Number 3 |
1st September 2006 |
IMMUNOLOGY
|
Siegel, SD., Antoni, MH., Fletcher, MA., Maher, K., Segota, MC and Klimas N. Impaired natural immunity, cognitive dysfunction, and physical symptoms in patients with chronic fatigue syndrome: preliminary evidence for a subgroup? Journal of Psychosomatic Research, 2006, 60, 6, 559-566.
The diagnostic criteria of CFS define a heterogeneous population composed of several sub-groups. Past efforts to identify subgroup markers have met with mixed success. This study was designed to examine natural killer cell activity (NKCA) as a potential subgroup marker by comparing the clinical presentations of CFS patients with and without clinically reduced NKCA.
Forty-one female CFS patients (CDC criteria ’94) were classified into having either low or normal NKCA levels. These subgroups were then compared on objective measures of cognitive functioning and subjective assessments of fatigue, vigor, cognitive impairment, and daytime dysfunction.
Relative to CFS patients in the normal-NKCA subgroup, low-NKCA patients reported less vigor, more daytime dysfunction, and more cognitive impairment. In addition, low-NKCA patients performed less well on objective measures of cognitive functioning relative to normal-NKCA patients.
The results are offered as preliminary evidence in support of using NKCA as an immunological subgroup marker in CFS. Findings are also discussed in terms of known associations between dysregulated immune functions, somatic symptoms, and psychological stress.
Bond, PA and Dinan, TG. Antibodies to Herpes Simplex types 1 and 2 in chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2006, 13, 1, 35-40.
It has been suggested that Herpes simplex virus (HSV) could play a role in the aetiology of CFS. An immune system that has been compromised, could account for HSV reactivating or infecting for the first time, and also being insufficiently under control in the body. Another consequence of inadequate control could be that several strains of HSV could simultaneously infect the body.
The objective of this study was to look for the presence of antibodies to HSV-1 and HSV-2 in patients with CFS and in controls. The presence of antibodies to both types of HSV could reflect infection by multiple strains of HSV.
Antibodies to HSV-1 and HSV-2 were measured in sera from 27 CFS patients and 26 age and sex-matched controls. CFS was diagnosed using the CDC criteria.
More CFS patients had antibodies to HSV-1, HSV-2 and both types simultaneously, than did the controls (all p< .019).
Gräns, H., Nilsson, M., Dahlman-Wright, K and Evengård, B. Reduced levels of oestrogen receptor β mRNA in Swedish patients with chronic fatigue syndrome. Journal of Clinical Pathology, 2006 May 26; [Epub ahead of print]. doi:10.1136/jcp.2005.035956
CFS is an illness with unknown aetiology and pathophysiology. The sex difference observed for CFS indicates a role for oestrogen and oestrogen receptors (ERs) for disease development. Furthermore, an immuno-mediated pathogenesis has been suggested for CFS which provides an additional connection to oestrogen, which displays immunomodular functions. The aim of this study was to investigate a possible association of ER mRNAs and two ERβ single nucleotide polymorphisms (SNPs) with CFS.
Messenger RNA levels of ERα, Erβwt and ERβcx were investigated in peripheral blood mononuclear cells (PBMCs) from 30 CFS patients (CDC criteria ’94) and 36 healthy controls by quantitative real-time PCR. Two ERβ SNPs were scored in the same material.
The CFS patient group showed significantly lower mRNA expression levels of Erβwt compared with the healthy control group. No differences were observed for ERα or ERβcx between patients and controls. There were no significant differences in frequency for the investigated Erβ SNPs between cases and controls.
The reduced Erβwt expression levels observed in this study is consistent with an immune-mediated pathogenesis of CFS. Additionally, the observation that ERβwt expression is decreased in CFS could provide an entry point to identify interesting, potentially disease causing, candidate molecules for further study. A possible connection between oestrogen, ERs and CFS should be further evaluated.
Jerjes, WK., Taylor, NF., Peters, TJ., Wessely, S and Cleare, AJ. Urinary cortisol metabolite excretion in chronic fatigue syndrome. Psychosomatic Medicine, 2006, 68, 578-582.
Reduced basal hypothalamic–pituitary–adrenal (HPA) axis output in CFS has been inferred from low cortisol levels in blood, saliva, and urine in some studies. Because >95% of cortisol is metabolized before excretion, we assessed cortisol output by assay of both cortisol metabolites and free cortisol in 24-hour urine collections and also investigated sex differences in these between CFS and control groups.
We calculated total urinary cortisol metabolites (TCM) and cortisol metabolite ratios from individual steroid data in 40 patients (20 males and 20 females) with CFS (CDC criteria ’94), who were free of medication or comorbid psychiatric disorder likely to influence the HPA axis. Results were compared with those of 40 healthy volunteers (20 males and 20 females) well matched for age and body mass index. Data for free cortisol was obtained on 28 of the patients and 27 of the controls.
The mean of TCM and cortisol metabolite ratios was not significantly different between patients and controls for either sex (p>.05 for all parameters). Previously established sex differences were confirmed in our controls and were found to be similar in CFS for TCM as well as the ratios 11OH/11OXO, 5α/5β THF, and 20OH/20OXO (p<.005, p<.05, p<.05, and p<.005, respectively). Urinary free cortisol values were numerically (but not statistically) lower in patients with CFS than controls, and correlated inversely with fatigue levels in patients.
The finding of normal urinary cortisol metabolite excretion in patients with CFS is at variance with earlier reports that CFS is a hypocortisolemic state. If serum and saliva cortisol levels are lower in CFS, this would suggest that metabolic clearance of cortisol is faster in patients with CFS than controls. This study also demonstrates that sex differences must be taken into account when interpreting results in patients with CFS.
