TGI Friday! Our weekly round-up of recently published research abstracts and related items | 8 May 2015

May 8, 2015

From the American Journal of Physical Medicine and Rehabilitation, 16 April 2015 (epublished ahead of print).

Physical Trauma and Infection as Precipitating Factors in Patients with Fibromyalgia.

Jiao, Juan MD; Vincent, Ann MD; Cha, Stephen S. MS; Luedtke, Connie A. RN; Kim, Chul H. MD; Oh, Terry H. MD



The objective of this study was to evaluate both precipitating factors in patients with fibromyalgia and any differences in clinical presentation, symptom severity, and quality-of-life between those with and without precipitating physical trauma or infection.


In a retrospective cross-sectional study, the authors compared patient characteristics and fibromyalgia symptom severity and quality-of-life with the Fibromyalgia Impact Questionnaire and the Short Form-36 Health Survey in patients seen in a fibromyalgia treatment program.


Of 939 patients, 27% reported precipitating factors (trauma, n = 203; infection, n = 53), with the rest having idiopathic fibromyalgia (n = 683). Patients with precipitating trauma were more likely to have worse Fibromyalgia Impact Questionnaire physical function than patients with idiopathic onset (P = 0.03). Compared with patients with idiopathic onset and precipitating trauma, patients with precipitating infection were more likely to have worse Short Form-36 Health Survey physical component summary (P = 0.01 and P = 0.003) but better role emotional (P = 0.04 and P = 0.005), mental health index (P = 0.02 and P = 0.007), and mental component summary (P = 0.03 and P = 0.004), respectively.


One-fourth of this study's patients with fibromyalgia had precipitating physical trauma or infection. Patients with precipitating infection had different sociodemographic characteristics, clinical presentation, and quality-of-life from the idiopathic and trauma groups. Further studies are needed to look into the relationships between precipitating events and fibromyalgia.

From Fatigue: Biommedicine, Health and Behaviour. Published online 27 April 2015.

Chronic fatigue syndrome and increased susceptibility to upper respiratory tract infections and illnesses

Andrew P. Smith(a*) & Marie A. Thomas(b)
a Centre for Occupational and Health Psychology, School of Psychology, Cardiff University, 63 Park Place, Cardiff, CF10 3AS, UK
b The Dyscovery Centre, University of South Wales, Newport, UK



Previous research has suggested that chronic fatigue syndrome (CFS) patients report more upper respiratory tract illnesses (URTIs) than controls.


The present study aimed to replicate and extend this research.


A prospective study of the incidence of URTIs was conducted. This was similar to previous work involving diary studies but also included objective measures of illness severity (e.g. nasal secretion; sub-lingual temperature) and infection (virus isolation from nasal swabs and antibody changes). Fifty-seven patients with CFS, diagnosed according to the 1994 CDC criteria, were recruited randomly from a volunteer panel compiled of patients who had attended the Cardiff CFS outpatient clinic. A further 57 individuals without CFS were recruited from a general population research panel.


The results confirmed that CFS patients report more upper respiratory virus infections and the virological results showed that this was not due to a reporting bias but reflected greater susceptibility to infection.


This increased susceptibility to infection in the CFS group can account for the increased reporting of URTIs found in this and previous studies.

From Mitochondrion. 28 April 2015 [E-pubished ahead of print].

Increased prevalence of two mitochondrial DNA polymorphisms in functional disease: Are we describing different parts of an energy-depleted elephant?

Boles RG(1), Zaki EA(2), Kerr JR(3), Das K(2), Biswas S(2), Gardner A(4).
1) Division of Medical Genetics and the Saban Research Institute, Children's Hospital Los Angeles, CA, USA; Department of Pediatrics, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA. Electronic address:
2) Division of Medical Genetics and the Saban Research Institute, Children's Hospital Los Angeles, CA, USA.
3)Division of Clinical Sciences, St. George's University of London, Cranmer Terrace, London, United Kingdom.
4) Department of Clinical Neuroscience, Division of Psychiatry, Karolinska Institutet, Stockholm, Sweden.


About 20% of the population suffers from “functional syndromes”. Since these syndromes overlap greatly in terms of co-morbidity,pathophysiology (including aberrant autonomic activity) and treatment responses, common predisposing genetic factors have been postulated.

