Number 2 |
1st June 2006 |
PHYSIOLOGY AND
BIOCHEMISTRY
|
Kennedy, G., Norris, G., Spence, V., McLaren, M and Belch, JJ. Is chronic fatigue syndrome associated with platelet activation? Blood Coagulation and Fibrinolysis, 2006, 17, 2, 89-92.
Recent investigations by other workers have suggested that individuals with CFS may have a hypercoagulable state. This study investigated various aspects of platelet activation and function in 17 patients with CFS (CDC criteria ’94) and in 16 age-matched and sex-matched healthy controls.
Platelet aggregation, platelet volume and coagulation tests were performed. A trend was observed for the patients to have lower aggregation results and a reduced mean platelet volume. However, this only reached statistical significance for one result; the rate of the aggregation slope by 1.0 μg/ml collagen (p=0.029). No significant differences were found for any of the measurements of coagulation. These results are in contrast to previously findings. However, due to the heterogeneous nature of the disease, and the resulting lifestyles of the patients, caution should be taken when comparing one group of patients with another. Nevertheless, we certainly found no evidence of increased platelet activation or of a hypercoagulable state in patients with CFS and, on the basis of these results, anti-platelet or anti-coagulant therapy is not warranted
Capuron, L., Welberg, L., Heim, C., Wagner, D., Solomon, L., Papanicolaou, DA., Craddock, RC, Miller, AH and Reeves, WC. Cognitive dysfunction relates to subjective report of mental fatigue in patients with chronic fatigue syndrome. Neuropsychopharmacology, 2006, online 4th January. doi:10.1038/sj.npp.1301005.
Patients with CFS frequently complain of cognitive dysfunction. However, evidence of cognitive impairment in CFS patients has been found in some, but not other, studies. This heterogeneity in findings may stem from the relative presence of mental fatigue in the patient populations examined. The present study assessed this possibility in a population-based sample of CFS patients.
In all, 43 patients with CFS (CDC criteria ’94, no psychiatric disorders and defined also by measurements recommended by the 2003 International CFS Study Group), and 53 age-, sex-, and race/ethnicity-matched non-fatigued subjects were included in the study. Mental fatigue was assessed using the mental fatigue subscale of the multidimensional fatigue inventory. Cognitive function was evaluated using an automated battery of computerized tests (Cambridge neuropsychological test automated battery (CANTAB) that assessed psychomotor function, planning and problem-solving abilities, and memory and attentional performance.
CFS patients with significant complaints of mental fatigue (score of mental fatigue 2 standard deviations above the mean of non-fatigued subjects) exhibited significant impairment in the spatial working memory and sustained attention (rapid visual information processing) tasks when compared to CFS patients with low complaints of mental fatigue and non-fatigued subjects. In CFS patients with significant mental fatigue, sustained attention performance was impaired only in the final stages of the test, indicating greater cognitive fatigability in these patients. CFS patients with low mental fatigue displayed performance comparable to non-fatigued subjects on all tests of the CANTAB battery.
These findings show strong concordance between subjective complaints of mental fatigue and objective measurement of cognitive impairment in CFS patients and suggest that mental fatigue is an important component of CFS-related cognitive dysfunction.
[Ed. Note: Although this study involved broadly-defined patients, it challenges the view of the Nijmegen team that patients exaggerate cognitive impairments.]
Janal, MN,, Ciccone, DS and Natelson, BH. Sub-typing CFS patients on the basis of 'minor' symptoms. Biological Psychology, 2006, Feb 10 [Epub ahead of print]. doi:10.1016/j.biopsycho.2006.01.003
The diagnosis of CFS, an illness characterized by medically unexplained fatigue, depends on a clinical case definition representing one or more pathophysiological mechanisms. To prepare for studies of these mechanisms, this study sought to identify subtypes of CFS.
