The Case Definition of Chronic Fatigue Syndrome

The 1994 case definition of chronic fatigue syndrome is widely used not only for diagnosis but also for clinical and laboratory-based observations of this clinical entity. The criteria for the 1994 case definition are based primarily on symptoms and not on physical signs or chemical or immunological tests. This situation has resulted in conflicting clinical and laboratory observations that in all likelihood is due to different populations of patients being studied in different centers. Based on some of the recent publications, there appears to be an emerging picture of this disease entity that we propose could be used to subgroup chronic fatigue syndrome into four different subclasses. These subclasses would consist of chronic fatigue with primarily nervous system disorders such as impaired memory or concentration and headache, chronic fatigue with primarily endocrine system disorders such as unrefreshing sleep and postexertional malaise, chronic fatigue with musculoskeletal system disorders such as muscle pain and joint pain, and chronic fatigue with immune system/infectious disorders such as sore throat and tender lymph nodes. It is suggested that if clinical and laboratory-based studies on chronic fatigue syndrome were conducted on more homogeneous subgroups of patients, the data from one center to the other might not be as conflicting and more insights can be shed on the nature of this clinical condition.     

慢性疲劳综合征的中医研究

通过对近年来有关慢性疲劳综合征文献的回顾,对慢性疲劳综合征的中医病名、病因病机等方面进行了综述。同时笔者主要从中医整体观念、辨证论治角度出发阐述慢性疲劳综合征近十年病因病机及中医药治疗进展,提出中医药治疗优势,综述中医药治疗慢性疲劳综合征的新路,以期为临床治疗慢性疲劳综合征提供思路。     

Acute Phase Responses and Cytokine Secretion in Chronic Fatigue Syndrome

This study addresses the hypothesis that clinical manifestations of chronic fatigue syndrome (CFS) are due in part to abnormal production of or sensitivity to cytokines such as interleukin-1 (IL-1) and IL-6 under basal conditions or in response to a particular physical stress: 15 min of exercise consisting of stepping up and down on a platform adjusted to the height of the patella. The study involved 10 CFS patients and 11 age-, sex-, and activity-matched controls: of these, 6 patients and 4 controls were tested in both the follicular and the luteal phases of the menstrual cycle, and the remainder were tested in only one phase, for a total of 31 experimental sessions. Prior to exercise, plasma concentrations of the acute phase reactant ₂-macroglobulin were 29% higher in CFS patients (P < 0.008) compared to controls. Secretion of IL-6 was generally higher for CFS patients (~38%), however, this difference was statistically significant only if all values over a 3-day period were analyzed by repeated-measures ANOVA (P = 0.035). IL-6 secretion correlated with plasma ₂-macroglobulin in control subjects at rest (R = 0.767, P = 0.001). Immediately after exercise, the CFS patients reported greater ratings of perceived exertion (P=0.027) compared to the healthy control subjects. Ratings of perceived exertion correlated with IL-1 secretion by cells from healthy control subjects (R = 0.603, P = 0.022), but not from CFS patients, and IL-1 secretion was not different between groups. Exercise induced a slight (<12%) but significant (P = 0.006) increase in IL-6 secretion, but the responses of the CFS patients were not different than controls. Furthermore, no significant exercise-induced changes in body temperature or plasma ₂-macroglobulin were observed. These data indicate that under basal conditions, CFS is associated with increased IL-6 secretion which is manifested by chronically elevated plasma ₂-macroglobulin concentrations. These modest differences suggest that cytokine dysregulation is not a singular or dominant factor in the pathogenesis of CFS.     

Sleep Quality and Psychological Adjustment in Chronic Fatigue Syndrome

Without specific etiology or effective treatment, chronic fatigue syndrome (CFS) remains a contentious diagnosis. Individuals with CFS complain of fatigue and poor sleep—symptoms that are often attributed to psychological disturbance. To assess the nature and prevalence of sleep disturbance in CFS and to investigate the widely presumed presence of psychological maladjustment we examined sleep quality, sleep disorders, physical health, daytime sleepiness, fatigue, and psychological adjustment in three samples: individuals with CFS; a healthy control group; and individuals with a definite medical diagnosis: narcolepsy. Outcome measures included physiological evaluation (polysomnography), medical diagnosis, structured interview, and self-report measures. Results indicate that the CFS sample had a very high incidence (58%) of previously undiagnosed primary sleep disorder such as sleep apnea/hypopnea syndrome and restless legs/periodic limb movement disorder. They also had very high rates of self-reported insomnia and nonrestorative sleep. Narcolepsy and CFS participants were very similar on psychological adjustment: both these groups had more psychological maladjustment than did control group participants. Our data suggest that primary sleep disorders in individuals with CFS are underdiagnosed in primary care settings and that the psychological disturbances seen in CFS may well be the result of living with a chronic illness that is poorly recognized or understood.     

