2004 – Page 5 – American ME and CFS Society

Study of immune alterations in patients with chronic fatigue syndrome with different etiologies

Abstract:

The Chronic Fatigue Syndrome (CFS) is characterized by symptoms lasting for at least six months and accompanied by disabling fatigue. The etiology of CFS is still unclear.

At the National Center for Study of the Infectious Diseases Department of the Chieti University some immune investigations were performed with the purpose of detecting markers of the disease. CD4+, CD8+, NK CD56+ and B CD19+ lymphocytes were studied in 92 male and 47 female patients and in 36 control subjects. CFS patients were divided in three groups with a post-infectious onset (PI-CFS), an non post-infectious onset (NPI-CFS) and a non post-infectious onset with associated infections (NPI-CFS + AI).

Both CD4+ and CD8+ lymphocytes were reduced in the CFS patients. However, the CD4+/CD8+ ratio was increased in the CFS patients without difference between males and females. CD56+ cells of CFS patients were also reduced. In particular, blood CD56+ cells counts were significantly higher in PI-CFS patients than in the NPI-CFS subjects. These data confirm our preliminary results suggesting a key-role of a dysfunction of the immune system as a precipitating and-or perpetuating factor of the syndrome.

Source: Racciatti D, Dalessandro M, Delle Donne L, Falasca K, Zingariello P, Paganelli R, Pizzigallo E, Vecchiet J. Study of immune alterations in patients with chronic fatigue syndrome with different etiologies. Int J Immunopathol Pharmacol. 2004 May-Aug;17(2 Suppl):57-62. http://www.ncbi.nlm.nih.gov/pubmed/15345193

Chronic fatigue syndrome: a clinical and laboratory study with a well-matched control group

Comment on: Chronic fatigue syndrome: a clinical and laboratory study with a well matched control group. [J Intern Med. 1995]

Dear Sir,

It is an ongoing debate whether concurrent occurrence of particular additional symptoms should be part of the definition of chronic fatigue syndrome (CFS) [1–5] or not. Studies on the similarities and differences between patients satisfying the various definitions are indispensable to solve this dispute.

Swanink et al. [6] studied CFS patients satisfying the criteria described by Sharpe et al. [3], i.e. additional symptoms may be present but are not required. Part of the group also satisfied the more stringent CFS criteria by the Centers for Disease Control (CDC) [1], which require the additional presence of at least eight specific symptoms. When the number of complaints was included as the covariate, no significant differences on fatigue severity, depression and functional impairment were found between CFS patients who fulfilled the CDC criteria and who did not. Furthermore, the authors remarked that the sole effect of applying the CDC symptom criteria to their study group is separating patients with few symptoms from patients with many symptoms.

These results are very misleading and have often been misinterpreted. The authors’ analysis of variance (anova) yielded a lot of significant differences between CDC–CFS and non-CDC–CFS patients. That these were lost in their subsequent analysis of covariance (ancova) is because the level of the covariate and the treatment (fulfilment of the CDC criteria) are highly dependent, as fulfilment of the CDC criteria requires the presence of at least nine symptoms (fatigue included). Because the ancova assumption that the covariate is statistically independent of the treatment is not met, the ancova results are artificial and have little practical meaning [7, 8].

What happened* is illustrated in Fig. 1. anova checks whether CDC–CFS and non-CDC–CFS patients have equal test score means and and . ancova, however, checks the equality of adjusted test score means and and . These are obtained by transporting and from the treatment covariate means and and along parallel regression lines to the grand covariate mean . Thus ancova predicts if test score means of CDC–CFS and non-CDC–CFS patients would have been equal if both groups had exactly the same mean number of complaints. It provides an answer to a question that has no relevance – the mean number of complaints is inherently different for these two groups. In particular, Table 1 of the article learns that the grand covariate mean as reported with the standardized questionnaire equals = 674/88 = 7.66: the adjusted mean corresponds to a group of CDC–CFS patients that does not even exist in reality!

Figure 1.

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Difference between analysis of variance (anova) and analysis of covariance (ancova).anova compares the treatment means and , whereas ancova compares the adjusted treatment means and corresponding to the same level of the covariate for both groups. Note that the grand covariate mean corresponds to a group of CDC–CFS patients that does not exist in reality.