In 161 women meeting 1994 criteria for CFS, principal components analysis of the 10 'minor' symptoms of CFS (from the 1988 definition) produced three factors interpreted to indicate musculoskeletal, infectious and neurological subtypes. Extreme scores on one or more of these factors characterized about 2/3 of the sample. In this sample, 67% had a gradual onset and 13% had major depression and current anxiety disorder with only 22% reporting disability.
Those characterized by the neurological factor were at increased risk of reduced scores on cognitive tests requiring attention, working memory, long-term memory or rapid performance. In addition, the neurological subtype was associated with reduced levels of function. Those characterized by the musculoskeletal factor were at increased risk for the diagnosis of fibromyalgia (chronic widespread pain and mechanical allodynia) and reduced physical function.
Those characterized by the infectious factor were less likely to evidence co-occurring fibromyalgia, and showed lesser risk of functional impairment. The prevalence of disability was increased in those with the highest scores on any of the subtypes, as well as in those with high scores on multiple factors. Depression and anxiety, while frequently present, were not more prevalent in any particular subtype, and did not increase with the severity of specific symptom reports.
Results suggest that subtypes of CFS may be identified from reports of the minor diagnostic symptoms, and that these subtypes demonstrate construct validity.
Cho, HJ., Skowera, A., Cleare, A and Wessely, S. Chronic fatigue syndrome: an update focusing on phenomenology and pathophysiology. Current Opinion in Psychiatry, 2006, 19, 1, 67-73.
CFS is a controversial condition especially concerning its clinical definition and aetiopathogenesis. Most recent research progress has been made in phenomenology and pathophysiology and we focused our review on these two areas.
The phenomenology research supports the notion of a discrete fatigue syndrome which can be distinguished from depression and anxiety. The current case definition, however, may need an improvement based on empirical data. Recent advances in understanding the pathophysiology of CFS continue to demonstrate the involvement of the central nervous system. Hyperserotonergic state and hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis constitute other findings, but the question of whether these alterations are a cause or consequence of CFS still remains unanswered. Immune system involvement in the pathogenesis seems certain but the findings on the specific mechanisms are still inconsistent. Genetic studies provide some evidence of the syndrome being a partly genetic condition, but environmental effects seem to be still predominant and identification of specific genes is still at a very early stage. The recent findings suggest that further research is needed in improving the current case definition; investigating overlaps and boundaries among various functional somatic syndromes; answering the question of whether the pathophysiologic findings are a cause or consequence; and elucidating the involvement of the central nervous system, immune system and genetic factors.
Gharibzadeh, S and Hoseini, SS. The potential role of nitric oxide metabolites in diagnosing chronic fatigue syndrome. Medical Hypotheses, 2006, 67, 1, 197-198. (Letter)
Sensitization of the central nervous system (CNS) has been suggested to be part of CFS pathophysiology. It is hypothesized recently that a nitric oxide (NO) dependent reduction in inhibitory activity of the CNS and consequent central sensitization accounts for some of the manifestations in CFS patients. ...We suggest that the assessment of urine nitrate, blood methemoglobin, nasal lavage NO, and exhaled NO can be used for diagnosis, severity assessment, evaluating response to treatment and prognosis of the CFS patients. Surely, the sensitivity and specificity of these tests should be evaluated in clinical trials.
Gharibzadeh, S and Hoseini, SS. Is there any relation between mouldy building exposure and chronic fatigue syndrome? Medical Hypotheses, 2006, 66, 6, 1243-1244.
Hoseini SS, Gharibzadeh S. Anakinra: a potential treatment for chronic fatigue syndrome. Medical Hypotheses, 2006, 67, 1, 1976-197. (Letter.)
Anakinra, a recombinant interleukin-1 receptor antagonist, has recently been introduced for treating some rheumatic diseases. Since the pathogenesis of CFS is based at least partly on these cytokines, we suggest that the use of these drugs may be a useful treatment in this syndrome.
