ME and CFS References


Number 1

1st February 2009






Mathew, SJ., Mao, X., Keegan, KA., Levine, SM., Smith, ELP., Heier, LA., Otcheretko, V., Coplan, J and Shungu DC. Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T 1H MRS imaging study. NMR in Biomedicine, 2008 Oct 21. [Epub ahead of print]. doi: 10.1002/nbm.1315

CFS is a controversial diagnosis because of the lack of biomarkers for the illness and its symptom overlap with neuropsychiatric, infectious, and rheumatological disorders. We compared lateral ventricular volumes derived from tissue-segmented T1-weighted volumetric MRI data and cerebrospinal fluid (CSF) lactate concentrations measured by proton MRS imaging (1H MRSI) in 16 subjects with CFS (modified CDC criteria ’94, 8 with fibromyalgia) with those in 14 patients with generalized anxiety disorder (GAD) and in 15 healthy volunteers, matched group-wise for age, sex, body mass index, handedness, and IQ.

Mean lateral ventricular lactate concentrations measured by 1H MRSI in CFS were increased by 297% compared with those in GAD (p<0.001) and by 348% compared with those in healthy volunteers (p<0.001), even after controlling for ventricular volume, which did not differ significantly between the groups. Regression analysis revealed that diagnosis accounted for 43% of the variance in ventricular lactate.

CFS is associated with significantly raised concentrations of ventricular lactate, potentially consistent with recent evidence of decreased cortical blood flow, secondary mitochondrial dysfunction, and/or oxidative stress abnormalities in the disorder.

[Ed. Note: The results were not related to levels of fatigue or other clinical variables. A subset of patients with CFS had normal results. The changes in brain lactate could be due to hypoperfusion.]



Roberts, ADL., Papadopoulos, AS., Wessely, S., Chalder, T and Cleare, AJ. Salivary cortisol output before and after cognitive behavioural therapy for chronic fatigue syndrome. Journal of Affective Disorders, 2008 Oct 18. [Epub ahead of print].

There is evidence that patients with CFS have mild hypocortisolism. One theory about the
aetiology of this hypocortisolism is that it occurs late in the course of CFS via factors such as inactivity, sleep disturbance, chronic stress and deconditioning. We aimed to determine whether therapy aimed at reversing these factors - cognitive behavioural therapy (CBT) for CFS - could increase cortisol output in CFS.

We measured diurnal salivary cortisol output between 0800 and 2000h before and after 15 sessions (or 6 months) of CBT in 41 patients with CDC-defined CFS attending a specialist, tertiary outpatient clinic. There was a significant clinical response to CBT, and a significant rise in salivary cortisol output after CBT. We were unable to control for the passage of time using a non-treated CFS group. There were no significant correlations between clinical and cortisol measures after CBT.

Hypocortisolism in CFS is potentially reversible by CBT. Given previous suggestions that lowered cortisol may be a maintaining factor in CFS, CBT offers a potential way to address this.

[Ed. Note: The researchers also used the Sharpe et al (Oxford) criteria to select patients. “Overall, 47% of the patients had responded to therapy at the time of repeat testing.” The lack of association between cortisol and clinical measures suggests that another factor explained the rise in cortisol, e.g. a relevant variable which was not assessed, possibly increased activity or a reduction in perceived stress. After treatment, the mean physical functioning score was 50.7 indicating severe disability. This was a clinical study, not a trial of CBT. Other clinical studies of CBT have reported equally disappointing results, e.g. Akagi et al, Quarmby et al]



Courjaret. J., Schotte, CKW., Wijnants, H., Moorkens, G and Cosyns, P. Chronic fatigue syndrome and DSM-IV personality disorders. Journal of Psychosomatic Research, 2009, 66, 13-20.

Personality is an important factor in the research of the CFS. Although some studies report a high rate of personality disorders - around the 40% level - in samples of patients with CFS, the generalizability of these findings can be questioned. The present study evaluates the prevalence of Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) personality disorders in a sample of female CFS patients and in two control groups.

The ADP-IV questionnaire (Assessment of DSM Personality Disorders IV) was used to assess the DSM-IV-TR personality disorders at a dimensional and categorical level in a sample of 50 female CFS patients (CDC criteria '94, moderate severity) and in two matched control samples of Flemish civilians (n=50) and psychiatric patients (n=50).

The results indicate a striking lack of statistical significant differences between the CFS sample and the Flemish control group at the level of dimensional Trait scores, number of criteria, and prevalence rates of personality disorder diagnoses. Unsurprisingly, higher scores at these levels were obtained within the psychiatric sample. The prevalence of an Axis II disorder was 12% in the Flemish and CFS samples, whereas the psychiatric sample obtained a prevalence of 54%.

The prominent absence of any significant difference in personality disorder characteristics between the female Flemish general population and the CFS samples seems to suggest only a minor etiological role for personality pathology, as defined by the DSM-IV Axis II, within CFS.

Friedberg, F and Sohl, SJ. Longitudinal change in chronic fatigue syndrome: what home-based assessments reveal. Journal of Behavioral Medicine, 2008 Dec 20. [Epub ahead of print].10.1007/s10865-008-9189-9.

The purpose of this 2-year prospective study was to compare standard self-report and ecologically-based outcome measures in patients with CFS (CDC criteria, '94 and 2003, no medical examination). Standard measures assessed physical function, fatigue impact, psychological variables, and global impression of change ratings. Ecological measures included actigraphy, a structured activity record, and an electronic fatigue/energy diary.

Results for this high functioning sample (n=75) revealed that self-report global improvement was significantly associated with lower momentary fatigue and fatigue impact, and a higher frequency of standing up (at home), but not with actigraphy or psychological
variables. However, actigraphy change was significantly correlated with change in self-report physical function. At follow-up, only a small minority (<20%) scored in the healthy adult range for fatigue impact and physical function.

The findings suggest that home-based measures of symptom severity and physical functioning may provide evidence of change (or lack of change) that is important for interpreting standard self-report outcomes in CFS.

[Ed. Note: The study supports the observation that about 25% tend to feel worse over time. Extracts: "Consistent with this activity pacing approach, a recent randomized trial (Jason et al. 2007) of four non-pharmacological interventions in moderately functional (45% full- or part-time employed) CFS patients utilized a central activity pacing component in their coping skills oriented cognitive behavioral treatment (CBT) condition. In comparison to the other treatment conditions (graded activity CBT, relaxation, and anaerobic exercise), coping skills CBT yielded the greatest overall improvement, including significant gains in SF-36 physical function scores. This intervention, which was intended (behaviorally) to substitute stress-reducing activities for stress-exacerbating activities rather than to increase activity levels per se (as in graded activity CBT), may have resulted in a more sustainable balance between activity and rest (cf. Bleijenberg et al. 2003)."]

Hadlandsmyth, K and Vowles, KE. Does depression mediate the relation between fatigue severity and disability in CFS sufferers? Journal of Psychosomatic Research, 2009, 66, 1, 31-35.

CFS is often associated with significant levels of disability. Although fatigue and depression have been found to be independently related to severity of disability, it is not clear how these three factors are mutually related. The present study sought to address this issue by specifically testing a model of mediation whereby depression was hypothesized to influence relations between fatigue and disability.