Although their ancova was inappropriate, the authors’anova did result in valuable information.anova of CDC–CFS versus non-CDC–CFS yielded significant differences (at least P < 0.05) in concentration, activity, sleep and rest, ambulation, alertness behaviour, and recreation and pastimes, which according to the authors means that CDC–CFS patients are significantly more impaired in daily functioning. As the subjective fatigue subscale of the checklist individual strength (CIS-fatigue) easily reaches the extreme end of its scale in CFS samples (see e.g. [9, 10]), it is obvious that no significant differences in fatigue severity as measured by CIS-fatigue could be found. Generally speaking, assessing fatigue severity using a scale without this flaw may well result in different outcomes (see e.g. [10]).

Because the inadequate ancova made it appear that there are no clinical differences between CDC–CFS and non-CDC–CFS patients, this study has often been cited to permit leaving out additional symptom criteria when considering CDC–CFS. This has had major consequences for scientific research as well as for clinical practice. In scientific literature, non-CDC–CFS patients are labelled as having ‘a diagnosis of CFS according to the CDC criteria’ [10] or fulfilling ‘the CDC criteria for CFS’ [11], although other sources by the same authors explicitly state that they do not [12, 13]. In a large randomized study on cognitive behaviour therapy for CFS [14], one of the two reasons that patients without the required number of additional symptoms were included is that ‘patients who fulfilled the CDC-criteria did not differ concerning the severity of the complaints from patients who did not satisfy the CDC criteria’ [13]. The CFS definition used for clinical practice in large parts of the Netherlands [15] is based on CDC criteria, but patients without the required additional symptoms are also diagnosed CFS because ‘clinically this distinction has no meaning, as it has turned out from Dutch research’ [16]. This means that if the mistakes above would have been noted at an earlier stage, literally thousands of chronically fatigued patients might have had a different diagnosis in the Netherlands.

Apparently [13] the incorrect results of the article have also been presented during a recent meeting held for revising the latest CDC–CFS definition (presentation Bleijenberg, CDC consensus meeting, Atlanta 2000). To prevent more scientific research on CDC–CFS that disregards additional symptoms and more CFS definitions that are based on statistical errors rather than on data, it is important that the mistakes in the article are corrected as soon as possible.

You can read the rest of this comment here: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2004.01378.x/full

Source: Stouten B. Chronic fatigue syndrome: a clinical and laboratory study with a well-matched control group. J Intern Med. 2004 Sep;256(3):265-7; author reply 268-9. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2004.01378.x/full (Full article)

Use of time-frequency analysis to investigate temporal patterns of cardiac autonomic response during head-up tilt in chronic fatigue syndrome

Abstract:

Although a number of studies have reported alterations in cardiac autonomic nervous system function in chronic fatigue syndrome (CFS), the results are not consistent across studies. Reasons for these discrepancies include (1) the use of a heterogeneous patient sample that included those with orthostatic postural tachycardia (POTS), a condition with an autonomic changes, and (2) the use of frequency domain techniques which require a stationary signal and averaging data across relatively long epochs.

To deal with these shortcomings, we used the smoothed pseudo-Wigner-Ville transform (SPWVT) to analyze heart rate variability (HRV) and blood pressure variability (BPV) during head-up tilt (HUT) by separating CFS patients into those with and without POTS. SPWVT has the advantage of providing instantaneous information about autonomic function under nonstable physiological conditions. We studied 18 CFS patients without POTS, eight CFS patients with POTS and 25 sedentary healthy controls during supine rest and during the first 10 min after HUT.

While we found significant effects of postural change in both groups for all autonomic variables, there were significant group x time interactions between CFS without POTS and controls for only instant center frequency (ICF) within the low frequency region both from HRV (p=0.02) and from BPV (p=0.01). Although the physiological meaning of ICF still remains unknown, the data suggest that even CFS patients without POTS may have a subtle underlying disturbance in autonomic function.