[Ed. Note: The duration of illness in this sample was comparatively short. In more chronically ill samples, the level of cortisol may have been lower, due to the effects of long-term stress etc.]
Carlo-Stella, N., Badulli, C., De Silvestri, A., Bazzichi, L., Martinetti, M., Lorusso, L., Bombardieri, S., Salvaneschi, L and Cuccia, M. A first study of cytokine genomic poly-morphisms in CFS: Positive association of TNF-857 and IFNγ 874 rare alleles. Clinical and Experimental Rheumatology, 2006, 24, 2, 179-182.
In the past two years we have developed a biological bank of genomic DNA, cDNA, serum and red blood cells of Italian patients with certified CFS from the two Italian referral centers for the syndrome. Recent studies have shown an imbalance in cytokine production in disease states similar to CFS, such as sickness behavior, both in animals and in humans. However we notice that serum cytokine concentrations are often inconstant and degrade rapidly. With this in mind, we investigated cytokine gene polymorphisms in 80 Italian patients with CFS in order to ascertain whether in this group of patients it is possible to describe a genetic predisposition to an inflammatory response.
We analyzed the promoter polymorphisms of IL-10, IL-6 and the IFNγ 874 T/A polymorphism in intron 1 with a PCR-SSP method (Cytogen One Lambda Inc. Canoga Park, CA, U.S.A) in 54 patients and TNF-308 G/A and -857 C/T promoter polymorphisms with a PCR-RFLP method (in 54 and 80 patients respectively).
There is a highly significant increase of TNF -857 TT and CT genotypes (p=0.002) among patients with respect to controls and a significant decrease of IFNγ low producers (A/A) (p=0.04) among patients with respect to controls.
We hypothesize that CFS patients can have a genetic predisposition to an immunomodulatory response of an inflammatory nature probably secondary to one or more environmental insults of unknown nature.
Nater, UM., Wagner, D., Solomon, L., Jones, JF., Unger, ER., Papanicolaou, DA., Reeves, WC and Heim, C. Coping styles in people with chronic fatigue syndrome identified from the general population of Wichita, KS. Journal of Psychosomatic Research, 2006, 60, 6, 567-573.
The researchers assessed coping styles of people with CFS (CDC criteria ‘94, operationalised) and persons with unexplained fatigue and non-fatigued controls in a population-based study.
The 43 subjects with CFS were matched with 61 subjects with chronic unexplained fatigue who did not meet criteria for CFS [insufficient symptoms or fatigue (ISF)] and 60 non-ill (NI) controls. Coping styles and clinical features of CFS were assessed using the Ways of Coping Questionnaire (WOCQ) and standard rating scales.
Subjects with CFS and ISF reported significantly more escape-avoiding behavior than NI controls. There were no differences between the CFS and ISF subjects. Among participants with CFS, escape-avoiding behavior was associated with fatigue severity, pain, and disability but not with muscle fatigue.
“We demonstrate significantly higher reporting of maladaptive coping in a population-based sample of people with CFS and other unexplained fatiguing illnesses defined by reproducible standardized clinical empirical means in comparison to NI controls.”
[Ed. Note: The instructions did not require the participants to focus on the illness as the stressor and the results therefore may not reflect how they deal with CFS. The exact wording of the instructions was: “To respond to the statements in this questionnaire, you must have a specific stressful situation in mind. Take a few moments and think about the most stressful situation that you have experienced in the past week”.
Moreover, Susan Folkman (co-author of the WOCQ) has written “Many investigators have asked if the Ways of Coping can be used to assess coping styles or traits. The measure is not designed for this purpose; it is designed as a process measure. It is possible though to look for consistency (style) across occasions by administering the measure repeatedly and then doing intra individual analyses. Each administration, however, is focused on coping processes in a particular stressful encounter and not on coping styles or traits. However, the researchers in this paper discuss ‘coping styles’ and whether these are a risk factor for illness severity. The responses on the escape-avoidance subscale may reflect strategies used to deal with problems other than their illness, e.g. tax\disability forms, relationships.
The items in the Escape-Avoidance subscale are as follows:
Wished that the situation would go away or somehow be over with.
Hoped a miracle would happen.
Had fantasies or wishes about how things might turn out.
Tried to make myself feel better by eating, drinking, smoking, using drugs or medication, etc.
Avoided being with people in general.
Refused to believe that it had happened.
Took it out on other people.
Slept more than usual.
It would be interesting to ascertain which items received higher scores as people with CFS are unlikely to respond to their illness by eating or drinking more, and there are no drugs likely to reduce symptoms. It should be noted that there is no item relating to reduced exercise, and therefore the results provide no evidence to promote graded exercise. People with other chronic and incurable diseases may have similar scores for this subscale and therefore the result should be interpreted with caution.]
Thomas, M., Sadlier, M and Smith, A. The effect of Multi Convergent Therapy on the psychopathology, mood and performance of chronic fatigue syndrome patients: A preliminary study. Counselling and Psychotherapy Research, 2006, 6, 2, 91-99.
Multi Convergent Therapy combines approaches such as Cognitive Behaviour Therapy (CBT) and Graded Exercise Therapy (GET) in an holistic treatment of CFS. Initial follow-up data showed that patients were benefiting from this individualised form of therapy. The objective of the present study was to evaluate this Multi Convergent approach, developed at a specialised CFS Outpatient clinic in Cardiff, and compare it to Relaxation Therapy and control groups using multiple outcome measures.
Thirty-five participants with CFS (CDC criteria ’94, Karnofsky score < 70) were recruited from two outpatient clinics and members of our existing patient panel. Patients were assigned to Multi Convergent Therapy (N=12), Relaxation Therapy (N=14) or recruited as controls (N=9).