Participants included 90 individuals seeking treatment for CFS at a tertiary care facility. Each provided demographic information and completed standardized measures of depression and fatigue severity, as well as a measure of disability, which assessed difficulties in physical, psychosocial, and independence domains.

Analyses indicated that depression and fatigue were positively correlated with one another, as well as all three disability domains. Analyses of mediation indicated that depression com-pletely mediated the relation between fatigue and psychosocial disability and partially mediated the relation between fatigue and the other two disability domains. Indirect effects tests indicated that the inclusion of depression in the statistical models was statistically meaningful.

These results replicate previous findings that fatigue and depression are independently related to disability in those with CFS. A more complex statistical model, however, suggested that depression severity substantially influenced the strength of the relation between fatigue and disability levels across a range of domains, including complete mediation in areas involving psychosocial functioning. These results may aid in clarifying contemporary conceptualizations of CFS and provide guidance in the identification of appropriate treatment targets.



Hickie, I., Davenport, T., Vernon, SD., Nisenbaum, R., Reeves, WC, Hadzi-Pavlovic, D., Lloyd, A; International Chronic Fatigue Syndrome Study Group. Are chronic fatigue and chronic fatigue syndrome valid clinical entities across countries and health-care settings? Australian and New Zealand Journal of Psychiatry, 2009, 43, 1, 25-35.

The validity of the diagnosis of CFS and related chronic fatigue states remains controversial, particularly in psychiatry. This project utilized international epidemiological and clinical research data to test construct validity across diagnostic categories, health-care settings and countries. Relevant demographic, symptom and diagnostic data were obtained from 33 studies in 21 countries. The subjects had fatigue lasting 1-6 months (prolonged fatigue), or >6 months (chronic fatigue), or met various diagnostic criteria for CFS. Common symptom domains were derived by factor analytic techniques. Mean scores on each symptom factor were compared across diagnostic categories, health-care settings and countries.

Data were obtained on 37,724 subjects (n = 20,845 female, 57%), including from population-based studies (n = 15,749, 42%), studies in primary care (n = 19 472, 52%), and secondary or specialist tertiary referral clinics (n = 2503, 7%). The sample included 2013 subjects with chronic fatigue, and 1958 with CFS.

A five-factor model of the key symptom domains was preferred ('musculoskeletal pain/fatigue', 'neurocognitive difficulties', 'inflammation', 'sleep disturbance/fatigue' and 'mood disturbance') and was comparable across subject groups and settings. Although the core symptom profiles were similar, some differences in symptoms were observed across diagnostic categories, health-care settings and between countries.

The construct validity of chronic fatigue and CFS is supported by an empirically derived factor structure from existing international datasets.

Extracts: “We suggest that this international study supports the proposition that chronic fatigue states share a common and stereotyped set of symptom domains, and that these can be readily identified in the community and at all levels of health care. Consequently, it is likely that they share common risk factors, are underpinned by a common pathophysiology, and may respond to common treatment strategies. We also suggest that there is little to be gained by further reorganization of the diagnostic criteria, or the related diagnostic entities. It is time to consider whether chronic fatigue states should be included formally in future international classification systems both in psychiatry and in general medicine...”

[Ed. Note: Most of the data was compiled from a few (large) studies. It appears from Table 1 that only four of the listed studies used the stricter 1988 criteria. There is no information comparing the symptom presentation of those meeting the stricter criteria versus the broader Oxford guidelines (6 studies) or 1994 criteria (18 studies). There are no data for studies which used criteria consistent with post-viral fatigue syndrome (e.g. Ho-Yen) or the older literature which focused on ME/epidemic neuromyasthenia. This means that the researchers limited themselves to studies on fatigue/tiredness and a number of ubiquitous symptoms, such as headaches and joint pain.

It follows that the concept of CFS in this analysis resembles neurasthenia/chronic stress, which is likely to share common aetiological factors (notably chronic stress and poor diet) and may respond to a single treatment modality (CBT). Having omitted studies on the more strictly defined categories, it is therefore not possible to deduce that the concept of CFS as classified in ICD-10 and including post-viral CFS is adequately diagnosed using the current CDC criteria.

Secondly, the lack of CDC criteria to assess 'inflammation' (alleged to be a ‘key’ symptom domain which includes dizziness, lightheadedness, shooting pains in the chest) means that it is difficult to support the argument that the existing criteria do not require amendment. None of the symptoms listed above feature in the current criteria. The same may be posited for the factor 'mood disturbance' (e.g. “felt life is entirely hopeless”). The musculoskeletal fatigue factor does not appear to include post-exertional fatigue, a core symptom of CFS, or delayed recovery of muscle power, a cardinal feature of ME. This requires clarification. Conversely, the differences in symptomatology between the fatigued and CFS group is consistent with previous research.

The make up of the study group (dominated by mental health professionals, virtually all associated with the CBT school, no ME specialists) may explain the suggestion that CFS might be added to psychiatric classifications. They include Bleijenberg G, van der Werf SP, Prins JB, Edwards R, Lynch S, Kirmayer LJ, Skapinakis P, Wessely S, Chalder T, Hotopf M, Nimnuan C, Candy B, Darbishire L, Ridsdale L, White PD and Thomas JM.

The conclusions reflect a lack of objectivity and respect for evidence reported by those with a different concept of CFS. The inclusion of Dr. Vernon suggests that her views in medical publications do not match those expressed in patient literature.]

Jason, LA., Porter, N., Shelleby, E., Bell, DS., Lapp, CW., Rowe, K and De Meirleir, K. A case definition for children with myalgic encephalomyelitis/chronic fatigue syndrome. Clinical Medicine: Pediatrics, 2008, 1, 53-57.

The case definition for CFS was developed for adults and this case definition may not be appropriate for use with children and adolescents. The lack of application of a consistent pediatric definition for this illness and the lack of a reliable instrument to assess it might lead to studies which lack sensitivity and specificity. In this article, a case definition is presented that has been endorsed by the International Association of ME/CFS.



Armitage, R., Landis, C., Hoffmann, R., Lentz, M., Watson, N., Goldberg, J and Buchwald, D. Power spectral analysis of sleep EEG in twins discordant for chronic fatigue syndrome. Journal of Psychosomatic Research, 2009, 66, 1, 51-57.

The purpose of the study was to evaluate quantitative sleep electroencephalogram (EEG) frequencies in monozygotic twins discordant for CFS (CDC criteria ’94). Thirteen pairs of female twins underwent polysomnography. During the first night, they adapted to the sleep laboratory, and during the second night, their baseline sleep was assessed. Visual stage scoring was conducted on sleep electroencephalographic records according to standard criteria, and power spectral analysis was used to quantify delta through beta frequency bands, processed in 6-s blocks. Data were averaged across sleep stage within each twin and coded for sleep stage and the presence or absence of CFS.

No significant differences in spectral power in any frequency band were found between those with CFS and their non-fatigued co-twins. Phasic alpha activity, coupled with delta was
noted in five subjects with CFS but was also present in 4/5 healthy twins, indicating this finding likely reflects genetic influences on the sleep electroencephalogram rather than disease-specific sleep pathology.