We had previously showed that two common mitochondrial DNA (mtDNA)polymorphisms at positions 16519 and 3010 are statistically associated with the functional syndromes of migraine, cyclic vomiting syndrome and non-specific abdominal pain. Herein, among individuals with mtDNA haplogroup H (HgH), the presence of these two mtDNA polymorphisms were ascertained in additional functional syndromes: chronic fatigue syndrome, complex regional pain syndrome, sudden infant death syndrome, and major depressive disorder.

Polymorphic prevalence rates were compared between disease and control groups, and within each disease group in participants with and without specific clinical findings.

In all four conditions, one or both of the polymorphisms was significantly associated with the respective condition and/or co-morbid functional symptomatology. Thus, we conclude that these two mtDNA polymorphisms likely modify risk for the development of multiple functional syndromes, likely constituting a proportion of the postulated common genetic factor, at least among individuals with HgH. Pathophysiology likely involves broad effects on the autonomic nervous

From the International Journal of Infectious Diseases, 1 May 2015. (E-published ahead of print).

Post-Poliomyelitis Syndrome as a possible viral disease.

Baj A(1), Colombo M(1), Headley JL(2), McFarlane JR(3), Liethof MA(1), Toniolo A(4).
1) Laboratory of Clinical Microbiology, University of Insubria Medical School, Varese, Italy; Polio Australia Incorporated Kew, Victoria, Australia.
2) Post-Polio Health International, Saint Louis, Missouri; Polio Australia Incorporated Kew, Victoria, Australia.
3) European Polio Union, Huldenberg, Belgium; Polio Australia Incorporated Kew, Victoria, Australia.
4) Laboratory of Clinical Microbiology, University of Insubria Medical School, Varese, Italy; Polio Australia Incorporated Kew, Victoria, Australia. Electronic address:


The review summarizes current concepts on the Post-Polio Syndrome (PPS), a condition that may arise in polio survivors after partial or complete functional recovery followed by an prolonged interval of stable neurologic function. PPS affects 15-20 million people

Epidemiologic data are reported, together with pathogenic pathways that possibly lead to the progressive degeneration and loss of neuromuscular motor units. As a consequence, polio survivors experience new weakness, generalized fatigue, atrophy of previously
unaffected muscles, and physical decline that may culminate in the loss of independent life.

Emphasis is given to the possible pathogenic role of persistent poliovirus infection and chronic inflammation. These factors could contribute to neurological and physical decline in polio survivors. A perspective is then given on novel anti-poliovirus compounds and monoclonal antibodies that have been developed for contributing to the final phases of polio eradication. These agents could also be useful for treating or preventing PPS. Some of these compounds/antibodies are in early clinical development.

Finally, current clinical trials for PPS are reported. In this area, the intravenous infusion of normal human immunoglobulins seems both feasible and promising.

Editorial in the British Medical Journal, 5 May 2015.

The long wait for a breakthrough in chronic fatigue syndrome

Andrew R Lloyd, professor(1), Jos W M van der Meer, professor(2)
1) Inflammation and Infection Research Centre, University of New South Wales, Sydney 2052, Australia
2) Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
Correspondence to: A R Lloyd

Not over yet

There hasn’t been much good news for patients with the prevalent but enigmatic disorder chronic fatigue syndrome (also referred to as myalgic encephalomyelitis). Over decades, research into the pathophysiology has failed to find convincing evidence of eitherpersistent infection or immunological, endocrine, or metabolic change, and has rejected simplistic notions of depression (typical or atypical) or primary sleep disorder.

Several notable “breakthroughs” have failed independent replication. The most noteworthy is the recent rise and fall of xenotropic murine leukaemia virus related virus (XMRV) as the cause, which was ultimately established as a murine DNA laboratory contaminant.1 Similarly, an exhaustive array of randomised controlled trials seeking curative outcomes from antiviral, immunological, hormonal, antidepressant, and many other therapies have
failed to show any benefit over placebo, or failed the replication test.

Where then is the progress? Firstly, there is reproducible evidence implicating certain infections as a trigger—notably, infectious mononucleosis caused by Epstein-Barr virus, but also infection with other pathogens.2 Secondly, there is clear evidence that a substantial proportion of patients have a coexisting mood disorder, and sometimes a sleep-wake disorder, and that these conditions may exacerbate or perpetuate the illness.