Each patient completed a battery of mood and performance tasks along with comprehensive set of questionnaires at baseline, post-treatment and at six-month follow-up. These measures, which included the Profile of Fatigue Related Symptoms (PFRS) , HAD and MOS SF-36, had been validated in previous studies on untreated patients and matched healthy controls.
Patients attending the Multi Convergent Therapy clinic showed statistically significant improvements in many of our measures. There was a 83.3% improvement in current health, consistent with reports from CBT trials. Most importantly we have produced data indicating that Multi Convergent Therapy provides improvements in objective measures of psychomotor performance and cognition. There was no significant improvement in depression or anxiety.
The outcomes of this small study are encouraging. Multi Convergent Therapy has not only produced results indicating significant improvements in standardised questionnaire based measures but also in objective cognitive performance tasks. The next step would be to assess Multi Convergent Therapy at the primary medical care level, with a greater number of patients to further evaluate its efficacy as a treatment for CFS.
[Ed. Note: This is an unusual trial as it included a measure of somatic symptoms.]
Van Houdenhove, B., Bruyninckx, K and Luyten, P. In search of a new balance. Can high "action-proneness" in patients with chronic fatigue syndrome be changed by a multidisciplinary group treatment? Journal of Psychosomatic Research, 2006, 60, 6, 623-625.
Short Communication. The purpose of this study is to investigate changes in action-proneness (a cognitive and behavioral tendency toward direct action, an ‘overactive lifestyle) after a multidisciplinary group intervention, including CBT and GET.
Patients with CFS (CDC criteria ’94, n=62) completed three versions of a Dutch self-report questionnaire evaluating action-proneness at time 1, referring to activities before illness onset, time 2, immediately before treatment and time 3, after treatment, asking about the future. Significant others (n=62) also gave their opinion about the patients' action-proneness at time points 1 and 2.
Pre-morbid action-proneness levels considerably dropped after illness onset. After treatment, action-proneness levels significantly increased again, although levels remained below pre-morbid levels.
High action-proneness retrospectively reported by CFS patients can be adaptively modified by a multidisciplinary group treatment including CBT and GET.
Jason, L.A., Corradi, K., Gress, S., Williams, S and Torres-Harding, S. Causes of death among patients with chronic fatigue syndrome. Health Care for Women International, 2006, 27, 7, 615-626.
At the present time, there are few studies that have investigated causes of death for those with CFS. The authors analyzed a memorial list tabulated by the National CFIDS Foundation of 166 deceased individuals who had had CFS. There were approximately three times more women than men on the list.
The three most prevalent causes of death were heart failure, suicide and cancer, which accounted for 59.6% of all deaths. The mean age of those who died from cancer and suicide was 47.8 and 39.3 years, respectively, which is considerably younger than those who died from cancer and suicide in the general population.
Ashby, B., Wright, B and Jordan, J. Chronic fatigue syndrome: an evaluation of a community based management programme for adolescents and their families. Child and Adolescent Mental Health, 2006, 11, 1, 13–18.
Young people with CFS, families and clinicians may differ in their attributions about CFS and consequently in their approach to treatment. Research that clarifies the best treatment approaches is clearly needed. We have sought to develop a model that engages young people and their families in a collaborative way. The approach adopts an optimistic and holistic stance using an active rehabilitation model paying attention to the integrated nature of the physiological and psychological aspects of the illness.
This small study (n=10, average illness duration = 9 months) set out to evaluate this approach from a service user perspective. Semi-structured interviews were carried out with young people and their parents separately in order to elicit their views on key treatment elements and their perceived degree of recovery.
Improvements are indicated in all key areas addressed and qualitative information suggests that families value this approach. Further research is needed to address treatment issues for families who choose not to opt into the service model.
[Ed. Note: It is not clear how many of the children were suffering from anxiety and chronic stress, as well as a post-viral syndrome. All claimed to have had an infection preceding the symptoms but there was evidence of other problems, including psychological issues and anaemia.]
http://www.blackwell-synergy.com/toc/camh/11/1;jsessionid=eg52e16P9T44OJ1fST
Vermeulen, RCW and Scholte, HR. Azithromycin in chronic fatigue syndrome (CFS), an analysis of clinical data. Journal of Translational Medicine, 2006, 4, 1, 34. 15th August. doi:10.1186/1479-5876-4-34.
CFS is a clinical state with defined symptoms, but undefined cause. The patients may show a chronic state of immune activation and treatment with an antibiotic in this subgroup has been suggested.
In a retrospective study, the response of CFS patients to azithromycin, an antibiotic and immunomodulating drug, has been scored from the patients records and compared with clinical and laboratory data. Azithromycin was not the first choice therapy, but offered when the effect of counseling and L-carnitine was considered insufficient by the patient and the clinician.
Of the 99 patients with CFS (CDC criteria ’94) investigated, 58 reported a decrease in the symptoms by the use of azithromycin. These responding patients had lower levels of plasma acetylcarnitine.
The efficacy of azithromycin in the responsive patients could be explained by the modulating effect on a chronic primed state of the immune cells of the brain, or the activated peripheral immune system. Their lower acetylcarnitine levels may reflect a decreased antioxidant defense and/or an increased consumption of acetylcarnitine caused by oxidative stress.
Meeus, M., Nijs, J and De Meirleir, K. Chronic musculoskeletal pain in patients with the chronic fatigue syndrome: A systematic review. European Journal of Pain, 2006 Jul 12; [Epub ahead of print]. doi:10.1016/j.ejpain.2006.06.005
In addition to debilitating fatigue the majority of patients with CFS experience chronic widespread pain. Conducting a systematic review to critically assess the existing knowledge on chronic pain in CFS. We focussed on the definition, the prevalence and incidence, the aetiology, the relevance and the therapy strategy for chronic musculoskeletal pain and post-exertional pain in CFS.