Pardaens, K., Haagdorens, L., Van Wambeke, P., Van den Broeck, A and Van Houdenhove, B. How relevant are exercise capacity measures for evaluating treatment effects in chronic fatigue syndrome? Results from a prospective, multidisciplinary outcome study. Clinical Rehabilitation, 2006, 20, 1, 56-66.
The aim of this study was to evaluate the outcome of a multidisciplinary treatment programme for patients with CFS, including health-related quality of life (HRQoL) and psychosocial variables, and exercise capacity measures. It was a six-month prospective outcome study set in a university outpatient rehabilitation clinic. The subjects comprised 116 women fulfilling the CDC ’94 criteria for CFS. Three patients of the initial 119 dropped out.
The interventions assessed were cognitive behaviourally and graded exercise-based strategies with an emphasis on adaptive lifestyle changes. The measures included the MOS Short Form General Health Survey (SF-36); Symptom Checklist (SCL-90); Causal Attribution List (CAL); Self-Efficacy Scale (SE); maximum progressive bicycle ergometer test with respiratory gas analysis; and isokinetic leg strength test, before and after treatment.
Patients were told “You are suffering from physical and mental effort intolerance because of a loss of resilience of your stress system”. It was further explained that an active therapeutic approach would not only facilitate symptom control but also optimize chances of recovery. The CBT took 2 days a week, 4 hours a day for the first month, then this was reduced, gradually, to once a month. Patients were seen in a group: one for CBT and one for graded exercise. Gradually, psycho-educational and supportive group discussions (one in the presence of the patient’s family), relaxation and breathing exercises, and (on demand) psychiatric and/or medical consultations were added to the programme.”
In line with our working hypothesis, the cognitive behavioural therapist encouraged patients to pace their activities and respect their physical and mental limitations, emphasizing at the same time the importance of progressively building up their physical condition. It was explained to the patients that by combining these two strategies they could regain physical and mental resilience, and restore a new physical and mental equilibrium which could eventually lead to symptomatic improvements and long-term recovery. Graded exercise training consisted of one-hour sessions, structured as follows: warming-up,/cycling, stretching, individual discussion of problems or progression. The main goal of graded exercise training during the first two weeks was to familiarize the patient with cycling and to titrate the training programme. Starting from week 3, all participants were asked to exercise three times a week. Thus, during weeks 3 and 4, the patients cycled twice a week at the centre and once at home; during months 2 and 3, once a week at the centre and twice at home; and from the fourth month on, three times a week at home, and once each month at the centre. The training programme was adjusted to a slower pace when deemed necessary, after discussion with the patient.
The total group significantly improved on nearly all reported HRQoL/psychosocial variables. Changes in exercise capacity measures were rather modest and did not correlate or only weakly correlated with HRQoL/psychosocial variables. Subgroup analyses indicated that less fit patients improved significantly more on exercise capacity measures than their more fit counterparts. Patients who were fitter at baseline scored better on pre-treatment HRQoL/psychosocial variables, but both subgroups improved similarly on these variables.
Health-related quality of life and psychosocial functioning in patients with CFS improves after a six-month cognitive behaviourally and graded exercise-based multidisciplinary treatment programme. Increase in exercise capacity measures is not a necessary condition for reported improvements, except for less fit patients.
[Ed. Note: This is an uncontrolled study with no follow-up. There are no data specifically relating to fatigue and other common symptoms. However, the MOS SF vitality scale (range 4-24) showed a negligible pre-post treatment change in both groups, 10.1 to 11.2 in the fitter group, 9 to 10.8 in the less fit group. A similarly modest increase was reported for the physical functioning subscale, which revealed continued disability following treatment. Self-efficacy, which increase significantly, may have mediated the effects and this may be more important than any increase in aerobic fitness.]
Saggini, R., Vecchiet, J., Iezzi, S., Racciatti, D., Affaitati, G., Bellomo, RG and Pizzigallo, E. Submaximal aerobic exercise with mechanical vibrations improves the functional status of patients with chronic fatigue syndrome. Europa Medicophysica, 2006, March 24 [Epub ahead of print].