The genetic influences on sleep polysomnography and microarchitecture appear to be stronger than the disease influence of CFS, despite greater subjective sleep complaint among the CFS twins. EEG techniques that focus on short duration events or paradigms that probe sleep regulation may provide a better description of sleep abnormalities in CFS.

Brimmer, DJ., McCleary, KK., Lupton, TA., Faryna, KM., Hynes, K and Reeves, WC. A train-the-trainer education and promotion program: chronic fatigue syndrome – a diagnostic and management challenge. BMC Medical Education, 2008, 8:49 doi:10.1186/1472-6920-8-49.

CFS is a complicated illness for providers and patients. Fewer than 20% of persons with CFS have been diagnosed and treated. For providers, compounding the issue are the challenges in making a diagnosis due to the lack of a biomedical marker. The objective of the CFS diagnosis and management curriculum was to instruct core trainers as to the evaluation, diagnosis, and management of CFS. Over a two year period, 79 primary care physicians, physician assistants, and nurse practitioners from diverse regions in the U.S. participated as core trainers in a two day Train-the-Trainer (TTT) workshop. As core trainers, the workshop participants were expected to show increases in knowledge, self-efficacy, and management skills with the primary goal of conducting secondary presentations.

The optimal goal for each core trainer to present secondary training to 50 persons in the health care field was not reached. However, the combined core trainer group successfully reached 2064 primary care providers. Eighty-two percent of core trainers responded “Very good” or “Excellent” in a post-test survey of self-efficacy expectation and CFS diagnosis. Data show the workshop was successful in meeting the objectives of increasing CFS knowledge and raising perceived self-efficacy towards making a diagnosis...

Chen, R., Moriya, J., Yamakawa, JI., Takahashi, T and Kanda, T. Traditional Chinese medicine for chronic fatigue syndrome. Evidence Based Complementary and Alternative Medicine, 2008 Feb 27. [Epub ahead of print]

As an alternative medicine, traditional Chinese medicine (TCM) has provided some evidences based upon ancient texts and recent studies, not only to offer clinical benefit but also offer insights into their mechanisms of action. It has perceived advantages such as being natural, effective and safe to ameliorate symptoms of CFS such as fatigue, disordered sleep, cognitive handicaps and other complex complaints, although there are some limitations regarding the diagnostic standards and methodology in related clinical or experimental studies. Modern mechanisms of TCM on CFS mainly focus on adjusting immune dysfunction, regulating abnormal activity in the hypothalamic-pituitary-adrenal (HPA) axis and serving as an antioxidant. It is vitally important for the further development to establish standards for ‘zheng’ of CFS, i.e. the different types of CFS pathogenesis in TCM, to perform randomized and controlled trials of TCM on CFS and to make full use of the latest biological, biochemical, molecular and immunological approaches in the experimental design.

Crawley, E and Sterne, J. Association between school absence and physical function in paediatric CFS/ME. Archives of Disease in Childhood, 2008 Nov 11. [Epub ahead of print].

This cross-sectional study investigated factors associated with school attendance and physical function in paediatric CFS/ME. Patients were children and young people aged <18. Outcome measures included self reported school attendance and physical function assessed using the physical function subscale of the SF36. Analyses were done in two groups of children: (1) with a completed Spence Children’s Anxiety Scale (SCAS) and (2) with a completed Hospital Anxiety and Depression Scale (HADS).

Of 211 children with CFS/ME (RCPCH criteria), 62% attended 40% of school or less. In children with completed SCAS, those with better physical function were more likely to attend school (adjusted OR 1.70, 95% CI 1.36 to 2.13). This was also true for those with completed HADS scores (adjusted OR 2.05 95% CI 1.4, 3.01). Increasing fatigue and pain and low mood were associated with worse physical function. There was no evidence that anxiety, gender, age at assessment, family history of CFS/ME or time from onset of symptoms to assessment in clinic were associated with school attendance or physical function.

Paediatricians should recognise that reduced school attendance is associated with reduced physical function rather than anxiety. Improving school attendance in children with CFS/ME should focus on evidence-based interventions to improve physical function, particularly concentrating on interventions that are likely to reduce pain and fatigue.

Lemle, MD. Hypothesis: Chronic fatigue syndrome is caused by dysregulation of hydrogen sulfide metabolism. Medical Hypotheses, 2009, 72, 1, 108-109.

The hypothesis is advanced that the multi-system disturbances in CFS/ME are caused by disturbances in the homeostasis of endogenous hydrogen sulfide (H2S) and result in mitochondrial dysfunction.

Exley, C., Swarbrick, L., Gherardi, RK and Authier, FJ. A role for the body burden of aluminium in vaccine-associated macrophagic myofasciitis and chronic fatigue syndrome. Medical Hypotheses, 2009, 72, 2, 135-139.

Macrophagic myofasciitis and CFS are severely disabling conditions which may be caused by adverse reactions to aluminium-containing adjuvants in vaccines. While a little is known of disease aetiology both conditions are characterised by an aberrant immune response, have a number of prominent symptoms in common and are coincident in many individuals. Herein, we have described a case of vaccine-associated CFS and macrophagic myofasciitis in an individual demonstrating aluminium overload. This is the first report linking the latter with either of these two conditions and the possibility is considered that the coincident aluminium overload contributed significantly to the severity of these conditions in this individual.

This case has highlighted potential dangers associated with aluminium-containing adjuvants and we have elucidated a possible mechanism whereby vaccination involving aluminium-containing adjuvants could trigger the cascade of immunological events which are associated with autoimmune conditions including CFS and macrophagic myofasciitis.

Friedberg, F. Cognitive-behavioral intervention in chronic fatigue syndrome: benefits, limitations, and open questions. Bulletin of the IACFS/ME, 2008, 16, 4, 22-27.

The cognitive-behavioral model of CFS postulates fear-based avoidance behavior and physical deconditioning to explain symptoms and impairments.  This article examines these assumptions and provides a brief critical perspective of CBT trials in patients with CFS.  Although CBT is effective to varying degrees in reducing symptoms and improving functioning, published reports often do not address (a) the influence of baseline functioning on intervention rationale; (b) clinical vs. statistical significance of outcomes; (c) patient non-response to CBT; and (d) the potential role of biological variables in predicting response to intervention.  A balanced assessment of the effectiveness of CBT in CFS is important in providing accurate information to both professionals and patients.

Fuller-Thomson, E and Nimigon, J. Factors associated with depression among individuals with chronic fatigue syndrome: Findings from a nationally representative survey. Family Practice, 2008, 25, 6, 414-422.

Most previous research regarding CFS and depression has relied on clinical samples. The current research determined the prevalence and correlates of depression among individuals with CFS in a community sample.

The nationally representative Canadian Community Health Survey, conducted in 2000/2001, included an un-weighted sample size of 1045 individuals with a self-reported diagnosis of CFS and had complete data on depression. Respondents with CFS who were depressed (n = 369) were compared to those who were not depressed (n = 676). Chi-square analyses, t-tests and a logistic regression were conducted.