Source: Yoshiuchi K, Quigley KS, Ohashi K, Yamamoto Y, Natelson BH. Use of time-frequency analysis to investigate temporal patterns of cardiac autonomic response during head-up tilt in chronic fatigue syndrome. Auton Neurosci. 2004 Jun 30;113(1-2):55-62. http://www.ncbi.nlm.nih.gov/pubmed/15296795

Chronic fatigue syndrome: lack of association between pain-related fear of movement and exercise capacity and disability

Abstract:

BACKGROUND AND PURPOSE: Patients who experience pain, a symptom of chronic fatigue syndrome (CFS), often exhibit kinesiophobia (irrational fear of movement). The purpose of this study was to examine whether pain-related fear of movement is associated with exercise capacity, activity limitations, or participation restrictions in patients with CFS who experience widespread pain.

SUBJECTS AND METHODS: Sixty-four subjects met the inclusion criteria. All subjects fulfilled the 1994 Centers for Disease Control and Prevention case definition for CFS and experienced widespread myalgias or arthralgias. The subjects completed the Tampa Scale for Kinesiophobia-Dutch Version (TSK-DV) and the Dutch Chronic Fatigue Syndrome-Activities and Participation Questionnaire (CFS-APQ). They then performed a maximal exercise test on a bicycle ergometer. Heart rate was monitored continuously by use of an electrocardiograph. Ventilatory factors were measured through spirometry. Correlations between the TSK-DV scores and both the exercise capacity data and the CFS-APQ scores were assessed using the Spearman rank correlation coefficient. Using the Mann-Whitney U test, the TSK-DV scores were compared between subjects who performed a maximal exercise stress test and those who did not perform the test.

RESULTS: Forty-seven subjects (73.4%) attained a total score of greater than 37 on the TSK-DV, indicating high fear of movement. Neither the exercise capacity data nor the CFS-APQ scores indicated a correlation with the TSK-DV scores (n=64). Subjects who did not perform a maximal exercise capacity test had more fear of movement (median TSK-DV score=43.0, interquartile range=10.3) compared with those who did perform a maximal exercise capacity test (median TSK-DV score=38.0, interquartile range=13.2; Mann-Whitney U-test score=322.5, z=-1.974, P=.048), but the correlation analysis was unable to reveal an association between exercise capacity and kinesiophobia in either subgroup.

DISCUSSION AND CONCLUSION: These results indicate a lack of correlation between kinesiophobia and exercise capacity, activity limitations, or participation restrictions, at least in patients with CFS who are experiencing widespread muscle or joint pain.

Source: Nijs J, Vanherberghen K, Duquet W, De Meirleir K. Chronic fatigue syndrome: lack of association between pain-related fear of movement and exercise capacity and disability. Phys Ther. 2004 Aug;84(8):696-705. http://ptjournal.apta.org/content/84/8/696.long (Full article)

Increased neutrophil apoptosis in chronic fatigue syndrome

Abstract:

BACKGROUND/AIMS: Many patients with chronic fatigue syndrome (CFS) have symptoms that are consistent with an underlying viral or toxic illness. Because increased neutrophil apoptosis occurs in patients with infection, this study examined whether this phenomenon also occurs in patients with CFS.

METHODS: Apoptosis was assessed in patients with CFS in conjunction with concentrations of the anti-inflammatory cytokine, transforming growth factor beta1 (TGFbeta1).

RESULTS: The 47 patients with CFS had higher numbers of apoptotic neutrophils, lower numbers of viable neutrophils, increased annexin V binding, and increased expression of the death receptor, tumour necrosis factor receptor-I, on their neutrophils than did the 34 healthy controls. Patients with CFS also had raised concentrations of active TGFbeta1 (p < 0.005).

CONCLUSIONS: These findings provide new evidence that patients with CFS have an underlying detectable abnormality in their immune cells.

Source: Kennedy G, Spence V, Underwood C, Belch JJ. Increased neutrophil apoptosis in chronic fatigue syndrome. J Clin Pathol. 2004 Aug;57(8):891-3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770396/ (Full article)

Exercise therapy for chronic fatigue syndrome

Update in: Exercise therapy for chronic fatigue syndrome. [Cochrane Database Syst Rev. 2015]

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is an illness characterised by persistent medically unexplained fatigue. CFS is a serious health-care problem with a prevalence of up to 3%. Treatment strategies for CFS include psychological, physical and pharmacological interventions.

OBJECTIVES: To investigate the relative effectiveness of exercise therapy and control treatments for CFS.