Typically CFS patients complain of a severe fatigue made worse by exercise, with a consistent reduction of working activity. A physical deconditioning could explain CFS features as well as a neuromuscular dysfunction of central or peripheral origin.
Ten CFS patients (CDC criteria ’94) were enrolled in a protocol of a rehabilitative treatment over a six-month period: they underwent a submaximal and predominantly aerobic exercise with a reduced O2 consumption using a Galileo 2000 system that provides mechanical vibrations characterised by sinusoid vertical sollecitations. Before and after such treatment, all patients underwent a pressure pain thresholds profile, an evaluation of physical and psychosocial parameters using the visual analogue scale (VAS) of Scott-Huskisson, and a muscle performance analysis by the CIBEX 6000 dynamometer.
After the six-month period of study there was an overall improvement in the above described parameters as compared to the basal determinations. We conclude that the rehabilitative exertion provides a useful treatment for CFS patients particularly to realize an effective training of the explosive strength.
[Ed. Note: three symptoms were measured using visual analogue scales. There was no objective measure of activity levels after therapy.]
Tanaka, M., Sadato, N., Okada, T., Mizuno, K., Sasabe, T., Tanabe, HC., Saito, DN., Onoe, H., Kuratsune, H and Watanabe, Y. Reduced responsiveness is an essential feature of chronic fatigue syndrome: a fMRI study. BMC Neurology, 2006, 6, 1, 9.
Although the neural mechanism of CFS has been investigated by a number of researchers, it remains poorly understood. Using functional magnetic resonance imaging, we studied brain responsiveness in 6 male patients with CFS (CDC criteria ’94) and in 7 age-matched male healthy volunteers. Responsiveness of auditory cortices to transient, short-lived, noise reduction was measured while subjects performed a fatigue-inducing continual visual search task.
Responsiveness of the task-dependent brain regions was decreased after the fatigue-inducing task in the normal and CFS subjects and the decrement of the responsiveness was equivalent between the 2 groups. In contrast, during the fatigue-inducing period, although responsiveness of auditory cortices remained constant in the normal subjects, it was attenuated in the CFS patients. In addition, the rate of this attenuation was positively correlated with the subjective sensation of fatigue as measured using a fatigue visual analogue scale, immediately before the magnetic resonance imaging session.
CFS may be characterised by attenuation of the responsiveness to stimuli not directly related to the fatigue-inducing task.
Toda, K and Kimura, H. Efficacy of neurotropin in chronic fatigue syndrome: a case report. Hiroshima Journal of Medical Science, 2006, 55, 1, 35-37.
A 28-year-old male visited an outpatient department due to general fatigue and pain involving the entire body. He did not suffer from fibromyalgia, but he was diagnosed with CFS. At the initial visit, he complained of lack of concentration, memory decline, frequent urination, insomnia and occasional difficulty of emotional control, as well as general fatigue and pain involving the entire body.
Four tablets of Neurotropin per day alone were administered. General fatigue and pain were gradually alleviated one week later. His sleep condition, concentration power, and memory also improved two weeks later. Medication was discontinued from 11 weeks based on the patient's judgment as he felt little general fatigue and pain involving the entire body. Treatment was completed 3 months later. The symptoms disappeared and did not recur five months after the discontinuation of Neurotropin. He was looking for a job without fatigue and pain 8 months later (5 months after the cessation of treatment). The functional mechanisms of Neurotropin in CFS are unknown.
VanNess, JM., Snell, CR., Stevens, SR., Bateman, L and Keller, BA. Using serial cardiopulmonary exercise tests to support a diagnosis of chronic fatigue syndrome. Medicine & Science in Sports & Exercise, 2006, 38, 5, Supplement p S85.