Thirty-six per cent of individuals with CFS were depressed. Among individuals with CFS, depression was associated with lower levels of mastery and self-esteem. In the logistic regression analyses, the odds of depression among individuals with CFS were higher for females, younger respondents, those with lower incomes and food insecurity and those whose activities were limited by pain. Two in five depressed individuals had not consulted with any mental health professional in the preceding year. Twenty-two per cent of depressed respondents had seriously considered suicide in the past year. Individuals with CFS who were depressed were particularly heavy users of family physicians, with an average of 11.1 visits annually (95% confidence interval = 10.7, 11.6).

It is important for clinicians to assess depression and suicidal ideation among their patients with CFS, particularly among females, those reporting moderate to severe pain, low incomes and inadequate social support.

Haig-Ferguson, A., Tucker, P., Eaton, N., Hunt, L and Crawley, E. Memory and attention problems in children with CFS/ME. Archives of Disease in Childhood, 2008 Nov 11. [Epub ahead of print].

To understand more about the problems which children with CFS/ME experience with their memory and attention, and to test the feasibility of quantitative measurement of both memory and attention, we administered a 4 item semi-structured questionnaire and neuropsychological test battery with 10 psychometric subtests in the family home of the child taking part.

Patients: 20 children with a diagnosis of CFS/ME and experiencing memory and/or concentration problems were recruited between April and October 2007 from a regional CFS/ME clinical service (Female=13; Average age 13.5yrs; Range 8 - 16 yrs). Each child, parent and teacher was asked to describe the child's memory and attention problems. Responses were subject to thematic analysis by two independent researchers. In addition each child completed a battery of 10 tests to measure: Processing speed; Attention; Immediate and Delayed Memory; Working Memory; Executive Function. Raw scores were converted into age-scaled scores and the children's psychometric scores on the 10 tests taken were compared with normative data using t-tests.

Children with CFS/ME, their parents and teachers described problems with focussed attention, sustained attention, recall and stress. Children's scores were compared to normative data. Scores for sustained attention (mean 8.1, 95% CI 6.3-9.9), switching attention (7.5, 5.5-9.4), divided attention (6.9, 5.5-8.2), auditory learning (8.2, 6.8-9.6) and immediate recall (8.7, 7.3-10.0) appeared lower than the normative mean of 10.

Children with CFS/ME appear to experience problems with attention, which may have adverse implications for verbal memory. These cognitive problems may explain some of the educational difficulties associated with CFS.

Kelly, M. Gagne, R., Newman, JD., Olney, C., Gualtieri, C and Trail D. Assessment of fibromyalgia & chronic fatigue syndrome: a new protocol designed to determine work capability - chronic pain abilities determination (CPAD). Irish Medical Journal, 2008, 101, 9, 277-278.

The objective was to design a protocol to assess work ability in people suffering ill-defined painful and disabling disorders, the outstanding prototype of which is fibromyalgia/CFS. Following an extensive literature search, the most appropriate components of current methods of assessment of physical and cognitive abilities were incorporated into the protocol, occasionally with appropriate modification to suit the specific requirements of the individual. The initial part of the assessment consists of a standard history taking, principally focusing on the patient's self-reported physical and cognitive abilities and disabilities, as well as the com-pletion of established pain and fatigue scales, and relevant disability questionnaires. Following this, physical and cognitive abilities are objectively assessed on two separate occasions... The designed system produces reliable, consistent and reproducible results. It also proves capable of detecting any inconsistencies in patient input and results, in addition to being independent of any possible assessor bias.

Kerr, JR. Gene profiling of patients with chronic fatigue syndrome/myalgic encephalomyelitis. Current Rheumatology Reports, 2008, 10, 6, 482-491.

CFS/ME is a multisystem disease, the pathogenesis of which remains undetermined. Following two microarray studies, we reported the differential expression of 88 human genes in patients with CFS; 85 of these genes were upregulated and 3 were downregulated. The top functional categories of these 88 genes were hematologic disease and function, immunologic disease and function, cancer, cell death, immune response, and infection.

Clustering of quantitative polymerase chain reaction data from CFS/ME patients revealed seven subtypes with distinct differences in Short Form (SF)-36 scores, clinical phenotypes, and severity. Gene signatures in each subtype implicate five human genes as possible targets for specific therapy. Development of a diagnostic test for subtype status is now a priority. The possibility that these subtypes represent individual host responses to particular microbial infections is being investigated and may provide another route to specific therapies for CFS patients.

Kumar, A., Garg, R and Kumar, P. Nitric oxide modulation mediates the protective effect of trazodone in a mouse model of chronic fatigue syndrome. Pharmacology Report, 2008, 60, 5, 664-672.

The present study was conducted with the aim of elucidating the possible role of nitric oxide (NO) in the neuroprotective effects of trazodone used to treat CFS in mice.

Male albino mice were forced to swim for a six minute session each day for 7 days and the immobility period was recorded every other day. Trazodone (5 mg/kg and 10 mg/kg) was administered each day 30 min before the forced swim test. In addition, L-arginine (100 mg/kg) and L-NAME (5 mg/kg) were administered 15 min before administration of trazodone (5 mg/kg). Various behavioral tests, including locomotor (actophotometer) and anxiety (mirror chamber and plus maze) tests, as well as biochemical parameters (lipid peroxidation, reduced glutathione, catalase, and nitrites) were evaluated on the 8th day.

Forced swimming for 7 days caused a chronic fatigue-like condition, anxiety-like behavior, impairments in locomotor activity, and oxidative damage (increased lipid peroxidation and nitrite levels, and depletions in the reduced forms of glutathione and catalase activity) in animals. Pretreatment with L-NAME (5 mg/kg) potentiated the antioxidant effect of trazodone (5 mg/kg). However, L-arginine (100 mg/kg) pretreatment reversed the protective effect of trazodone (5 mg/kg) (p < 0.05).

The present study suggests the possible involvement of NO signaling in the protective effect of trazodone.

Magnus, P., Brubakk, O., Nyland. H., Wold, BH., Gjessing, HK., Brandt, I., Eidem, T., Nřkleby, H and Stene-Larsen, G. Vaccination as teenagers against meningococcal disease and the risk of the chronic fatigue syndrome. Vaccine, 2009, 1, 23-27.

In Norway, a vaccine against Neisseria meningitides group B was administered to teenagers in 1988-1989 in a protection trial. In order to estimate the relative risk of CFS/ME according to vaccine history, we conducted a case-control study in 2007, with 201 cases diagnosed at one of two hospitals and 389 controls.

The adjusted odds ratio for CFS/ME was 1.06 (95% CI: 0.67-1.66) for subjects who received the active vaccine contrasted to subjects who did not. Using this design, no statistically significant association between vaccination against meningococcal disease in teenagers and occurrence of CFS/ME could be observed.

Nancy, AL and Shoenfeld, Y. Chronic fatigue syndrome with autoantibodies - The result of an augmented adjuvant effect of hepatitis-B vaccine and silicone implant. Autoimmunity Reviews, 2008, 8, 1, 52-55.

