Efficacy of cognitive behavioral therapy for chronic fatigue syndrome: a meta-analysis

A meta-analysis of the efficacy of cognitive behavioral therapy (CBT) in treating chronic fatigue included 15 effect sizes for between-group outcome comparisons. Across analyses, which included a total of 1371 participants, there was a significant difference, d=0.48, in post-treatment fatigue between participants receiving CBT and those in control conditions. Results indicate that CBT for chronic fatigue syndrome tends to be moderately efficacious. Dropout rates in CBT varied from 0-42%, with a mean of 16%. In the five studies that reported the number of CBT clients who were no longer in the clinical range with regard to fatigue at the latest follow-up, the percentage varied from 33% to 73% of those assigned to CBT, with a mean of 50%. Moderator results suggest directions for future investigations.     

Immunoglobulin subclass levels in chronic fatigue syndrome

The levels of immunoglobulin subclasses were determined for 46 patients meeting the original Centers for Disease Control case definition of chronic fatigue syndrome and were compared to values obtained for 50 age- and gender-matched healthy volunteer blood donor controls. The levels of immunoglobulin subclasses in these groups were further compared to a third group of additional chronic fatigue syndrome cases from whom samples had been obtained and frozen prospectively over a period of 7 years. These data do not demonstrate significant immunoglobulin subclass deficiencies in patients with chronic fatigue syndrome.     

The prognosis after multidisciplinary treatment for patients with postinfectious chronic fatigue syndrome and noninfectious chronic fatigue syndrome

The prognosis after multidisciplinary treatment for patients with postinfectious chronic fatigue syndrome (CFS, n = 9) and noninfectious CFS (n = 9) was clarified. After treatment, natural killer (NK) cell activity increased in the postinfectious CFS group but did not recover to within normal range in the noninfectious CFS group. In the postinfectious CFS group, physical and mental symptoms improved, and 8 patients returned to work. In the noninfectious CFS group, symptoms did not improve, and only 3 patients returned to work. The prognosis of postinfectious CFS group was better than that of noninfectious CFS group. Classification of CFS patients into postinfectious and noninfectious groups is useful for choosing the appropriate treatment in order to obtain better prognosis.     

Paradoxical response to intravenous immunoglobulin in a case of Parvovirus B19-associated chronic fatigue syndrome

We describe a case of chronic fatigue syndrome (CFS) associated to Parvovirus B19 infection where administration of intravenous immunoglobulins (IVIG), previously reported as effective, induced a paradoxical clinical response and increased viral replication. The indication of IVIG administration in the treatment of Parvovirus B19-associated CFS should be carefully reconsidered.     

Specific correlations between muscle oxidative stress and chronic fatigue syndrome: a working hypothesis

Chronic fatigue syndrome (CFS) is a relatively common disorder defined as a status of severe persistent disabling fatigue and subjective unwellness. While the biological basis of the pathology of this disease has recently been confirmed, its pathophysiology remains to be elucidated. Moreover, since the causes of CFS have not been identified, treatment programs are directed at symptom relief, with the ultimate goal of the patient regaining some level of pre-existing function and well-being. Several studies have examined whether CFS is associated with: (i) a range of infectious agents and or immune disturbance; (ii) specific changes of activity in the central or peripheral nervous systems; and (iii) elevated stress periods, which may be associated with the pathology via genetic mechanisms. The role of oxidative stress in CFS is an emerging focus of research due to evidence of its association with some pathological features of this syndrome. New data collectively support the presence of specific critical points in the muscle that are affected by free radicals and in view of these considerations, the possible role of skeletal muscle oxidative imbalance in the genesis of CFS is discussed.     