Reduced functional capacity and post-exertional malaise following physical activity are hallmark symptoms of CFS. That these symptoms are often delayed may explain the equivocal results for clinical cardiopulmonary exercise testing (GXT) with CFS patients. The reproducibility of VOmax in healthy subjects is well documented. This may not be the case with CFS due to delayed recovery symptoms.
The purpose of the study was to compare results from repeated exercise tests as indicators of post exertional malaise in CFS.
Peak oxygen consumption (VO2peak), percentage of predicted peak heart rate (HR%), and VO2 at anaerobic threshold (AT), were compared between six CFS patients and six control subjects for two maximal exercise tests separated by 24 hours.
Multivariate analysis showed no significant differences between control and CFS,
respectively, for test 1: VO2peak (28.4 ± 7.2 ml/kg/min; 26.2 ± 4.9
ml/kg/min), AT (17.5 ± 4.8 ml/kg/min; 15.0 ± 4.9 ml/kg/min) or HR% (87.0 ±
25.4%; 94.8 ± 8.8%). However, for test 2 the CFS patients achieved significantly
lower values for both VO2peak (28.9 ± 8.0 ml/kg/min; 20.5 ± 1.8
ml/kg/min, p=0.031) and AT (18.0 ± 5.2 ml/kg/min; 11.0 ± 3.4 ml/kg/min, p=
0.021). HR% was not significantly different (97.6 ± 27.2%; 87.8 ± 9.3%, p=0.07).
A follow-up classification analysis differentiated between CFS patients and
controls with an overall accuracy of 92%.
In the absence of a second exercise test, the lack of any significant differences for the first test would appear to suggest no functional impairment in CFS patients. However, the results from the second test indicate the presence of a CFS related post-exertional malaise. It might be concluded then that a single exercise test is insufficient to demonstrate functional impairment in CFS patients. A second test may be necessary to document the atypical recovery response and protracted malaise unique to CFS.
Vernon, SD., Whistler, T., Aslakson, E., Rajeevan, M and Reeves, WC. Challenges for molecu-lar profiling of chronic fatigue syndrome. Pharmacogenomics, 2006, 7, 2, 211-218.
CFS is prevalent, disabling and costly. Despite extensive literature describing the epidemiology and clinical aspects of CFS, it has been recalcitrant to diagnostic biomarker discovery and therapeutic intervention. This is due to the fact that CFS is a complex illness defined by self-reported symptoms and diagnosed by the exclusion of medical and psychiatric diseases that may explain the symptoms.
Studies attempting to dissect the pathophysiology are challenging to design as CFS affects multiple body systems, making the choice of which system to study dependant on an investigators area of expertise. However, the peripheral blood appears to be facilitating the molecular profiling of several diseases, such as CFS, that involve bodywide perturbations that are mediated by the CNS. Successful molecular profiling of CFS will require the integration of genetic, genomic and proteomic data with environmental and behavioral data to define the heterogeneity in order to optimize intervention
Fang, H., Xie, Q., Boneva, R., Fostel, J., Perkins. R and Tong, W. Gene expression profile exploration of a large dataset on chronic fatigue syndrome. Pharmacogenomics, 2006, 7, 3, 429-440.
The objective is to gain understanding of the molecular basis of CFS through gene expression analysis using a large microarray data set in conjunction with clinically administrated questionnaires.
Data from the CDC’s Wichita CFS Surveillance Study was used, comprising 167 participants with two self-report questionnaires (multidimensional fatigue inventory [MFI] and Zung depression scale [Zung]), microarray data, empiric classification, and others. Microarray data was analyzed using informatics tools from ArrayTrack.
Correspondence analysis was applied to the MFI questionnaire to select the 23 samples having either the most or the least fatigue, and to the Zung questionnaire to select the 26 samples having either the most or least depression; ten samples were common, resulting in a total of 39 samples. The MFI and Zung-based CFS/non-CFS (NF) classifications on the 39 samples were consistent with the empiric classification.