Case presentation: A 56-year-old woman was diagnosed with CFS accompanied by FM, demyelination and autoantibodies. Her illness begun following the 2nd dose of hepatitis-B vaccine, and was aggravated by the 3rd vaccination. She underwent silicone breast implantation 6 years before vaccination with no adverse events. However, between the 2nd and 3rd vaccination she suffered a breast injury with local inflammation. Upon examination of her breast implants, silicone leak was observed.

Vaccines have been reported to precede CFS mainly following exposure to multiple vaccinations (e.g. the Gulf war syndrome), or as an adverse response to the vaccine adjuvant (e.g. the macrophagic myofasciitis syndrome). Silicone is considered an adjuvant to the immune system, and may induce "the adjuvant disease". Our patient’s illness started following hepatitis-B vaccine, suggesting that it was caused or accelerated by vaccination. In parallel to vaccination our patient suffered from breast injury, which might represent the time of silicone leak. The exposure to the adjuvant, silicone, might have augmented her immune response to the vaccine. To the best of our knowledge this is the first case of combined adverse effect to vaccine and silicone. Vaccine safety in individuals with silicone implants requires further studies.

Neu, D., Hoffmann, G., Moutrier, R., Verbanck, P., Linkowski, and Le Bon, O. Are patients with chronic fatigue syndrome just 'tired' or also 'sleepy'? Journal of Sleep Research, 2008, 17, 4, 427-431.

It is presently unclear whether CFS patients exhibit daytime sleepiness in addition to fatigue. Both fatigue, such as that seen in CFS patients, and excessive daytime sleepiness, such as in sleep apnea-hypopnea syndrome (SAHS), remain poorly understood. Both daytime conditions are generally related to unrefreshing sleep and show affective symptoms. This study's objective was to contribute to the understanding of the relationship between fatigue and sleepiness in CFS patients not co-morbid for primary sleep or psychiatric disorders. We compared 16 untreated patients with CFS (CDC criteria ’94, mean age 32.8, all females) with 13 untreated SAHS (mean age 47.7, all females) patients and 12 healthy controls (mean age 32.2, all females).

Objective sleepiness was measured using multiple sleep latency tests (MSLT). Subjective sleepiness and fatigue were assessed with the Epworth Sleepiness Scale and the Fatigue Severity Scale, respectively.

Mean Sleep Latency (SL) on the MSLT was significantly shorter in SAHS patients than in CFS patients and CFS patients showed significantly shorter mean SL than matched controls but within normal range. Subjective sleepiness was greatest in SAHS patients and subjective
fatigue was highest in CFS patients. Affective symptoms showed highest intensities in CFS patients. While higher than the control group on all measures, compared to SAHS, the CFS group had higher subjective fatigue and lower subjective and objective sleepiness.

Despite possible overlap in symptoms and signs of both daytime conditions, our data indirectly support the clinical distinction between fatigue and sleepiness.

Nijs, J., Van de Putte, K., Louckx, F., Truijen, S and De Meirleir, K. Exercise performance and chronic pain in chronic fatigue syndrome: The role of pain catastrophizing. Pain Medicine, 2008, 9, 8, 1164-1172.

This study aimed to examine the associations between bodily pain, pain catastrophizing, depression, activity limitations/participation restrictions, employment status, and exercise performance in female patients with CFS who experience widespread pain.

This was a cross-sectional observational study in a university-based clinic. Sample comprised 36 female CFS patients (CDC criteria '94) who all experienced widespread pain. They filled in the Medical Outcomes Short-Form 36 Health Status Survey, the Chronic Fatigue Syndrome Activities and Participation Questionnaire, the Beck Depression Inventory, and the Pain Catastrophizing Scale, and underwent a maximal exercise stress test with continuous monitoring of electrocardiographic and ventilatory parameters.

Pain catastrophizing was related to bodily pain (r = -0.70), depression (r = 0.55), activity limitations/participation restrictions (r = 0.68), various aspects of quality of life (r varied between -0.51 and -0.64), and exercise capacity (r varied between -0.41 and -0.61). Based on hierarchical multiple regression analysis, pain catastrophizing accounted for 41% of the variance in bodily pain in female CFS patients who experience chronic widespread musculoskeletal pain. Among the three subscale scores of the Pain Catastrophizing Scale, helplessness and rumination rather than magnification were strongly related to bodily pain. Neither pain catastrophizing nor depression was related to employment status.

These data provide evidence favoring a significant association between pain catastrophizing, bodily pain, exercise performance, and self-reported disability in female patients with CFS
who experience widespread pain. Further prospective longitudinal studying of these variables is required.

[Ed. Note: The women were all available for work yet the mean MOS physical functioning subscale was 36.7, indicating severe disability. Aside from questions about the reliability of the findings, there is an issue about generalisability to other samples. There are no data about onset, type of symptoms experienced and their severity. Without this information, it is possible that these patients were reporting pain due to dietary factors, stress etc. Consequently, speculation about activity avoidance should be interpreted with caution.]

Presson, AP., Sobel, EM., Papp, JC., Suarez , CJ., Whistler, T., Rajeevan, MS., Vernon, SD and Horvath, S. Integrated weighted gene co-expression network analysis with an application to chronic fatigue syndrome. BMC Systems Biology, 2008, 2:95 doi:10.1186/1752-0509-2-95

Systems biologic approaches such as Weighted Gene Co-expression Network Analysis (WGCNA) can effectively integrate gene expression and trait data to identify pathways and candidate biomarkers. Here we show that the additional inclusion of genetic marker data allows one to characterize network relationships as causal or reactive in a CFS (CFS) data set.

Our integrated gene screening strategy results in 20 candidate genes. We show that our approach yields biologically interesting genes that function in the same pathway and are causal drivers for their parent module. We use a separate data set to replicate findings and use Ingenuity Pathways Analysis software to functionally annotate the candidate gene pathways.

We show how WGCNA can be combined with genetic marker data to identify disease-related pathways and the causal drivers within them. The systems genetics approach described here can easily be used to generate testable genetic hypotheses in other complex disease studies.

Smith, A.K., Maloney, EM., Falkenberg, VR., Dimulescu, I and Rajeevan, MS. An angiotensin-1 converting enzyme polymorphism is associated with allostatic load mediated by C-reactive protein, interleukin-6 and cortisol. Psychoneuroendocrinology, 2008, doi:10.1016/j.psyneuen.2008.10.022

Allostatic load (AL) is a theoretical framework that describes the cumulative physiologic effects of adaptation to change or stress throughout the lifespan. AL is operationalized by a composite index of multiple biomarkers. Accordingly, genes, behavior and environment contribute to AL. To determine if individual differences in AL may be influenced by inherent genetic variation, we calculated an allostatic load index (ALI) for 182 Caucasian subjects derived from a population-based study of CFS. Nearly 65% of the subjects in this study sample reported fatiguing illness. 50 had either a CFS-like illness or CFS (Reeves et al, 2005), 68 subjects had chronic fatigue but did not meet the criteria (ISF) and 62 acted as non-fatigued controls. ALI was calculated based on 11 measures representing metabolic, cardiovascular, inflammatory, hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) activities. Subjects were dichotomized into high (ALI>3) or low (ALI<3) AL groups, and the association between high AL and 129 polymorphisms in 32 genes related to the HPA axis, neurotransmission, inflammation, cardiovascular and meta-bolic functions were evaluated.