To identify relevant articles, we searched eight medical search engines. The search terms "chronic fatigue syndrome" AND "pain", "nociception", "arthralgia" and "myalgia", were used to identify articles concerning pain in CFS. Included articles were reviewed by two blinded researchers.
Twenty-five articles and two abstracts were identified and selected for further appraisal. Only 11 search results focused on musculoskeletal pain in CFS patients. Regarding the standardized review of the articles, a 96% agreement between the researchers was observed. There is no consensus in defining chronic widespread pain in CFS, and although there is little or no strong proof for the exact prevalence, chronic pain is strongly disabling in CFS. Aetiological theories are proposed (sleep abnormalities, tryptophan, parovirus-B, hormonal and brain abnormalities and central sensitisation) and a reduction of pain threshold after exercise has been shown. Furthermore depression seemed not related to pain in CFS and a staphylococcus toxoid vaccine caused no significant pain reduction.
The results from the systematic review highlight the clinical importance of chronic pain in CFS, but only a few studies addressing the aetiology or treatment of chronic pain in CFS are currently available.
Puri, BK. Proton and 31-phosphorus neurospectroscopy in the study of membrane phospholipids and fatty acid intervention in schizophrenia, depression, chronic fatigue syndrome (myalgic encephalomyelitis) and dyslexia. International Review of Psychiatry, 2006, 18, 2, 145-147.
Puri, BK. High-resolution magnetic resonance imaging sinc-interpolation-based subvoxel registration and semi-automated quantitative lateral ventricular morphology employing threshold computation and binary image creation in the study of fatty acid interventions in schizophrenia, depression, chronic fatigue syndrome and Huntington's disease. International Review of Psychiatry, 2006, 18, 2, 149-154.
Serial high-resolution structural magnetic resonance imaging scans of the brain can now be precisely aligned, with six degrees of freedom (three mutually orthogonal translational and three rotational degrees of freedom around three mutually orthogonal axes), using a rigid-body subvoxel registration technique. This is driven by the in-plane point spread function for images acquired in the Fourier domain with data obtained over a bounded region of k-space, namely the sinc interpolation function, where sinc z = (sin z)/z, with z being any complex number (including zero). Computational subtraction of the three-dimensional Cartesian spatial representation matrices of serially acquired scan data allows for the determination of structural cerebral changes with great precision, since voxel signals from unchanged structures are almost completely cancelled. Thus changes readily show up against a background of noise.
Furthermore, lateral ventricular changes can now be accurately quantified using a semi-automated method involving contour production, threshold computation, binary image creation and ventricular extraction. These techniques have been applied to the investigation of the effects on cerebral structure of intervention with fatty acids, particularly the long-chain polyunsaturated n-3 fatty acid eicosapentaenoic acid (EPA), in disorders such as schizophrenia, treatment-resistant depression, chronic fatigue syndrome (myalgic encephalomyelitis or ME), and Huntington's disease.
Shepherd, C. The debate: myalgic encephalomyelitis and chronic fatigue syndrome. British Journal of Nursing, 2006, 15, 12, 662-669.
Taylor, RR. Rehabilitation programs for individuals with chronic fatigue syndrome: a review. Journal of Chronic Fatigue Syndrome, 2006, 13, 1, 41-55.
Wu, HS and Mengel, MB. Unexplained prolonged fatigue in primary care. Journal of Chronic Fatigue Syndrome, 2006, 13, 1, 15-34.
A literature review was undertaken with the MEDLINE databases chosen as the primary electronic resources to retrieve the literature.
Lack of consistent scientific language is a major problem. ...Clinicians are dubious about perceiving fatigue as a clinical entity and ignore the diagnosis criteria. Many more patients are excluded than included from the current classifications and lack appropriate evaluation and treatment.
The predisposing factors are not well established with the exception of being female and relatively young. Laboratory testing and immune and endocrine abnormalities are inconsistent in determining the causes. Psychological and social factors play an important but inconclusive role in mediating fatigue status.
Hyland, ME., Sodergren, SC and Lewith, GT. Chronic fatigue syndrome: the role of positivity to illness in chronic fatigue syndrome patients. Journal of Health Psychology, 2006, 11, 5, 731-741.
Fifty-three patients with CFS (CDC criteria ’94) treated at a complementary medical centre were assessed over 12 months. Measures included the Chalder Fatigue scale, the General Health Questionnaire (GHQ) and positivity in illness (Silver Lining Questionnaire, SLQ).
The SLQ measured at 6 and 9 months predicted (p<.01) mental (but not physical) fatigue at 12 months independently of current mental fatigue, initial mental fatigue, duration since diagnosis and time between start of treatment and entry to the study. “It was a response to improvements”. The GHQ did not predict fatigue at any time point. The results suggest that a caring therapeutic intervention increases positive interpretations of illness prior to improvements in mental fatigue, but that positivity does not play a causal role in the reduction of fatigue.
Jones, G and Godlee, F. Letter to the editor (Editorial bias in the BMJ). Journal of Chronic Fatigue Syndrome, 2006, 13, 1, 69-70.
Letter challenging the findings of Goudsmit et al published earlier. With reply from Stouten, B, Goudsmit EM and Howes, S. Ibid, 71-73.
Kelsall, H., Sim, M., McKenzie, D., Forbes, A., Leder, K., Glass, D., Ikin, J and McFarlane, A. Medically evaluated psychological and physical health of Australian Gulf War veterans with chronic fatigue. Journal of Psychosomatic Research, 2006, 60, 575– 584.