3 Thirdly, independent studies using both structural and functional imaging techniques have identified alterations in the brains of patients with chronic fatigue syndrome, implicating the central nervous system as the site of pathophysiology.4 Fourthly, there is solid evidence from multiple controlled studies that patients can gain control of symptoms and functional improvement through multidisciplinary interventions incorporating graded exercise therapy and cognitive behavioural therapy. These interventions have clearly positive outcomes in systematic reviews and meta-analyses.5 6 7 For instance, the recent Cochrane review of graded exercise therapy5 states that “patients with CFS [chronic fatigue syndrome] may generally benefit and feel less fatigued following exercise therapy, and no evidence suggests that exercise therapy may worsen outcomes. A positive effect with respect to sleep, physical function and self-perceived general health has been observed.”

How therapy works

Plausibly, graded exercise may reverse a perpetuator in the form of physical deconditioning. However, there is little evidence for loss of aerobic fitness in patients with chronic fatigue syndrome, and limited evidence for improved physical performance after successful graded exercise therapy.

8 Instead, graded exercise has been proposed to act by desensitising an exaggerated central nervous system response to the physiological signals associated with exercise.9 In psychological terms, patients may avoid activity because of the prolonged exacerbation of symptoms that follows minor physical activity; this leads to an understandable conclusion that exercise is harmful or to a conditioned fear of such activity.

10 In this respect, the recent mediation analysis of the outcomes of the PACE trial is of interest.11 This trial compared standard medical care, cognitive behavioural therapy, graded exercise, and adaptive pacing therapy, concluding that both cognitive behavioural and graded exercise therapy were more effective at reducing fatigue and improving physical disability than standard care or adaptive pacing.12 The mediation analysis suggested that both cognitive behavioural therapy and graded exercise worked by reducing avoidance of activity.

This is broadly consistent with findings by others,13 although whether the effect simply relates to the behavioural change itself (that is, exercise) or reconditioning of the associated fear of activity remains unclear. In addition, a substantial proportion of patients do not avoid activity but have repeated boom-bust cycles of overactivity when feeling relatively well (the boom) followed by reduced activity when symptoms are exacerbated thereafter (the bust). These data argue for a personalised approach to both therapies.

Cognitive behavioural therapy for patients with chronic fatigue syndrome is based on the premise that inappropriate cognitive attributions (thinking patterns) and behaviours help perpetuate symptoms. It seeks to alter these attributions and modify the associated behaviour, targeting activity patterns and sleep-wake
behaviours. For example, although primary sleep disorders do not explain chronic fatigue syndrome,14 patients typically report that their night-time sleep is unrefreshing, and as fatigue is the dominant symptom, patients may consider that increased sleep will relieve symptoms and aid recovery. This idea commonly leads to frequent
daytime naps and a delayed sleep-wake cycle.

Prospects for cure

There has been recent contention about the possibility of cure after graded exercise and cognitive behavioural therapy. An analysis of the PACE trial suggested cure was possible, but recovery outcomes were defined post hoc using population norms with generous thresholds (such as the population mean plus one standard deviation for self reported fatigue).

15 This analysis was criticised because of the limited assessments and less than full restoration of health,16 leading to a recommendation that trials use more accurate outcomes (such as clinically relevant improvement) defined in advance and capturing a broad based return to health with assessments of fatigue and function.

Trialists must also consider patients’ perceptions of their recovery.17 In this context, the increase in volume of grey matter associated with clinical response to cognitive behavioural therapy, as reported in one study, needs further investigation.18 Even with the unduly liberal designation of recovery, less than one quarter of
patients “recovered” in the PACE trial.

What then of the long awaited breakthrough? As is often the case in medical research, progress is predominantly made in modest increments not breakthroughs. The evidence for graded exercise and cognitive behavioural therapy is already clear, so this treatment should be made widely available. The next increments are to find ways to increase the symptom relief and functional improvement achieved by these treatments and to identify factors predicting clinically relevant improvement and non-response in order to increase the proportion of patients who

Competing interests: We have read and understood BMJ policy on
declaration of interests and have no relevant interests to declare.

Provenance and peer review: Commissioned; not externally peer reviewed.