SEARCH STRATEGY: CCDANCTR-Studies and CENTRAL were searched using “Chronic Fatigue” and Exercise. The Journal of Chronic Fatigue Syndrome and CFS conferences were handsearched. Experts in the field were contacted. Clinicaltrials.gov and controlled-trials.com were searched.

SELECTION CRITERIA: Only Randomised Controlled Trials (RCT) including participants with a clinical diagnosis of CFS and of any age were included.

DATA COLLECTION AND ANALYSIS: The full articles of studies identified were inspected by two reviewers (ME and HMG). Continuous measures of outcome were combined using standardised mean differences. An overall effect size was calculated for each outcome with 95% confidence intervals. One sensitivity analysis was undertaken to test the robustness of the results.

MAIN RESULTS: Nine studies were identified for possible inclusion in this review, and five of those studies were included. At 12 weeks, those receiving exercise therapy were less fatigued than the control participants (SMD -0.77, 95% CIs -1.26 to -0.28). Physical functioning was significantly improved with exercise therapy group (SMD -0.64, CIs -0.96 to -0.33) but there were more dropouts with exercise therapy (RR 1.73, CIs 0.92 to 3.24). Depression was non-significantly improved in the exercise therapy group compared to the control group at 12 weeks (WMD -0.58, 95% CIs -2.08 to 0.92). Participants receiving exercise therapy were less fatigued than those receiving the antidepressant fluoxetine at 12 weeks (WMD -1.24, 95% CIs -5.31 to 2.83). Participants receiving the combination of the two interventions, exercise + fluoxetine, were less fatigued than those receiving exercise therapy alone at 12 weeks, although again the difference did not reach significance (WMD 3.74, 95% CIs -2.16 to 9.64). When exercise therapy was combined with patient education, those receiving the combination were less fatigued than those receiving exercise therapy alone at 12 weeks (WMD 0.70, 95% CIs -1.48 to 2.88).

REVIEWERS’ CONCLUSIONS: There is encouraging evidence that some patients may benefit from exercise therapy and no evidence that exercise therapy may worsen outcomes on average. However the treatment may be less acceptable to patients than other management approaches, such as rest or pacing. Patients with CFS who are similar to those in these trials should be offered exercise therapy, and their progress monitored Further high quality randomised studies are needed.

Source: Edmonds M, McGuire H, Price J. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2004;(3):CD003200. http://www.ncbi.nlm.nih.gov/pubmed/15266475

The nosology of sub-acute and chronic fatigue syndromes that follow infectious mononucleosis

Abstract:

BACKGROUND: A previous principal components analysis of symptoms occurring after infectious mononucleosis suggested that a discrete fatigue syndrome occurs, which is independent of psychiatric disorder. This work has not been replicated and no latent class analysis of subjects has been published.

METHOD: We prospectively examined a cohort of 150 American primary care patients 2 and 6 months after the onset of corroborated infectious mononucleosis. A subset of 50 subjects was studied 4 years after onset. We performed principal components analyses of both psychological and somatic symptoms and latent class analyses of subjects.

RESULTS: Principal components analyses consistently delineated two fatigue factors at 2 and 6 months and one fatigue factor at 4 years. These factors were separate from a mixed anxiety and depressive factor. A four-class solution for the latent class analyses consisted of most subjects with few symptoms, a few with many symptoms, a group with predominantly mood symptoms and some subjects with fatigue symptoms.

CONCLUSIONS: The symptoms of the principal factors with fatigue were similar to those previously described. Both the factors and classes were independent of an equally delineated mood factor and class. These results support the existence of two discrete chronic fatigue syndromes after infectious mononucleosis, one of which is still demonstrable 4 years after onset.

Source: White PD, Thomas JM, Sullivan PF, Buchwald D. The nosology of sub-acute and chronic fatigue syndromes that follow infectious mononucleosis. Psychol Med. 2004 Apr;34(3):499-507. http://www.ncbi.nlm.nih.gov/pubmed/15259835

In vivo magnetic resonance spectroscopy in chronic fatigue syndrome

Abstract:

The pathogenic mechanisms of chronic fatigue syndrome (CFS) are not clearly known. Fatigue, poor short-term memory and muscle pain are the most disabling symptoms in CFS. Research data on magnetic resonance spectroscopy (MRS) of muscles and brain in CFS patients suggest a cellular metabolic abnormality in some cases.