Two differentially-expressed gene lists were determined, 188 fatigue-related genes and 164 depression-related genes, which shared 24 common genes and involved 11 common pathways. Principal component analysis based on 24 genes clearly separates 39 samples with respect to their likelihood to be CFS. Most of the 24 genes are not previously reported for CFS, yet their functions are consistent with the prevailing model of CFS, such as immune response, apoptosis, ion channel activity, signal transduction, cell-cell signaling, regulation of cell growth and neuronal activity. Hierarchical cluster analysis was performed based on 24 genes to classify 128 (=167-39) unassigned samples. Several of the 11 identified common pathways are supported by earlier findings for CFS, such as cytokine-cytokine receptor interaction and neuroactive ligand-receptor interaction. Importantly, most of the 11 common pathways are interrelated, suggesting complex biological mechanisms associated with CFS.
Bioinformatics is critical in this study to select definitive sample groups, analyze gene expression data and gain insight into biological mechanisms. The 24 identified common genes and 11 common pathways could be important in future studies of CFS at the molecular level.
Fostel, J., Boneva, R and Lloyd, A. Exploration of the gene expression correlates of chronic unexplained fatigue using factor analysis. Pharmacogenomics, 2006, 7, 3, 441-454.
The aim is to identify biomarkers of CFS and related disorders through analysis of microarray data, pathology test results and self-report symptom profiles.
To empirically derive the symptom domains of the illnesses, factor analysis was performed on responses to self-report questionnaires (multidimensional fatigue inventory, Centers for Disease Control and Prevention (CDC) symptom inventory and Zung depression scale) from the CDC study (as above), before validation with independent datasets. Gene expression patterns that distinguished subjects across each factor dimension were then sought.
A four-factor solution was favored, featuring 'fatigue' and 'mood disturbance' factors. Scores on these factors correlated with measures of disability on the Short Form (SF)-36. A total of 57 genes that distinguished subjects along each factor dimension were identified, although the separation was significant only for subjects beyond the extreme (15(th) and 85(th)) percentiles of severity. Clustering of laboratory parameters with expression of these genes revealed associations with serum measurements of pH, electrolytes, glucose, urea, creatinine, and liver enzymes (aspartate amino transferase [AST] and alanine amino transferase [AST]); as well as hematocrit and white cell count.
CFS is a complex syndrome that cannot simply be associated with changes in individual laboratory tests or expression levels of individual genes. No clear association with gene expression and individual symptom domains was found. However, analysis of such multifacetted datasets is likely to be an important means to elucidate the pathogenesis of CFS.
Vollmer-Conna, U., Aslakson, E and White, PD. An empirical delineation of the heterogeneity of chronic unexplained fatigue in women. Pharmacogenomics, 2006, 7, 3, 355-364.
The aim of this study was to test the hypothesis that medically unexplained chronic fatigue and CFS are heterogeneous conditions, and to define the different conditions using both symptom and laboratory data.
The researchers assessed samples from 159 women from the CDC’s study (as above). A total of 51 of these suffered from fatigue consistent with established criteria for CFS, 55 had chronic fatigue of insufficient symptoms/severity for a CFS diagnosis and 53 were healthy controls matched by age and body mass index (BMI) against those with CFS. We used principal components analyses to define factors that best described the variable space and to reduce the number of variables. The 38 most explanatory variables were then used in latent class analyses to define discrete subject groups.
Principal components analyses defined six discrete factors that explained 40% of the variance. Latent class analyses provided several interpretable solutions with four, five and six classes. The four-class solution was statistically most convincing, but the six-class solution was more interpretable. Class 1 defined 41 (26%) subjects with obesity and relative sleep hypnoea. Class 2 were 38 (24%) healthy subjects. Class 3 captured 24 (15%) obese relatively hypnoeic subjects, but with low heart rate variability and cortisol. Class 4 were 23 (14%) sleep-disturbed and myalgic subjects without obesity or significant depression. The two remaining classes with 22 (14%) and 11 (7%) subjects consisted of the most symptomatic and depressed, but without obesity or hypnoea. Class 5 had normal sleep indices. Class 6 was characterized by disturbed sleep, with low sleep heart rate variability, cortisol, and sex hormones.