1. Van Kuppeveld FJ, van der Meer JW. XMRV and CFS—the sad end of a story. Lancet2012;379:e27-8.
2. Hickie I, Davenport T, Wakefield D, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ2006;333:575.
3. Prins JB, van der Meer JW, Bleijenberg G. Chronic fatigue syndrome. Lancet 2006;367:346-55.
4. Tanaka M, Ishii A, Watanabe Y. Neural mechanisms underlying chronic fatigue. Rev Neurosci2013;24:617-28.
5. Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev2015;2:CD003200.
6. Reid S, Chalder T, Cleare A, Hotopf M, Wessely S. Chronic fatigue syndrome. BMJ 2000;320:292-6.
7. Knight SJ, Scheinberg A, Harvey AR. Interventions in pediatric chronic fatigue syndrome/myalgic encephalomyelitis: a systematic review. J Adolesc Health2013;53:154-65.
8. Moss-Morriss R, Sharon C, Tobin R, Baldi JC. A randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change. J Health Psychol2005;10:245-59.
9. Nijs J, Meeus M, Van Oosterwijck J, et al. In the mind or the brain? Scientific evidence for central sensitisation in chronic fatigue syndrome. Eur J Clin Invest2011;42:203-11.
10. Clark LV, White PD. The role of deconditioning and therapeutic exercise in chronic fatigue syndrome (CFS). J Mental Health2005;14:237-52.
11. Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry2015;2:141-52.
12. White PD, Goldsmith KA, Johnson AL, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet2011;377:823-36.
13. Wiborg JF, Knoop H, Prins JB, Bleijenberg G. Does a decrease in avoidance behavior and focusing on fatigue mediate the effect of cognitive behavior therapy for chronic fatigue syndrome? J Psychosom Res2011;70:306-10.
14. Jackson ML, Bruck D. Sleep abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a review. J Clin Sleep Med2012;8:719-28.
15. White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med2013;43:2227-35.
16. Kindlon T, Baldwin A. Response to: reports of recovery in chronic fatigue syndrome may present less than meets the eye. Evid Based Mental Health 2014. doi:10.1136/eb-2014-101961.
17. Adamowicz JL, Caikauskaite I, Friedberg F. Defining recovery in chronic fatigue syndrome: a critical review. Qual Life Res2014;23:2407-16.
18. De Lange FP, Koers A, Kalkman JS, et al. Increase in prefrontal cortical volume following cognitive behavioural therapy in patients with chronic fatigue syndrome. Brain2008;131:2172-80.

From Archives of Disease in Childhood, May 2015.

[Royal College of Paediatrics and Child Health, Abstracts of the Annual Conference, 28-30 April 2015, The ICC, Birmingham]

A systematic review to identify the definitions of recovery for paediatric patients with chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) used in studies since 1994

Y Moore, NME Anderson, E Crawley
School of Social and Community Medicine, University of Bristol,
Bristol, UK



To describe how recovery from paediatric CFS/ME is defined, how many children recover and how long it takes.


We conducted detailed literature searches of MEDLINE, EMBASE, PsycInfo and the Cochrane library, searched trial registration sites, contacted authors if results have not been published and hand searched reference
lists. Three categories of search terms were used; paediatric, CFS/ME and recovery.


Randomised controlled trials or observational studies of participants <19 years old with a diagnosis of CFS/ME, related to a Western Health Care system, some measure of recovery (partial or full) reported and the time taken to reach it.RESULTS21 papers were identified. The study populations ranged from 1 to 64 participants, their duration of illness ranged from 3 months to 7 years between studies and also showed great variety within each study. Some studies used a single measurement outcome for recovery, others measured several and some integrated multiple outcomes to formulate one value for recovery.The recovery rate ranged from 25-100% in those accessing treatment and 4.5-100% in those without specialist care. School attendance was the most common measurement outcome (n=11), of which 4 of these combined this with at least one other measure. 7 studies measured physical ability as an outcome, 8 used fatigue and 9 measured a global improvement that was either self-rated or qualitatively assessed by an investigator. 2 studies described recovery as no longer fulfilling the diagnostic criteria.CONCLUSIONRecovery rates are relatively high in children accessing specialist treatment however, the discrepancies between the measurement outcomes, makes interpretation of recovery rates difficult.

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