Frequent IgG subclass and mannose binding lectin deficiency in patients with chronic fatigue syndrome

Chronic fatigue syndrome (CFS) is a severe disease characterized by various symptoms of immune dysfunction. CFS onset is typically with an infection and many patients suffer from frequently recurrent viral or bacterial infections. Immunoglobulin and mannose binding lectin (MBL) deficiency are frequent causes for increased susceptibility to infections. In this study we retrospectively analysed 300 patients with CFS for immunoglobulin and MBL levels, and B-cell subset frequencies. 25% of the CFS patients had decreased serum levels of at least one antibody class or subclass with IgG₃ and IgG₄ subclass deficiencies as most common phenotypes. However, we found elevated immunoglobulin levels with an excess of IgM and IgG₂ in particular in another 25% of patients. No major alteration in numbers of B cells and B-cell subsets was seen. Deficiency of MBL was found in 15% of the CFS patients in contrast to 6% in a historical control group. In a 2nd cohort of 168 patients similar frequencies of IgG subclass and MBL deficiency were found. Thus, humoral immune defects are frequent in CFS patients and are associated with infections of the respiratory tract.     

Viral serologies in patients with chronic fatigue and chronic fatigue syndrome

Chronic fatigue syndrome (CFS) is an illness characterized by disabling fatigue associated with complaints of fevers, sore throat, myalgia, lymphadenopathy, sleep disturbances, neurocognitive difficulties, and depression. A striking feature of CFS is its sudden onset following an acute, presumably viral, illness and the subsequent recurrent “flu-like” symptoms. It has been speculated that both CFS and debilitating chronic fatigue (CF) that does not meet strict criteria for CFS may be the direct or indirect result of viral infections. We therefore tested 548 chronically fatigued patients who underwent a comprehensive medical and psychiatric evaluation for antibodies to 13 viruses. Our objectives were to compare the seroprevalence and/or geometric mean titer (GMT) of antibodies to herpes simplex virus 1 and 2, rubella, adenovirus, human herpesvirus 6, Epstein-Barr virus, cytomegalovirus, and Coxsackie B virus, types 1–6 in patients with CF to healthy control subjects. Other goals were to determine if greater rates of seropositivity or higher GMTs occurred among subsets of patients with CFS, fibromyalgia, psychiatric disorders, a self-reported illness onset with a viral syndrome, and a documented temperature >37°C on physical examination. Differences in the seroprevalence or GMTs of antibodies to 13 viruses were not consistently found in those with CF compared with control subjects, or in any subsets of patients including those with CFS, an acute onset of illness, or a documented fever. These particular viral serologies were not useful in evaluating patients presenting with CF. © 1996 Wiley-Liss, Inc.     

Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome

Chronic fatigue syndrome (CFS) patients often report symptom flare (SF) for >24 h after moderate exercise (post‐ex). We hypothesized that SF is linked to increases in circulating cytokines and CD40 Ligand (CD40L). In 19 CFS patients and 17 controls, mental and physical fatigue and pain symptom ratings were obtained together with serum for 11 cytokines and CD40L before and at 0.5, 8, 24, and 48 h post‐ex. Before exercise, CFS had lower CD40L (p<.05) but similar cytokines versus controls. In subgroups based on SF at 48 h, high SF patients (n=11) increased in IL‐1β, IL‐12, IL‐6, IL‐8, IL‐10, and IL‐13 (p<.05) 8 h post‐ex. Low SF patients (n=8) showed post‐ex decreases in IL‐10, IL‐13, and CD40L, and controls decreased in IL‐10, CD40L, and TNFα (p<.05). Thus, in CFS, cytokine activity may vary directly with SF, which may explain prior inconsistent findings.     

Longitudinal change in chronic fatigue syndrome: what home-based assessments reveal

The purpose of this 2-year prospective study was to compare standard self-report and ecologically-based outcome measures in patients with chronic fatigue syndrome (CFS). Standard measures assessed physical function, fatigue impact, psychological variables, and global impression of change ratings. Ecological measures included actigraphy, a structured activity record, and an electronic fatigue/energy diary. Results for this high functioning sample (N = 75) revealed that self-report global improvement was significantly associated with lower momentary fatigue and fatigue impact, and a higher frequency of standing up (at home), but not with actigraphy or psychological variables. However, actigraphy change was significantly correlated with change in self-report physical function. At follow-up, only a small minority (<20%) scored in the healthy adult range for fatigue impact and physical function. The findings suggest that home-based measures of symptom severity and physical functioning may provide evidence of change (or lack of change) that is important for interpreting standard self-report outcomes in CFS.     

