20 (assessment 2), 18 FINE trial participants met PACE trial post-hoc recovery thresholds (SF36 PF ≥ 60 and CFQ Likert ≤ 18) compared to only 3 participants who met the stricter, protocol-defined recovery thresholds (SF36 PF ≥ 85 and CFQ bimodal ≤ 3). Therefore, at assessment 2, the post-hoc changes increased the “recovery” rate by a factor of 6.

By week 70 (assessment 3), between 10 and 12 of the original 18 had relapsed so that they no longer met the post-hoc recovery thresholds (data are missing for two participants). Such a high rate of relapse within a year shows that the post-hoc recovery thresholds, said to represent a “strict criterion for recovery” in a Comment (5) which accompanied the original publication of PACE trial results, are neither strict nor reliable indicators of sustained wellbeing.

Regarding the Chalder fatigue questionnaire, White et al wrote that “we changed the original bimodal scoring of the Chalder fatigue questionnaire (range 0–11) to Likert scoring to more sensitively test our hypotheses of effectiveness” (1). However, data from the FINE trial show that Likert and bimodal scores are often contradictory and thus call into question White et al’s assumption that Likert scoring is necessarily more sensitive than bimodal scoring.

For example, of the 33 FINE trial participants who met the post-hoc PACE trial recovery threshold for fatigue at week 20 (Likert CFQ score ≤ 18), 10 had a bimodal CFQ score ≥ 6 so would still be fatigued enough to enter the PACE trial and 16 had a bimodal CFQ score ≥ 4 which is the accepted definition of abnormal fatigue.

Therefore, for this cohort, if a person met the PACE trial post-hoc recovery threshold for fatigue at week 20 they had approximately a 50% chance of still having abnormal levels of fatigue and a 30% chance of being fatigued enough to enter the PACE trial.

A further problem with the Chalder fatigue questionnaire is illustrated by the observation that the bimodal score and Likert score of 10 participants moved in opposite directions at consecutive assessments i.e. one scoring system showed improvement whilst the other showed deterioration.

Moreover, it can be seen that some FINE trial participants were confused by the wording of the questionnaire itself. For example, a healthy person should have a Likert score of 11 out of 33, yet 17 participants recorded a Likert CFQ score of 10 or less at some point (i.e. they reported less fatigue than a healthy person), and 5 participants recorded a Likert CFQ score of 0.

The discordance between Likert and bimodal scores and the marked increase in those meeting post-hoc recovery thresholds suggest that White et al’s deviation from their protocol-specified analysis is likely to have profoundly affected the reported efficacy of the PACE trial interventions.

An independent re-analysis of anonymised PACE trial data as described in its published protocol is urgently required to quantify the effects of the revised outcome and recovery criteria.

References

(1) White PD et al (2011) Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial.
Lancet Mar 5;377(9768):823-36.
(2) White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M (2013) Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. Oct;43(10):2227-35.
(3) White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R (2007) Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy.
BMC Neurol Mar 8;7:6.
(4) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4685991/bin/pone.0144623.s002.dta
(5) Bleijenberg G, Knoop H. (2011) Chronic fatigue syndrome: where to PACE from here? Lancet. Mar 5;377(9768):786-8.

ME Research UK article, 11 Feb 2016: Orosomucoid and ME/CFS

Most scientific reports either confirm what we already know or reveal mildly interesting findings that contribute to the field in a small way. Every now and then, however, a research paper arrives that makes you stop and think (at least for a few minutes), and the most recent comes from researchers at the Second Military Medical University, Shanghai.

The Chinese researchers had been using an animal model to investigate ‘fatigue’ and how the body responds to and regulates it. Their investigations showed that fatigue was accompanied by a rise in orosomucoid (ORM, or alpha-1-acid glycoprotein), with significant increases in a plethora of tissues, including blood and muscle (read more). This was interesting but not surprising as ORM is one of the major ‘acute-phase proteins’ which increase or decrease in blood plasma when inflammation is present. ORM itself is produced by many tissues, though mainly by the liver, and its manufacture is influenced by many factors, such as tissue injury, infection, tobacco smoke, or the presence of other proteins produced by cells. Oddly enough, its precise biological function remains poorly understood, but it is known to be involved in immunity and in the metabolism of various drugs (see a review). The clear relationship between ORM and fatigue in their experimental model led the researchers to wonder whether the protein might, in fact, be raised in people with ME/CFS – with results that (one suspects) surprised even themselves.

Compared with a healthy control group, ORM levels were dramatically elevated in blood serum in Fukuda-defined CFS patients (Figure below).
Indeed, ORM levels were <1 mg/mL in all the healthy controls, but >1 mg/mL in all except one of the ME/CFS patients. ORM expression was not related to serum cortisol level as might have been expected (see a review); hypocortisolism was present in the ME/CFS patients, as expected, but to a mild degree.

[Figure: Blood serum ORM level (mg/mL)]

This result is reported in short letter format, and aims only to bring this unusual phenomenological finding to a wider audience. No published evidence exists to support an association between raised ORM and ME/CFS, apart from the presence of ORM2 (one of the two isoforms of ORM) in a set of 5 proteins found to be increased the cerebrospinal fluid of ME/CFS patients in a study in 2005 (read more). So, a cloud of unknowing hangs over the meaning and validity of this single observation.

There is evidence that levels of ORM (and other acute phase proteins) are raised by infection and inflammation, and that concentrations of ORM in the blood are increased in smokers compared with past or never smokers (read more), though not to the extent seen in the ME/CFS patients in this study. Also, raised levels of ORM, in combination with other markers, have been associated with all-cause mortality in elderly people (read more), as well as some pathological conditions (read more). Interestingly, another member of the acute phase protein family, C-reactive protein, is also raised in ME/CFS patients, as ME Research UK-funded work has shown (read more), with potential consequences for cardiovascular health.

Of course, as Aristotle said, “a single swallow does not a summer make, nor one fine day”, and we are a long way from knowing whether or not ORM will become a valid ‘biomarker’ for a diagnosis of ME/CFS. Any number of confounding factors can throw up an isolated unexpected result, as the XMRV story illustrated some years ago. The next step is for the group in Shanghai to confirm and extend its findings (hopefully with funding from the National Natural Science Foundation of China which kindly funded their previous investigations), and for researchers elsewhere to test for ORM and related acute phase proteins in the blood of their ME/CFS patients. We’ll watch the space with interest.