31P MRS of skeletal muscles in a subset of patients indicate early intracellular acidosis in the exercising muscles. 1H MRS of the regional brain areas in CFS have shown increased peaks of choline derived from the cell membrane phospholipids.

Cell membrane oxidative stress may offer a common explanation for the observed MRS changes in the muscles and brain of CFS patients and this may have important therapeutic implications. As a research tool, MRS may be used as an objective outcome measure in the intervention studies. In addition, regional brain 1H MRS has the potential for wider use to substantiate a clinical diagnosis of CFS from other disorders of unexplained chronic fatigue.

Source: Chaudhuri A, Behan PO. In vivo magnetic resonance spectroscopy in chronic fatigue syndrome. Prostaglandins Leukot Essent Fatty Acids. 2004 Sep;71(3):181-3. http://www.ncbi.nlm.nih.gov/pubmed/15253888

Electrodermal dissociation of chronic fatigue and depression: evidence for distinct physiological mechanisms

Abstract:

Chronic fatigue syndrome (CFS) has an estimated prevalence between 0.5% and 3%, yet its diagnosis remains contentious. CFS is characterized by subjective symptoms that can be difficult to verify; moreover, depression is a commonly reported CFS complaint, whereas fatigue is a common symptom of depression.

Our primary goal was dissociation of these disorders using psychophysiological methods. As previous research has implicated the autonomic nervous system in CFS, we conducted what we believe to be the first analysis of bilateral electrodermal and skin temperature responses of dextral females in a cross-modal orienting task, to investigate differences between these two patient groups and controls.

A multivariate analysis of variance (MANOVA) examining three measures of electrodermal activity revealed prestimulus tonic skin conductance levels (SCLs) were markedly lower for the CFS group, with no difference between controls and depressives. Concurrent skin temperature levels were higher for the CFS group than the other two groups.

These findings indicate that, despite overtly similar cognitive and symptom profiles, depression and CFS patients can be differentiated with psychophysiological measures. This study adds to the growing body of evidence demonstrating that CFS and depression have distinct neurobiological profiles, consistent with unique aetiologies.

Source: Pazderka-Robinson H, Morrison JW, Flor-Henry P. Electrodermal dissociation of chronic fatigue and depression: evidence for distinct physiological mechanisms. Int J Psychophysiol. 2004 Aug;53(3):171-82. http://www.ncbi.nlm.nih.gov/pubmed/15246671

Chronic fatigue syndrome (cfs)

Abstract:

The Chronic Fatigue Syndrome (CFS) is described based on the revision of Fukuda et al. The question “whether CFS can be discussed as a homogenous disorder?” has been reviewed and the answer is “no”. Other overlapping syndromes are mentioned. Disorders with fatigue as a symptom are depression, somatisation, irritable bowel syndrome, effort-syndrome, hyperventilation, conservation-withdrawal.

Among the pathogenetic factors of CFS immune systems disorders, neuroendocrine abnormalities, autonomic activity, neuroimaging, neuropsychological abnormalities, exercise capacity and muscle function and psychological processes (attribution, perception, symptom avoidance and neutralisation of conflicts) are discussed.

Since CFS cannot be comprehended without knowledge of the ontogenetic development of the affect “fatigue”, it is extensively described. Based on this knowledge, fatigue as an affect and the CFS are embedded in a context, which has as its basis the fight-flight reaction and the conservation-withdrawal reaction. Weighing the evidence, it is concluded that CFS in its varieties can best be understood as a manifestation of the activation of the two biological emergency reactions: fight-flight and conservation-withdrawal.

The physician should interview and examine each individual patient according to the Harvey Cushing dictum: The physician should not only study the diseased organ, but the man with his diseased organ, and not only these. He should comprehend the man with his diseased organ in his environment. This leads to study of the biological, psychological and social factors contributing to each patient’s illness. Work-up and therapy have to be based on this integrated approach. The latter encompasses conflict centred psychotherapy, stepwise increasing physical activation and antidepressive drugs.

Source: Adler RH. Chronic fatigue syndrome (cfs). Swiss Med Wkly. 2004 May 15;134(19-20):268-76. http://www.smw.ch/for-readers/archive/backlinks/?url=/docs/archive200x/2004/19/smw-10213.html (Full article)