A real-time assessment of the effect of exercise in chronic fatigue syndrome

Patients with chronic fatigue syndrome (CFS) report substantial symptom worsening after exercise. However, the time course over which this develops has not been explored. Therefore, the objective of this study was to investigate the influence of exercise on subjective symptoms and on cognitive function in CFS patients in natural settings using a computerized ecological momentary assessment method, which allowed us to track the effects of exercise within and across days. Subjects were 9 female patients with CFS and 9 healthy women. A watch-type computer was used to collect real-time data on physical and psychological symptoms and cognitive function for 1week before and 2weeks after a maximal exercise test. For each variable, we investigated temporal changes after exercise using multilevel modeling. Following exercise, physical symptoms did get worse but not until a five-day delay in CFS patients. Despite this, there was no difference in the temporal pattern of changes in psychological symptoms or in cognitive function after exercise between CFS patients and controls. In conclusion, physical symptoms worsened after several days delay in patients with CFS following exercise while psychological symptoms or cognitive function did not change after exercise.     

Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome

Recent evidence suggests immune and inflammatory alterations are important in chronic fatigue syndrome (CFS). This study was done to explore the association of functionally important genetic variants in inflammation and immune pathways with CFS. Peripheral blood DNA was isolated from 50 CFS and 121 non-fatigued (NF) control participants in a population-based study. Genotyping was performed with the Affymetrix Immune and Inflammation Chip that covers 11 K single nucleotide polymorphisms (SNPs) following the manufacturer’s protocol. Genotyping accuracy for specific genes was validated by pyrosequencing. Golden Helix SVS software was used for genetic analysis. SNP functional annotation was done using SPOT and GenomePipe programs. CFS was associated with 32 functionally important SNPs: 11 missense variants, 4 synonymous variants, 11 untranslated regulatory region (UTR) variants and 6 intronic variants. Some of these SNPs were in genes within pathways related to complement cascade (SERPINA5, CFB, CFH, MASP1 and C6), chemokines (CXCL16, CCR4, CCL27), cytokine signaling (IL18, IL17B, IL2RB), and toll-like receptor signaling (TIRAP, IRAK4). Of particular interest is association of CFS with two missense variants in genes of complement activation, rs4151667 (L9H) in CFB and rs1061170 (Y402H) in CFH. A 5′ UTR polymorphism (rs11214105) in IL18 also associated with physical fatigue, body pain and score for CFS case defining symptoms. This study identified new associations of CFS with genetic variants in pathways including complement activation providing additional support for altered innate immune response in CFS. Additional studies are needed to validate the findings of this exploratory study.     

Personality and chronic fatigue syndrome: methodological and conceptual issues

Among clinical psychologists, consulting physicians, scientific researchers and society in general an image has emerged of patients with chronic fatigue syndrome (CFS) as perfectionist, conscientious, hardworking, somewhat neurotic and introverted individuals with high personal standards, a great desire to be socially accepted and with a history of continuously pushing themselves past their limits. The aim of this article is to (a) give a concise review of the main recent studies on personality and CFS, (b) address the major methodological problems in the study of personality in CFS and (c) discuss some of the conceptual assumptions that seem to limit the research on personality and CFS. The results of the reviewed studies range from no evidence of major differences between the personalities of patients with CFS and controls, to evidence of severe psychopathology and personality disorder in patients with CFS. Although personality seems to play a role in CFS, it is difficult to draw general conclusions on the relation between personality and CFS. It is argued that this is partially due to the diversity and heterogeneity in study methods, patient populations, control groups and CFS case definitions. Personality should be regarded as an important factor to be studied in CFS. However, additional studies are needed, not focusing exclusively on personality disorder, or personality considered on a general trait level. In recent developments in personality research, the continually evolving life narrative that makes sense of, and gives direction to, an individual's life is also regarded as an important aspect of personality. New insights into personality and CFS might be gained by systematically studying the self-narratives of patients with the syndrome.     

Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome

Post-exertional exacerbation of symptoms is one of the major characteristics of chronic fatigue syndrome (CFS). In this study, we evaluated the hypothesis that disturbances in circadian chronobiological regulation may play a role in generating this phenomenon. We recorded physical activity for 6-day periods in 16 women (10 CFS and 6 sedentary healthy controls, CON) before and after performing a maximal treadmill test. We calculated activity rhythms by computing autocorrelation coefficients by cutting 1 day apart from the data as a template and sliding it sequentially through each of the other days; all of 6 days were used as the templates. The peak value of autocorrelation coefficient (R) and the time between peak R's (circadian period, CP) were calculated. CFS patients had a lengthening (P < .05) of mean circadian period (MCP) that was longer than 24 h (P < .05), while MCP in CON remained unchanged. No difference was found in the standard error of each subject's MCP (circadian period variability, CPV) before and after exercise for both groups. We interpret this increase in circadian rest-activity period seen in CFS patients following exercise to indicate that exhaustive exercise interferes with normal entrainment to 24-h zeitgeber(s). This effect may be associated in part with the common patient complaint of symptom worsening following exertion.     

Lymphocyte phenotype and function in the chronic fatigue syndrome

Lymphocytes of 18 patients meeting the Centers for Disease Control (CDC) case definition for the chronic fatigue syndrome (CFS), 10 similar, chronically fatigued patients not fully conforming to the CDC case definition, and 17 matched, healthy individuals were studied to determine the presence of abnormalities of peripheral cell phenotype and function. Extensive phenotypic analyses of B- and T-cell subsets, natural killer (NK) cells, and macrophages were performed using single-, dual-, and three-color flow cytometry. Compared to controls, in CFS patients the percentage of CD4 T cells and CD4, CD45RA, or naive T cells, was reduced. The CD4, CD45RO, or memory T-cell, subset was numerically normal but expressed increased levels of adhesion markers (CD29, CD54, and CD58). CFS patient lymphocytes showed reduced proliferative responses to phytohemagglutinin, concanavalin A, and staphylococcal enterotoxin B. Lymphocytes from fatigue patients not meeting the CDC definition showed similar abnormalities. These data indicate that peripheral T cells manifest an increased state of differentiation in CFS and related conditions. This may arise as a consequence of an underlying neuropsychiatric and/or neuroendocrine disorder or because of exposure to antigens or superantigens of an infectious agent.     

Norepinephrine and epinephrine responses to physiological and pharmacological stimulation in chronic fatigue syndrome

Chronic fatigue syndrome (CFS) is characterized by fatigue lasting 6 months or longer. CFS has been associated with a disturbed (re-)activity of the autonomic nervous system. However, the sympathetic adrenomedulla (SAM) remains under-examined in CFS. To investigate SAM reactivity, we implemented a submaximal cycle ergometry (ERGO) and a pharmacological test (Insulin Tolerance Test, ITT) in 21 CFS patients and 20 age-, sex-, and BMI-matched controls. Plasma norepinephrine and epinephrine were collected once before and twice after the tests (+10/+20, and +30 min). Lower baseline levels and attenuated responses of epinephrine to the ERGO were found in CFS patients compared to controls, while the groups did not differ in their responses to the ITT. To conclude, we found evidence of altered sympathetic-neural and SAM reactivity in CFS. Exercise stress revealed a subtle catecholaminergic hyporeactivity in CFS patients. It is conceivable that inadequate catecholaminergic responses to physical exertion might contribute to CFS symptoms.     