Polymorphisms in angiotensin-1 converting enzyme (ACE), corticotropin-releasing hormone receptor 1 (CRHR1), and serotonin receptors (HTR3A and HTR4) were associated with AL (p=0.0007-0.0486), but only one polymorphism, rs4968591 in ACE, remained significant after correction for multiple comparisons. The T allele of ACE rs4968591 was more common in subjects with high AL (67.5%) than in subjects with low AL (49.3%) (p=0.0007), and this effect appeared independent of age, sex, body mass index and fatigue status. Additionally, high interleukin-6 (IL-6; p=0.04), and C-reactive protein (CRP; p=0.01) levels, as well as low urinary cortisol levels in females (p=0.03) were associated with the T allele, which may result in allele-specific binding of the transcription factor, E2F1.

Our results suggest a role for ACE in the bi-directional communication between the central nervous and immune systems in response to stress. Further studies will be needed (a) to replicate the association between AL and ACE polymorphisms in population studies designed to differentiate the effects of sex, age and racial/ethnic background, (b) to evaluate the effect of allele-specific binding of E2F1 at rs4968591, and (c) to examine the role of ACE in the co-regulation of CRP, IL-6 and cortisol.

Sorensen, B., Jones, JF., Vernon, SD and Rajeevan, MS. Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome. Molecular Medicine, 2009, 15, 1-2, 34-42.

Complement activation resulting in significant increase of C4a split product may be a marker of post-exertional malaise in CFS subjects. This study was focused to identify the transcriptional control that may contribute to the increased C4a in CFS subjects post-exercise. Differential expression of genes in the classical and lectin pathways were evaluated in peripheral blood mononuclear cells (PBMCs) using quantitative reverse transcription PCR. All nine genes tested, except mannose-binding lectin 2 (MBL2), were expressed in PBMCs.

At 1 hr post-exercise, C4, mannan-binding lectin serine protease 2 (MASP2) and ficolin 1 (FCN1) transcripts were detected at higher levels (≥ 2-fold) in at least 50% (4 out of 8) of CFS subjects that increased to 88% (7 out of 8) CFS subjects when subjects with over-expression of either C4 or MASP2 were combined. Only an increase in MASP2 transcript was statistically significant. This may be due to the significant but transient down-regulation of MASP2 in control subjects. By 6 hrs post-exercise, MASP2 expression was similar in both groups. In conclusion, lectin pathway responded to exercise differentially between CFS and controls subjects. MASP2 down-regulation may act as an anti-inflammatory acute-phase response in healthy subjects, whereas its elevated level may account for increased C4a and inflammation mediated post-exertional malaise in CFS subjects.

Thambirajah, AA., Sleigh, K., Stiver, HG and Chow, AW. Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls. Clinical Investigative Medicine, 2008 Dec 1;31(6):E319.

Since physical exertion is known to exacerbate the symptoms of CFS and metabolic changes and including oxidative stress can modulate heat shock protein (HSP) expression responses, we sought to determine whether HSP expression is altered in CFS patients before and after exercise. HSP27, HSP60, HSP70 and HSP90 expression from 6 CFS patients and 7 age- and sex-matched controls were examined by western blot analysis of PBMC immediately before, after, and at 1 day and 7 days following a standardized treadmill exercise.

Basal HSP27 was higher among CFS patients than in controls (p<0.01). In addition, these levels in CFS patients decreased immediately post-exercise (p<0.05) and remained below basal levels at day 1 post-exercises (p<0.05). This declining expression of HSP27 during the post-exercise period among CFS patients was confirmed by one-way ANOVA analysis with repeated measures (p<0.05). In contrast, HSP27 levels remained relatively constant following exercise among control subjects. Similar patterns of declining HSP levels in CFS patients were also observed for HSP60 (p<0.05), and for HSP90 (p<0.05) at day 7 post-exercise compared with basal levels, respectively. In contrast, HSP60 levels in control subjects increased at day 1 and day 7 post-exercise compared to corresponding levels immediately post-exercise (p<0.05, respectively).

These preliminary findings suggest an abnormal or defective adaptive response to oxidative stress in CFS, and raise the possibility that HSP profiling may provide a more objective biologic marker for this illness.

Van de Putte, E., Böcker, KB., Buitelaar, J., Kenemans, JL., Engelbert, RHH., Kuis, W., Kimpen, JLL and Uiterwaal, CSPM. Deficits of interference control in adolescents with chronic fatigue syndrome. Archives of Pediatric and Adolescent Medicine, 2008, 162, 12, 1196-1197.

Cognitive problems are key symptoms of CFS. Adults with CFS encounter difficulties completing complex information-processing tasks with considerable interference. Performance on neuropsychological tasks have not been studied in adolescents with CFS. Considering our knowledge of adults with CFS, focusing on tasks with a high level of interference is most promising in differentiating adolescents with CFS from healthy adolescents. Interference control is the ability to protect a response from interruption by competing responses or events. We investigated whether adolescents with CFS show less interference control than healthy adolescents. We also explored the importance of confounding factors, such as depression and anxiety.

A total of 64 adolescents (aged 12-18 years) with severe fatigue were referred to the adolescent fatigue clinic at the University Medical Center Utrecht in 2004. The final diagnosis of CFS (CDC '94) was established in 34 patients. As a reference group, 102 adolescents aged 12 to 18 years from a secondary school were invited to participate. Adopted children or children with a chronic illness were excluded (n = 3). From the remaining 99 adolescents, 29 adolescents (29%) agreed to participate.

Adolescents with CFS were more fatigued in all measures (p<.001). Symptoms of anxiety were more present in the adolescents with CFS (p<.001) as were depressive symptoms (p<.001). Performance on the incongruent trials was significantly worse in the CFS group (p=.001). When age, sex, anxiety, and depression were included in the model as possible confounding factors, the diminished performance persisted. This worse performance was particularly evident in the incongruent trials that followed congruent trials, that is, those that induced the highest possible conflict.

Our findings are in line with studies in adult CFS patients that show that the impairment in information processing is not fully explained by depression or anxiety. Our findings support the notion that a decrease in conflict-monitoring abilities might be an important factor in the
development of CFS. Additional longitudinal studies should investigate whether this is a consequence of CFS or a primary etiological factor.

Young, ME., Norman, GR and Humphreys, KR. The role of medical language in changing public perceptions of illness. PLoS ONE, 2008, 3(12): e3875.doi:10.1371/journal.pone.0003875.

This study was designed to investigate the impact of medical terminology on perceptions of disease. Specifically, we look at the changing public perceptions of newly medicalized disorders with accompanying newly medicalized terms (e.g. impotence has become erectile dysfunction disorder, ME became CFS). Does using "medicalese" to label a recently medicalized disorder lead to a change in the perception of that condition? Undergraduate students (n = 52) rated either the medical or lay label for recently medicalized disorders and established medical conditions (such as a myocardial infarction vs. heart attack) for their perceived seriousness, disease representativeness and prevalence.