The aim of this study was to evaluate fatigue in Australian Gulf War veterans and a military comparison group according to the 1994 CFS definition and investigate the relation with exposures. Comprehensive medical, psychological and reported exposure assessments of 1456 veterans and 1588 comparison group in a cross-sectional study.
More Gulf War veterans had fatigue at all levels than did the military comparison group. The findings may be at least partly explained as an “active-deployment effect.” The odds ratios increased with increasing clinical evaluation of the nature of the fatigue, even after adjustment for current psychiatric disorders in addition to other possible confounding factors.
Medically unexplained chronic fatigue was more common, but not more disabling, in veterans than in the comparison group, but veterans with unexplained chronic fatigue had poorer health than veterans without. Within both populations, CFS is uncommon and at a similar level to the general community.
Lindal, E., Stefansson, JG and Bergmann, S. The prevalence of chronic fatigue syndrome in Iceland- a national comparison by gender drawing on four different criteria. Nordic Journal of Psychiatry, 2006, 60, 2, 183.
Letter correcting earlier data on the prevalence of CFS in Iceland. The total prevalence using the Oxford criteria was 3.8%, using the CDC criteria ’94, it was 2.2%. There were no cases of CFS using the CDC criteria ’88.
[Ed. note; the comparatively high prevalence rate for the Lloyd et al criteria (7.8%) is noteworthy as the latter are generally accepted as being more restrictive than Oxford and CDC definitions.]
McDermott, C., Richards, SCM., Thomas, PW., . Montgomery, J and Lewith, G. A placebo-controlled, double-blind, randomized controlled trial of a natural killer cell stimulant (BioBran MGN-3) in chronic fatigue syndrome. Quarterly Journal of Medicine, 2006, 99, 461-468.
Previous research has suggested that natural killer (NK) cell activity may be reduced in patients with CFS. The aim of this study was to evaluate the effectiveness of a putative NK cell stimulant, BioBran MGN-3, in reducing fatigue in CFS patients. This was a randomized, double-blind, placebo controlled trial.
We recruited 71 patients with CFS (CDC criteria ’94) attending an out-patient specialist CFS service. Participants were given oral BioBran MGN-3 for 8 weeks (2g three times per day) or placebo equivalent. The primary outcome measure was the Chalder physical fatigue score. Self-reported fatigue measures, self-assessment of improvement, change in key symptoms, quality of life, anxiety and depression measures were also included.
Data were complete in 64/71 patients. Both groups showed marked improvement over the study duration, but without significant differences. The mean Chalder fatigue score (physical scale) was lower in the placebo group at week 8.
The findings do not support a specific therapeutic effect for BioBran in CFS. The improvement showed by both groups over time highlights the importance of placebo controls when evaluating interventions in CFS.
Moss-Morris, R and Spence, M. To "Lump" or to "Split" the functional somatic syndromes: Can infectious and emotional risk factors differentiate between the onset of chronic fatigue syndrome and irritable bowel syndrome? Psychosomatic Medicine, 2006, 68, 463-469.
Recent academic debate has centered on whether functional somatic syndromes should be defined as separate entities or as one syndrome. The aim of this study was to investigate whether there may be significant differences in the etiology or precipitating factors associated with two common functional syndromes, irritable bowel syndrome (IBS) and CFS.
We prospectively studied 592 patients with an acute episode of Campylobacter gastroenteritis and 243 with an acute episode of infectious mononucleosis who had no previous history of CFS or IBS. At the time of infection, patients completed a baseline questionnaire that measured their levels of distress using the Hospital Anxiety and Depression scale (HAD). At 3- and 6-month follow-up, they completed questionnaires to determine whether they met published diagnostic criteria for chronic fatigue (CF), CFS, and/or IBS.
The odds of developing IBS were significantly greater post-Campylobacter than post–infectious mononucleosis at both 3- (odds ratio, 3.45 [95% confidence interval (CI), 1.75–6.67]) and 6- (2.22 [95% CI, 1.11–6.67]) month follow-up. In contrast, the odds for developing CF/CFS were significantly greater after infectious mononucleosis than after Campylobacter at 3 (2.77 [95% CI, 1.08–7.11]) but not 6 (1.48 [95% CI, 0.62–3.55]) months post-infection. Anxiety and depression were the strongest predictors of CF/CFS, whereas the nature of the infection was the strongest predictor of IBS.
These results support the argument to distinguish between post-infectious IBS and CFS. The nature of the precipitating infection appears to be important, and pre-morbid levels of distress appear to be more strongly associated with CFS than IBS, particularly levels of depression.
[Ed. note: The researchers had no data for anxiety and depression before onset of infection (glandular fever) and therefore any reference to ‘premorbid’ levels of distress is speculative. The presence of depression in people with glandular fever, possibly associated with Epstein-Barr virus, has been documented elsewhere. It is possible that anxiety was a response to the illness.]
Naschitz, JE., Mussafia-Priselac, R., Kovalev, Y., Zaigraykin, N., Slobodin, G., Elias, N and Rosner, I. Patterns of hypocapnia on tilt in patients with fibromyalgia, chronic fatigue syndrome, nonspecific dizziness, and neurally mediated syncope. American Journal of Medical Science, 2006, 331, 6, 295-303.
The objective was to assess whether head-up tilt-induced hyperventilation is seen more often in patients with CFS, fibromyalgia, dizziness, or neurally mediated syncope (NMS) as compared to healthy subjects or those with familial Mediterranean fever (FMF).