“Chronic medically unexplained fatigue is heterogeneous. The putative syndromes were differentiated by obesity, sleep hypnoea, depression, physiological stress response, sleep disturbance, interoception and menopausal status. If these syndromes are externally validated and replicated, they may prove useful in determining the causes, pathophysiology and treatments of CFS.”
Vernon, SD and Reeves, WC. The challenge of integrating disparate high-content data: epidemiological, clinical and laboratory data collected during an in-hospital study of chronic fatigue syndrome. Pharmacogenomics, 2006, 7, 3, 345-354.
Review of the studies in this issue, which all utilized data obtained from patients with CFS, other medically and psychiatrically unexplained fatiguing illnesses and nonfatigued controls identified from the general population of Wichita, KS, USA.
[Ed. Note: The studies in this issue used broad criteria and some relied on a limited number of measures and variables to include in their analysis, which makes it difficult to draw conclusions about CFS in general and subgroups of CFS in particular. The papers confirm the heterogeneity of the CFS population and show that there is a difference between genes for fatigue and CFS.]
Wearden, AJ., Riste, L., Dowrick, C., Chew-Graham, C., Bentall, RP., Morriss, RK., Peters, S., Dunn, G., Richardson, G., Lovell, K and Powell, P. Fatigue Intervention by Nurses Evaluation - The FINE Trial. A randomised controlled trial of nurse led self-help treatment for patients in primary care with chronic fatigue syndrome: study protocol. BMC Medicine 2006, 4:9
Description of the FINE trial.
[Ed. Note: The authors chose not to use the Canadian guidelines to diagnose patients because they have not been validated for research. However, the criteria they selected instead have not been validated either. Indeed, there are no criteria which have been validated.]
Cameron, B., Bharadwaj, M., Burrows, J., Fazou, C., Wakefield, D., Hickie, I., Ffrench, R., Khanna, R and Lloyd, A, for the Dubbo Infection Outcomes Study. Prolonged illness after infectious mononucleosis is associated with altered immunity but not with increased viral load. Journal of Infectious Diseases, 2006, 193, 664-671.
Primary Epstein-Barr virus (EBV) infection causes a spectrum of characteristics that range from asymptomatic seroconversion to severe infectious mononucleosis (IM), sometimes with prolonged symptoms and disability. We examined the relationships between clinical course, number of viral copies, and immunological parameters in a prospective cohort of subjects with recent IM.
Eight case patients with at least 6 months of disabling symptoms and 31 matched control subjects who had recovered promptly were included. Mean duration of illness before enrolment was 27 days. Symptom scores were recorded at regular intervals over the course of 12 months. Cellular EBV load, EBV-specific antibody responses, lymphocyte subsets, and EBV-specific interferon (IFN)-γ induction were measured.
The mean duration of the entire illness was 34 weeks for cases and 8 weeks for controls (p<.001). In case patients with prolonged illness, the severity of acute-phase symptoms was greater (even at baseline), the development of anti-EBV nuclear antigen-1 immunoglobulin G was more rapid, and the time to development of the peak IFN-γ response to the majority of latent-cycle EBV peptides was generally slower than those in control subjects. However, in both groups, neither viral nor immune parameters correlated with the severity or duration of symptoms.