Students considered the medical label of the recently medicalized disease to be more serious (mean = 4.95 (SE = .27) vs. mean = 3.77 (SE = .24) on a ten point scale), more representative of a disease (mean = 2.47 (SE = .09) vs. mean = 1.83 (SE = .09) on a four point scale), and have lower prevalence (mean = 68 (SE = 12.6) vs. mean = 122 (SE = 18.1) out of 1,000) than the same disease described using common language. A similar pattern was not seen in the established medical conditions, even when controlled for severity.

This study demonstrates that the use of medical language in communication can induce bias in perception; a simple switch in terminology results in a disease being perceived as more serious, more likely to be a disease, and more likely to be a rare condition. These findings regarding the conceptualization of disease have implications for many areas, including medical communication with the public, advertising, and public policy.



De Veer, AJE and Francke, AL. Zorg voor ME/CVS-patiënten. Ervaringen van de achterban van patiëntenorganisaties met de gezondheidszorg. (Care for ME/CFS patients. Experiences of health care reported by supporters of patient organizations.) NIVEL,Utrecht 2008.

Frequently advised treatments for patients with ME/CFS in The Netherlands appear to lead to deterioration of their condition as often, or even more often, as to improvement. This applies to CBT and exercise therapy. These are the findings of a study by NIVEL (Netherlands Institute for Health Research) based on a survey of the ME/CFS patient organizations. Most patients are dissatisfied with the way doctors diagnose CFS. They find their doctors have insufficient specific knowledge and feel they are not taken seriously enough.

According to the survey, better outcomes are achieved with diets, guidance to find a balance between activity and rest, guided bedrest, and painkillers. The study further reveals that the consequences of ME/CFS can be very serious. Many patients are restricted regarding to work, school and household activities, raising children, social contacts and recreation. They indicate that they need more support – in such areas as income, work, school and daily life – than they actually receive. Almost half of all patients disagree with the outcome of medical examinations related to various social benefits, applications for transportation provisions and home adjustments. A large percentage finds that factors as prolonged recovery time, varying physical tolerance, concentration and memory problems, pain and dizziness, have not sufficiently been recognized.

JCFS (Published October 2008).

Axe, EK., Satz, and Fawzy, FI. Cognitive function and major depression in chronic fatigue: The apathy construct. Journal of Chronic Fatigue Syndrome, 2007, 14, 4, 19-38.

The current study examined cognitive function, major depressive disorder (MDD), and apathy construct symptoms in a large multi-site surveillance study of CFS conducted by the Centers for Disease Control and Prevention.

Subjects with CFS (n=565, CC criteria ’94) underwent neuropsychological testing and were administered the Diagnostic Interview Schedule to establish psychiatric diagnoses. Questions in the Beck Depression Inventory relating to motivation were used to develop an apathy construct.

Neuropsychological test results showed impairment in multiple cognitive domains in over 25% of the cohort, and raised proportions of outliers in motor and executive function. Memory complaints were not associated with tests of memory function. The apathy construct rather than MDD was associated with impaired cognition.

Impaired cognition in chronic fatigue does not appear to be associated with MDD but rather with endorsement of construct symptoms. Similar associations were reported in medical conditions with known etiologies. These results suggest a potential biological basis for apathy construct symptoms.

Jason, LA., Torres-Harding, S., Maher, K., Reynolds, N., Brown, M., Sorenson, M., Donalek, J., Corradi, K., Fletcher, M and Lu, T. Baseline cortisol levels predict treatment outcomes in chronic fatigue syndrome nonpharmacologic clinical trial. Journal of Chronic Fatigue Syndrome, 2007, 14, 4, 39-59.

Understanding how non-pharmacologic interventions differentially affect the subgroups of patients with CFS might provide insights into the pathophysiology of this illness. In this exploratory study, baseline measures of normal versus abnormal cortisol were compared on a variety of immune markers and other self-report measures. Normal versus abnormal cortisol ratings were used as predictors in a nurse-delivered non-pharmacologic intervention.

Participants diagnosed with CFS (CDC criteria ’94) were assigned to 6-month non-pharmacologic interventions. Individuals were classified as having abnormal or normal cortisol levels on the basis of scores over the five testing times. Cortisol levels were considered abnormal if they continued to rise, were flat, or were at abnormally low over time.

Complete data was available for 78 participants. Across interventions, those with abnormal cortisol at the baseline appeared not to improve over time, whereas those with normal baseline cortisol evidenced improvements on a number of immunologic and self-report measures. It appears that, in subgroups of individuals with CFS, baseline cortisol markers are associated with outcome trajectories for non-pharmacologic treatment trials.

There are several theories about how cortisol might be implicated in the CFS illness, in terms of both etiology and maintenance. Clauw and Chrousos (1997) suggest that individuals who develop CFS might be genetically predisposed to the development of the condition. These researchers also hypothesize that susceptible individuals might evidence a number of organ-specific illnesses before finally progressing to develop CFS. Supportive data is also available for this thesis, as, before developing CFS, individuals have significantly more upper-respiratory-tract infections, lethargy, and vertigo than controls (Hamilton, Hall, & Round, 2001). Moreover, Clauw and Chrousos suggest that once the individual develops CFS, which can occur abruptly or slowly through viral infections or emotional stressors, there is a blunting of the human stress response. Symptom heterogeneity may be due to different axes of the physiologic stress response, acting either independently, or concurrently functioning in an aberrant way. This pattern might typify some with CFS. Future research efforts are needed to better develop the ways to subgroup within this dimension, as some individuals might be in an early phase and others in a later phase of the illness process.”

[Ed. Note: Further research may help to clarify if the patients with abnormal cortisol levels had a history of stress and constitute a separate ‘chronic stress’ subset.]

Jason, LA and Richman, JA. How science can stigmatize: The case of chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2007, 14, 4, 85-103.

This article reviews issues involving the name of an illness, CFS, along with flawed epidemiologic approaches, which may have further contributed to the diagnostic skepticism and stigma that those with CFS encounter. Patient groups around the world are currently engaged in a major effort to rename this syndrome as either myalgic encephalomyelitis or myalgic encephalopathy, to undo the negative effects of the name previously given to this illness by scientists. Moreover, during the last 15 years, estimated rates of CFS have dramatically increased in both Great Britain and the United States.

We suggest that the increases in both the United States and Great Britain are due to a broadening of the case definition to additionally include cases with primary psychiatric conditions. Using a broad or narrow definition of CFS will have crucial influences on CFS epidemiologic findings, on rates of psychiatric comorbidity, and ultimately on the likelihood of finding a biological marker and identified etiology.

[Ed. Note: This is a significant paper which deserves wide readership.]

Nicolson, GL., Nicolson, NL and Haier, J. Chronic fatigue syndrome patients subsequently diagnosed with Lyme Disease Borrelia burgdorferi: Evidence for Mycoplasma species coinfections. Journal of Chronic Fatigue Syndrome, 2007, 14, 4, 5-17.

We examined the blood of 48 North American CFS patients subsequently diagnosed with Lyme disease (Borrelia burgdorferi infection) and compared these with 50 North American CFS patients without evidence of Borrelia burgdorferi infections for presence of Mycoplasma species co-infections using forensic polymerase chain reaction.