A total of 585 patients were assessed with a 10-minute supine, 30-minute head-up tilt test combined with capnography. Experimental groups included CFS (n=90), non-CFS fatigue (n=50), fibromyalgia (n=70), nonspecific dizziness (n=75), and NMS (n=160); control groups were FMF (n=90) and healthy persons (n=50). Hypocapnia, the objective measure of hyperventilation, was diagnosed when end-tidal pressure of CO2 (PETCO2) less than 30 mm Hg was recorded consecutively for 10 minutes or longer. When tilting was discontinued because of syncope, one PETCO2 measurement of 25 or less was accepted as hyperventilation.
Hypocapnia was diagnosed on tilt test in 9% to 27% of patients with fibromyalgia, CFS, dizziness, and NMS versus 0% to 2% of control subjects. Three patterns of hypocapnia were recognized: supine hypocapnia (n=14), sustained hypocapnia on tilt (n=76), and mixed hypotensive-hypocapnic events (n=80). Hypocapnia associated with postural tachycardia syndrome (POTS) occurred in 8 of 41 patients.
Hyperventilation appears to be the major abnormal response to postural challenge in sustained hypocapnia but possibly merely an epiphenomenon in hypotensive-hypocapnic events. Our study does not support an essential role for hypocapnia in NMS or in postural symptoms associated with POTS. Because unrecognized hypocapnia is common in CFS, fibromyalgia, and nonspecific dizziness, capnography should be a part of the evaluation of patients with such conditions.
Naschitz, J., Fields,M., Isseroff, H., Sharif, D, Sabo, E and Rosner, I. Shortened QT interval: a distinctive feature of the dysautonomia of chronic fatigue syndrome. Journal of Electrocardiology, Feb 28; [Epub ahead of print]. doi:10.1016/j.jelectrocard.2005.10.014
Because autonomic nervous functioning is frequently abnormal in CFS, we examined whether the corrected QT interval (QTc) in CFS differs from QTc in other populations.
The QTc was calculated at the end of 10 minutes of recumbence and the end of 10 minutes of head-up tilt. In a pilot study, groups of 15 subjects, CFS, and controls, matched for age and sex, were investigated. In a second phase of the study, the QTc was measured in larger groups of CFS (CDC criteria ’94, n=30) and control patients (n = 96) not matched for demographic features.
In the pilot study, the average supine QTc in CFS was 0.371 +/- 0.02 seconds and QTc on tilt, 0.385 +/- 0.02 seconds, significantly shorter than in controls (p= .0002 and .0003, respectively). Results of phase II confirmed this data.
Relative short QTc intervals are features of the CFS-related dysautonomia. The significance of this finding is discussed.
Nicolson, GL and Ellithorpe, R. Lipid replacement and antioxidant nutritional therapy for restoring mitochondrial function and reducing fatigue in chronic fatigue syndrome and other fatiguing illnesses. Journal of Chronic Fatigue Syndrome, 2006, 13, 1, 57-68.
Evidence in the literature indicates that diminished mitochondrial function through loss of efficiency in the electron transport chain caused by oxidation occurs during aging and in fatiguing illnesses. Lipid Replacement Therapy (LRT) administered as a nutritional supplement with antioxidants can prevent oxidative membrane damage, and LRT can be used to restore mitochondrial and other cellular membrane functions via delivery of undamaged replacement lipids to cellular organelles.
Recent clinical trials using patients with chronic fatigue have shown the benefit of LRT plus antioxidants in restoring mitochondrial electron transport function and reducing moderate to severe chronic fatigue. These studies indicate the benefits of LRT plus antioxidants in reducing fatigue and preventing loss of mitochondrial function, most likely by protecting mitochondrial and other cellular membranes from oxidative and other damage and removing damaged lipids by lipid replacement.
In one clinical study, we determined if mitochondrial function is reduced in subjects with mild to severe chronic fatigue, and if this can be reversed with NT Factor®, a nutritional supplement that replaces damaged cellular lipids. With the use of the Piper Fatigue Scale, there was a significant time-dependent reduction in overall fatigue in moderately or severely fatigued subjects while on the dietary supplement for 4-8 weeks.
Analysis of mitochondrial function indicated that four and eight weeks of the dietary supplement in moderately or severely fatigued subjects significantly increased mitochondrial function. Similarly, CFS patients administered antioxidants plus LRT also show reductions in fatigue. The results indicate that LRT plus antioxidants can significantly reduce moderate to severe chronic fatigue and restore mitochondrial function. Dietary use of unoxidized membrane lipids plus antioxidants is recommended for patients with moderate to severe chronic fatigue.
Nijs, J., Meeus, M and de Meirleir, K. Chronic musculoskeletal pain in chronic fatigue syndrome: Recent developments and therapeutic implications. Manual Therapy, 2006 Jun 13; [Epub ahead of print]. doi:10.1016/j.math.2006.03.008
Patients with CFS experience chronic musculoskeletal pain which is even more debilitating than fatigue. Scientific research data gathered around the world enables clinicians to understand, at least in part, chronic musculoskeletal pain in CFS patients. Generalized joint hypermobility and benign joint hypermobility syndrome appear to be highly prevalent among CFS sufferers, but they do not seem to be of any clinical importance. On the other hand, pain catastrophizing accounts for a substantial portion of musculoskeletal pain and is a predictor of exercise performance in CFS patients.
The evidence concerning pain catastrophizing is supportive of the indirect evidence of a dysfunctional pain processing system in CFS patients with musculoskeletal pain. CFS sufferers respond to incremental exercise with a lengthened and accentuated oxidative stress response, explaining muscle pain, postexertional malaise, and the decrease in pain threshold following graded exercise in CFS patients.