A review and meta-synthesis of qualitative studies on myalgic encephalomyelitis/chronic fatigue syndrome

Objective

To review and synthesize findings across qualitative studies on Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Methods

Articles were systematically reviewed and analyzed within a meta-analytic framework. Analyses included a multi-perspective examination of ME/CFS, as well as a comparative analysis of ME/CFS versus other chronic conditions.

Results

Thirty-four qualitative studies on ME/CFS were included. Findings include three substantive thematic areas that focus on: (1) experiences of people with ME/CFS, (2) experiences of physicians, and (3) themes that intersect both of these groups. For patients, illness development influenced identity, reductions in functioning, and coping. Physician-specific themes described lack of awareness about ME/CFS and recommended improvement in educational resources. Intersecting themes expressed issues with diagnosis creating tensions and fueling the stigmatization of ME/CFS.

Conclusions

Findings indicate multilayered, context-specific experiences and ways in which both people with ME/CFS, as well as those involved in their lives (e.g., family or the medical community), interpret this illness. Future qualitative studies should recognize the various facets of the ME/CFS experience, the network members of people with ME/CFS, and the sociocultural environment through which the illness is understood.

Practice implications

Health care professionals can gain unique insight from patient experiences, allowing for more accurate diagnoses and treatment recommendations.     

Sympathetic cardiovascular control during orthostatic stress and isometric exercise in adolescent chronic fatigue syndrome

The chronic fatigue syndrome (CFS) has been shown to be associated with orthostatic intolerance and cardiovascular dysregulation. We investigated the cardiovascular responses to combined orthostatic stress and isometric exercise in adolescents with CFS. We included a consecutive sample of 15 adolescents 12–18 years old with CFS diagnosed according to a thorough and standardized set of investigations, and a volunteer sample of 56 healthy control subjects of equal sex and age distribution. Heart rate, systolic, mean and diastolic blood pressure, stroke index, and total peripheral resistance index were non-invasively recorded during lower body negative pressure (LBNP) combined with two consecutive periods of handgrip. In addition, we measured baseline plasma catecholamines, and recorded symptoms. At rest, CFS patients had higher heart rate, diastolic blood pressure, plasma norepinephrine (P < 0.01), mean blood pressure and plasma epinephrine (P < 0.05) than controls. During LBNP, CFS patients had a greater increase in heart rate, diastolic blood pressure, mean blood pressure (P < 0.05) and total peripheral resistance index (n.s.) than controls. During handgrip, CFS patients had a smaller increase in heart rate, diastolic blood pressure (P < 0.05), mean blood pressure and total peripheral resistance index (n.s.) than controls. Our results indicate that adolescents with CFS have increased sympathetic activity at rest with exaggerated cardiovascular response to orthostatic stress, but attenuated cardiovascular response when performing isometric exercise during orthostatic stress. This suggests that CFS might be causally related to sympathetic dysfunction.     

Psychosocial characteristics and immunological functions in patients with postinfectious chronic fatigue syndrome and noninfectious chronic fatigue syndrome

Differences between patients with postinfectious chronic fatigue syndrome (CFS, n = 16) and noninfectious CFS (n = 20) were clarified. The noninfectious CFS group had problems in family and developmental history, and had chronic stresses. Members of the postinfectious CFS group were social extroverts while those in the noninfectious CFS group was neurotic and introspective. Natural killer cell activity was suppressed in both groups. These findings suggest that the postinfectious CFS group and the noninfectious CFS group differed in their pathogenesis until the onset of CFS. The latter group should be considered as a variant of psychiatric disorder and treated accordingly.     

Chronic fatigue syndrome impairs circadian rhythm of activity level

Some of the symptoms of chronic fatigue syndrome (CFS) are the same as for disrupted circadian rhythm. Activity level is frequently used to study circadian rhythm. Continuous waist activity measurements taken every minute 24 h/day for from 5 to 7 days in 10 controls and from 2 to 7 days in 8 patients with CFS yielded two primary findings: (a) lower daytime activity and (b) less regular activity-rest cycles in persons with CFS than in controls.