“Interestingly, data from the present cohort demonstrate that personality style (e.g., neuroticism) and psychological disorder (e.g., depression) do not predict prolonged illness (I.H., T. Davenport, D.W., U. Vollmer-Conna, B.C., S. Vernon, W. Reeves, and A. Lloyd, unpublished data). Differences in the magnitude and duration of the cytokine response could explain the ongoing symptoms. Indeed, correlations between the production of the pro-inflammatory cytokines IL-1 and IL-6 and acute-phase symptoms have been demonstrated in this cohort... However, we have recently found that the levels of pro-inflammatory cytokines did not remain elevated in the case patients (U. Vollmer-Conna, B.C., I.H., T. Davenport, D.W., R. Nisenbaum, S. Vernon, W. Reeves, and A. Lloyd, unpublished data). Accordingly, we propose that alternative neurobiological mechanisms triggered during the severe, acute illness and sustained in the absence of ongoing peripheral inflammation underpin prolonged illness after EBV infection”.
The researchers conclude that “resolution of symptomatic IM is not determined by control of viremia, nor is it easily explained by altered host responses to EBV infection. The detailed determinants of delayed recovery remain to be elucidated.”
Huibers MJ, Leone SS, Kant I, Knottnerus JA. Chronic fatigue syndrome-like caseness as a predictor of work status in fatigued employees on sick leave: four- year follow-up study. Occupational and Environmental Medicine, 2006, May 12 [Epub ahead of print]. doi:10.1136/oem.2005.023176
Many CFS patients are unemployed or unable to work, but most prognostic studies have failed to assess occupational outcomes in CFS. We aimed to assess whether CFS-like caseness (meeting own criteria for CFS focusing on severity of fatigue) predicts work status in the long-term.
We conducted a prospective study in a sample of fatigued employees absent from work. Data were collected at baseline and four years later, and included CFS-like caseness and work status (inactive work status and full work incapacity). We used multiple logistic regression models to determine the association between CFS-like caseness and work status, controlling for potential confounders.
CFS-like cases at baseline were three times more likely to be unable to work at follow-up than fatigued employees who did not meet CFS criteria at baseline (ORs between 3 and 3.3). These associations grew even stronger when we controlled for demographic and clinical confounders (ORs between 3.4 and 4.4).
A CFS-like status (compared to non-CFS fatigue) proved to be a strong predictor of an inactive work status and full work incapacity in the long-term. Since little is known about effective interventions that prevent absenteeism and work incapacity or facilitate return to work in subjects with chronic fatigue, there is a great need for powerful early interventions that restore or preserve the ability to work, especially for workers who meet criteria for CFS.
Takahashi, T., Yu, F., Zhu, S., Moriya, J., Sumino, H., Morimoto, S., Yamaguchi, N and Kanda, T. Beneficial effect of brewers' yeast extract on daily activity in a murine model of chronic fatigue syndrome. Evidence Based Complementary and Alternative Medicine, 2006, 3, 1, 109-115.
The aim of this study was to assess the effect of Brewers' yeast extract (BYE) on daily activity in a mouse model of CFS (induced by repeated injection of Brucella abortus (BA) antigen every 2 weeks. The authors evaluated daily running activity in mice receiving BYE as compared with that in untreated mice. Weekly variation of body weight (BW) and survival in both groups was monitored during the observation period. Spleen weight (SW), SW/BW ratio, percent splenic follicular area and expression levels of interferon-gamma (IFN-γ) and interleukin-10 (IL-10) mRNA in spleen were determined in both groups at the time of sacrifice.
The daily activity during 2 weeks after the second BA injection was significantly higher in the treated group than in the control. There was no difference in BW between both groups through the experimental course. Two mice in the control died 2 and 7 days after the second injection, whereas no mice in the treated group died. Significantly decreased SW and SW/BW ratio were observed in the treated mice together with elevation of splenic follicular area. There were suppressed IFN-γ and IL-10 mRNA levels in spleens from the treated mice.
Our results suggest that BYE might have a protective effect on the marked reduction in activity following repeated BA injection via normalization of host immune responses.
[Ed. Note: Brucella abortus has not been associated with the aetiology of CFS. Although undulant fever shares some symptoms, the use of a bacterium may not justify the extrapolation of findings to CFS.]
E. Goudsmit. AFBPsS.
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