Applying the scientific evidence to the manual physiotherapy profession, pacing self-management techniques and pain neurophysiology education are indicated for the treatment of musculoskeletal pain in CFS patients. Studies examining the effectiveness of these strategies for CFS patients are warranted.
Rajeevan, MS., Smith, AK., Dimulescu, I., Unger, ER., Vernon, SD., Heim, C and Reeves, WC. Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome. Genes, Brain and Behavior, 2006, Jun 1; [Epub ahead of print]. doi: 10.1111/j.1601-183X.2006.00244.
CFS is a significant public health problem of unknown etiology, the pathophysiology has not been elucidated, and there are no characteristic physical signs or laboratory abnormalities. Some studies have indicated an association between CFS, deregulation of immune functions and HPA axis activity. In this study, we examined the association of sequence variations in the glucocorticoid receptor gene (NR3C1) with CFS because NR3C1 is a major effector of the HPA axis.
There were 137 study participants (40 with CFS defined using the CDC criteria ‘94, 55 with insufficient symptoms or fatigue, termed as ISF, and 42 non-fatigued controls) who were clinically evaluated and identified from the general population of Wichita, KS. Nine single nucleotide polymorphisms (SNPs) in NR3C1 were tested for association of polymorphisms and haplotypes with CFS.
We observed an association of multiple SNPs with chronic fatigue compared to non-fatigued (NF) subjects (p<0.05) and found similar associations with quantitative assessments of functional impairment (by the SF-36), with fatigue (by the Multidimensional Fatigue Inventory) and with symptoms (assessed by the CDC Symptom Inventory). Subjects homozygous for the major allele of all associated SNPs were at increased risk for CFS with odds ratios ranging from 2.61 (CI 1.05-6.45) to 3.00 (CI 1.12-8.05). Five SNPs, covering a region of approximately 80 kb, demonstrated high linkage disequilibrium (LD) in CFS, but LD gradually declined in ISF to NF subjects. Furthermore, haplotype analysis of the region in LD identified two associated haplotypes with opposite alleles: one protective and the other conferring risk of CFS.
These results demonstrate NR3C1 as a potential mediator of chronic fatigue, and implicate variations in the 5' region of NR3C1 as a possible mechanism through which the alterations in HPA axis regulation and behavioural characteristics of CFS may manifest.
Sakudo, A., Kuratsune, H., Kobayashi, T., Tajima, S., Watanabe, Y and Ikuta, K. Spectroscopic diagnosis of chronic fatigue syndrome by visible and near-infrared spectroscopy in serum samples. Biochemical and Biophysical Research Communications, 2006, May 22; [Epub ahead of print]. doi:10.1016/j.bbrc.2006.05.074
To investigate visible and near-infrared (Vis-NIR) spectroscopy enabling CFS diagnosis, we subjected sera from CFS patients (CDC criteria ’94) as well as healthy donors to Vis-NIR spectroscopy.
Vis-NIR spectra in the 600-1100nm region for sera from 77 CFS patients and 71 healthy donors were subjected to principal component analysis (PCA) and soft independent modeling of class analogy (SIMCA) to develop multivariate models to discriminate between CFS patients and healthy donors. The model was further assessed by the prediction of 99 masked other determinations (54 in the healthy group and 45 in the CFS patient group).
The PCA model predicted successful discrimination of the masked samples. The SIMCA model predicted 54 of 54 (100%) healthy donors and 42 of 45 (93.3%) CFS patients of Vis-NIR spectra from masked serum samples correctly. These results suggest that Vis-NIR spectroscopy for sera combined with chemometrics analysis could provide a promising tool to objectively diagnose CFS.
Schonfeldt-Lecuona, C., Connemann, BJ., Wolf, RC., Braun, M and Freudenmann, RW. Bupropion augmentation in the treatment of chronic fatigue syndrome with coexistent major depression episode. Pharmacopsychiatry, 2006, 39, 4, 152-154.
While psychoeducational strategies and general support are always indicated for the treatment of CFS, pharmacological strategies are yet not well established. Antidepressants such as selective serotonin re-uptake inhibitors have been shown to influence positively symptoms and immunological parameters. However, a considerable part of CFS patients do not satisfactorily respond to them. Bupropion, a centrally acting catecholamine-transporter blocker without classic psycho-analeptic properties, shows theoretical potential to improve fatigue symptoms. In the reported case paroxetine was augmented with bupropion at high dosage, a strategy which consecutively led to a rapid relief of CFS-symptoms.
Smith, WR., Noonan, C and Buchwald, D. Mortality in a cohort of chronically fatigued patients. Psychological Medicine, 2006, 36, 9, 1301-1306.
Comprehensive studies of mortality among patients with chronic fatigue (CF) and CFS have not been published, but several sources suggest that CFS is associated with an elevated risk for suicide.
Data on 1201 chronically fatigued patients followed in a university-affiliated tertiary-care clinic for up to 14 years were submitted to the Center for Disease Control and Prevention (CDC) National Death Index (NDI) to evaluate all-cause and suicide-caused death rates against standardized mortality rates (SMRs). We used Life Table Analysis to examine the influence of sex and diagnoses of CFS and depression.
All-cause mortality in chronically fatigued patients was no higher than expected, but suicide-caused death rates were more than eight times higher than in the US general population. The significant elevation in the SMR of suicide was restricted to those who did not meet criteria for CFS. Among chronically fatigued patients who did not meet CFS criteria, those with a lifetime history of major depression (MD) had higher suicide-caused death rates than among their non-depressed counterparts although the difference was not significant.
CFS does not appear to be associated with increased all-cause mortality or suicide rates. Clinicians, however, should carefully evaluate patients with CF for depression and suicidality.