We found that 68.75% of CFS/Lyme patients show evidence of mycoplasma coinfections (p<.001) compared with controls, whereas 50% of CFS patients without a diagnosis of Lyme disease show Mycoplasma co-infections (p<.001) compared with controls. Because CFS patients without a diagnosis of Lyme disease have a high prevalence of one of four Mycoplasma species and a majority show evidence of multiple infections, we examined CFS/Lyme patients' blood for various Mycoplasma species. We found that CFS patients with Lyme disease mostly had single species Mycoplasma infections (p<.001) with a preponderance of Mycoplasma fermentans infections (50% of patients; p<.001), whereas the most commonly found Mycoplasma species in CFS patients without Lyme disease was Mycoplasma pneumoniae (34% of patients; p<.001).

The results indicate that a subset of CFS patients show evidence of infection with Borrelia burgdorferi, and a large fraction of these patients were also infected with Mycoplasma fermentans and to a lesser degree with other Mycoplasma species.

Osoba, T., Pheby, D., Gray, S and Nacul, L. The development of an epidemiological definition for myalgic encephalomyelitis/chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2007, 14, 4, 61-84.

An epidemiological case-definition was developed to distinguish myalgic encephalomyelitis/CFS from other chronic fatiguing conditions by evaluating the discriminatory potential of different criteria from previous definitions. 162 people with unexplained chronic fatigue were enrolled in the trial. Their symptoms were assessed by a number of physicians with a special interest in CFS/ME.

A two-part model was derived using consensus and discriminant analytic approaches. The optimal discriminators for the first part were severe debilitating fatigue affecting physical and mental functioning, a reduction in activity to less than 50% of the patient's premorbid activity level, and muscle discomfort (sensitivity 92%, specificity 66%). The variables for the second part included a reduction in activity to less than 50% of the patient's premorbid activity, myalgia, generalized muscle weakness, migratory arthralgia, and swollen lymph nodes (sensitivity 77%, specificity 88%).



Goudsmit, EM and Howes, S. Is multiple chemical sensitivity a result of expectations and beliefs? A critical evaluation of provocation studies. Journal of Nutritional & Environmental Medicine, 2008, 17, 3, 195-211.

See also, editorial, p. 145-147.

Nijrolder, I., van der Windt, DAWM and van der Horst, E. Prognosis of fatigue and functioning in primary care: A 1-Year follow-up study. Annals of Family Medicine, 2008, 6, 6, 519-527.

A study on patients from general practice who presented with a new episode of fatigue were assessed after 1, 4, 8, and 12 months. A total of 642 patients were enrolled. Four distinct groups were identified: 26% had high scores on fatigue, 17% had a fast recovery, 25% had a slow recovery, and 32% initially improved and then had a recurrence. All four groups had similar psychological symptom scores. findings of this study suggest a longitudinal relationship between the severity of fatigue, impaired functioning, psychological symptoms, and poor sleep. Physicians should be aware that a substantial proportion of patients seeking care for fatigue have these additional health and psychosocial problems.

Schutte, NS., Malouff, JM and Brown, RF. Efficacy of an emotion-focused treatment for prolonged fatigue. Behavior Modification, 2008, 32, 5, 699-713.

Previous research findings have suggested a relationship between less adaptive emotional functioning and fatigue. The present study used a research design involving multiple baselines across participants to evaluate the efficacy of a new emotion-focused treatment for prolonged fatigue delivered in a cognitive behavioral therapy framework. The 13 adults participating in the study met the criteria for prolonged fatigue and provided fatigue baselines of 2, 5, or 8 weeks. The results indicated that the treatment was effective, with fatigue severity levels after the initiation of treatment significantly lower than that predicted by baseline patterns, as determined by the split median method of trend estimation. At 3-4 months after treatment, 8 of 11 clients who completed the treatment no longer met the criteria for prolonged fatigue.

Vollmer-Conna, U.,  Piraino, BF., Cameron, B., Davenport, T., Hickie, I., Wakefield, D and Lloyd AR, for the Dubbo Infection Outcomes Study Group. Cytokine polymorphisms have a synergistic effect on severity of the acute sickness response to infection. Clinical Infectious Diseases, 2008, 47, 1418-1425.

Functional polymorphisms in immune response genes are increasingly recognized as important contributors to the marked individual differences in susceptibility to and outcomes of infectious disease. The acute sickness response is a stereotypical set of illness manifestations mediated by the proinflammatory cytokines induced by many different pathogens. The genetic determinants of severity of the acute sickness response have not previously been explored.

We examined the impact of functional polymorphisms in cytokine genes with critical roles in the early immune response (tumor necrosis factor–α, interleukin-6, interleukin-10, and interferon-γ) on the severity and duration of illness following acute infection with Epstein-Barr virus, Coxiella burnetii (the causative agent of Q fever), or Ross River virus. Subjects included 300 patients followed following an infectious episode, differentiated according to severity of symptoms (high/low).

We found that the interferon-γ +874T/A and the interleukin-10 −592C/A polymorphisms significantly affected illness severity, cytokine protein levels, and the duration of illness. These cytokine genotypes acted in synergy to potentiate their influence on disease outcomes.

These findings suggest that genetically determined variations in the intensity of the inflammatory response underpin the severity of the acute sickness response and predict the recovery time across varied infections.

“Although the contribution of the IL-10 - 592C/A SNP to illness severity was modest, individuals with any A allele at -592 and the IFN-γ - 874TT genotype had 8-fold greater odds of a severe illness response. This discovery of a significant risk potentiation for the “high risk” genotype combinations points to the importance in the field of immunogenetics of moving beyond the study of individual cytokines to examination of the complex micro-environment resulting from the interaction of several genes and gene products. Examination of cytokine protein production confirmed the functional significance of the reported genetic associations. In addition to expected changes in the levels of IFN-γ and IL-10, cell cultures of individuals with genotypes that would favor more intense inflammatory responses (high IFN-γ, low IL-10 production) also demonstrated higher levels of proinflammatory cytokines, including IL-1β, TNF-α, and IL-6, which suggests a feedback mechanism of IFN-γ (produced by T lymphocytes) affecting production of these proinflammatory cytokines (likely pre-dominantly produced by monocytes). This premise is consistent with our findings of a more severe acute illness and delayed recovery associated with the IFN-γ +874T allele... Accordingly, we suspect that in individuals with a prolonged postinfective illness, a prominent cytokine response in the acute phase causes sensitization in these CNS pathways, which leads to sustained neurobehavioral phenomena that manifest with ongoing symptoms in the absence of persistent peripheral cytokine production... Those individuals whose genetic makeup favors a more intense inflammatory reaction are likely to experience more severe symptoms of infectious disease and a more protracted illness.”




  • Given the large number of publications on ME and CFS, we will only include summaries of the most interesting or significant findings. Sources used include Co-Cure and Medline. Editors: EM Goudsmit PhD and S. Howes. With thanks to Ray Colliton.

  • This update is for personal use only. Not all abstracts were checked with the original document and there may be errors due to conversion between programs. For reliable information, please refer to the original articles.

  • Copyright EM Goudsmit 2009 ©

  • All rights reserved. Not to be reproduced without permission

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