Underhill, RA and O'Gorman, RL. Prevalence of chronic fatigue syndrome and chronic fatigue within families of CFS patients. Journal of Chronic Fatigue Syndrome, 2006, 13, 1, 3-13.
The prevalence of CFS and chronic fatigue were investigated in family members of CFS patients using a questionnaire-based study.
Significant differences were seen between the prevalence of CFS in all groups of family members relative to the published community prevalence of 0.422%, (spouses/partners: 3.2%, p<0.001; offspring: 5.1%, p<.001; parents and siblings: 1.1%, p<0.02; second and third degree blood relatives 0.8%, p<0.02.)
The prevalence of CFS was higher in genetically unrelated household contacts and in non-resident genetic relatives than in the community, indicating that both household contact and genetic relationship are risk factors for CFS.
Van de Putte, EM., van Doornen, LJP., Engelbert, RHH., Kuis, W., Kimpen, JLL and Uiterwaal, CSPM. Mirrored symptoms in mother and child with chronic fatigue syndrome. Pediatrics, 2006, 117, 6, 2074-2079.
Our aim with this study was to assess the relation between CFS in adolescents and fatigue and associated symptoms in their fathers and mothers, more specifically the presence of CFS-like symptoms and psychologic distress.
In this cross-sectional study, 40 adolescents with CFS (36 with all CDC criteria ’94, 6 with less than four symptoms) were compared with 36 healthy control subjects and their respective parents. Questionnaires regarding fatigue (Checklist Individual Strength), fatigue-associated symptoms, and psychopathology (Symptom Checklist-90) were applied to the children and their parents.
Psychologic distress in the mother corresponds with an adjusted odds ratio of 5.6 for the presence of CFS in the child. The presence of fatigue in the mother and dimensional assessment of fatigue with the Checklist Individual Strength revealed odds ratios of, respectively, 5.29 and 2.86 for the presence of CFS in the child. An increase of 1 SD of the hours spent by the working mother outside the home reduced the risk for CFS in their child with 61%. The fathers did not show any risk indicator for CFS in their child.
Mothers of adolescents with CFS exhibit fatigue and psychologic symptoms similar to their child in contrast with the fathers. The striking difference between the absent association in fathers and the evident association in mothers suggests that the shared symptom complex of mother and child is the result of an interplay between genetic vulnerability and environmental factors.
Van de Putte, EM., Engelbert, RH., Kuis, W., Kimpen, JL and Uiterwaal, CSPM. How fatigue is related to other somatic symptoms. Archives of Disease in Childhood, 2006 Jun 5; [Epub ahead of print]. doi:10.1136/adc.2006.094623
In this study we assessed the relation between fatigue and somatic symptoms in healthy adolescents and adolescents with CFS/Myalgic Encephalopathy (CFS/ME).
72 adolescents with CFS (66 CDC criteria ’94, 6 did not meet all criteria) were compared within a cross-sectional study design with 167 healthy controls. Fatigue and somatic complaints were measured using self-report questionnaires, respectively the subscale subjective fatigue of the Checklist Individual Strength (CIS-20) and the Children's Somatization Inventory.
Healthy adolescents reported the same somatic symptoms as adolescents with CFS/ME, but with a lower score of severity. The top 10 of somatic complaints were the same: low energy, headache, heaviness in arms/legs, dizziness, sore muscles, hot/cold spells, weakness in body parts, pain in joints, nausea/upset stomach, back pain. There was a clear positive relation between log somatic symptoms and fatigue (linear regression coefficient: 0.041 points log somatic complaints per score point fatigue (95% Confidence Interval 0.033; 0.049, p<0.001) which did not depend on disease status (interaction between CFS/ME and fatigue: p= 0.847).
Our findings suggest a continuum with a gradual transition from fatigue with associated symptoms in healthy adolescents to the symptom complex of CFS/ME.
[Ed. note: The researchers did not assess important symptoms such as post-exertional fatigue and tender lymph nodes, and these may well have differentiated the patients from healthy controls.]
Leone, SS., Huibers, MJH., Kant, I., Van Schayck, CP., Belijenberg, G and Knottnerus, JA. Long-term predictors of outcome in fatigued employees on sick leave: a 4-year follow-up study. Psychological Medicine, 2006 Jun 6; 1-8 [Epub ahead of print] doi:10.1017/S0033291706008099
Persistent fatigue is strongly associated with functional status and can lead to absenteeism and work disability. Despite several prognostic studies on chronic fatigue, little attention has been paid to occupational outcomes.
A total of 127 fatigued employees on sick leave were followed-up after 4 years to determine long-term predictors of work disability, fatigue caseness and CFS-like caseness (CDC criteria ’94 but no medical assessment to confirm CFS). Measures included fatigue, physical functioning, illness attributions, psychological problems and emotional exhaustion.
Thirty-three participants (26%) were receiving work disability benefits at the 4-year follow-up. Older age and lower levels of physical functioning predicted work disability. Weaker psychological attributions and lower levels of physical functioning were predictors of fatigue caseness. CFS-like caseness was predicted by female gender and lower levels of physical functioning. Self-reported physical functioning remained a strong and statistically significant determinant of work disability [odds ratio (OR) 0.45, 95% confidence interval (CI) 0.24-0.87] and CFS-like caseness (OR 0.20, 95% CI 0.09-0.43) after controlling for confounders. Not having psychological attributions was associated with fatigue caseness but not with CFS-like caseness.
This study suggests that physical functioning plays an important role in the persistence of fatigue complaints and work disability in employees on sick leave. The course of fatigue is a complex process, and exploring temporal relationships between fatigue, functional status and work status in future research could provide valuable information for the improvement of fatigue management.
E. Goudsmit. AFBPsS.
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