Patient Outcomes in Association With Significant Other Responses to Chronic Fatigue Syndrome: A Systematic Review of the Literature

Social processes have been suggested as important in the maintenance of chronic fatigue syndrome (also known as myalgic encephalomyelitis; CFS/ME), but the specific role of close interpersonal relationships remains unclear. We reviewed 14 articles investigating significant other responses to close others with CFS/ME and the relationships between these responses and patient outcomes. Significant other beliefs attributing patient responsibility for the onset and ongoing symptoms of CFS/ME were associated with increased patient distress. Increased symptom severity, disability, and distress were also associated with both solicitous and negative significant other responses. Specific aspects of dyadic relationship quality, including high Expressed Emotion, were identified as important. We propose extending current theoretical models of CFS/ME to include two potential perpetuating interpersonal processes; the evidence reviewed suggests that the development of significant other–focused interventions may also be beneficial.     

慢性疲劳综合征在大学生群体中患病情况的调查分析

目的 首次评价和分析大学生群体慢性疲劳综合征(CFS)患病情况.方法 对289名医学院校大学生集中进行CFS调查.结果 大学生中不同程度疲劳感的人有227人,占被调查者的78.5％;符合CFS诊断标准的占5.4％;最常见的3个症状是:“注意力难以集中”(占被调查总体的83.3％),“记忆力下降”(占65.2％),“睡眠...     

从脾肾阳虚论治慢性疲劳综合征

慢性疲劳综合征的发生与脾有密切的关系。慢性疲劳综合征与中医对眩晕、脏躁症、虚损等的辨证治疗相似,其病因可归纳为外感时邪、饮食失常、劳累过度,导致脏腑阴阳气血功能失调。所以,临床从脾主运化,脾胃升清降浊等机理方面研究,把慢性疲劳综合症辨证为脾虚气陷、肝脾不调、脾虚湿阻,并分别进行论治。     

Immunogenetic Background of Patients with Autoimmune Fatigue Syndrome

We have previously reported that approximately 50% of children with chronic nonspecific complaints were positive for antinuclear antibodies (ANA), and that a novel autoantibody to a 62kD protein (anti-Sa) was found in 40% of these ANA-positive patients. Therefore, we proposed a distinct disease entity termed autoimmune fatigue syndrome (AIFS). We hypothesized that if autoimmune mechanisms did play an important role in the pathogenesis of AIFS, it is possible that it is immunogenetically regulated as observed in other autoimmune disorders. In order to examine the immunogenetic background of AIFS patients, HLA-A, -B, -C, and -DR loci were analyzed serologically in 61 AIFS patients. AIFS was found to be positively associated with the class I antigen HLA-B61 and with the class II antigen HLA-DR9, with odds ratios of 2.77 (p = 0.015, P_corr = 0.48) and 2.60 (p= 0.012, P_corr = 0.17), respectively. A negative association was also found between AIFS and HLA-DR2 with odds ratio of 0.25 (p = 0.029, P_corr = 0.041). When comparing anti-Sa positive AIFS patients with healthy controls, the odds ratios associated with HLA-B61, DR9, and DR2 were 3.42 (p = 0.021, P_corr = 0.22), 3.96 (p = 0.0011, P_corr= 0.015), and 0.16 (p = 0.0022, P_corr= 0.031), respectively. Thus, the HLA associations observed in this study suggested that immunogenetic background might play a role in AIFS     

Cognitive Behavioral Therapy and Graded Exercise for Chronic Fatigue Syndrome: A Meta‐Analysis

[Clin Psychol Sci Prac 18: 311–324, 2011] Several reviews have concluded that graded exercise therapy (GET) and cognitive behavioral therapy (CBT) may be the most efficacious treatments for chronic fatigue syndrome (CFS). The current review extends the evidence for overall and outcome‐specific effects of CBT and GET by directly comparing the treatments and addressing the methodological limitations of previous reviews. GET (n = 5) and CBT (n = 16) randomized controlled trials were meta‐analyzed. Overall effect sizes suggested that GET (g = 0.28) and CBT (g = 0.33) were equally efficacious. However, CBT effect sizes were lower in primary care settings and for treatments offering fewer hours of contact. The results suggested that both CBT and GET are promising treatments for CFS, although CBT may be a more effective treatment when patients have comorbid anxiety and depressive symptoms.     

Autoimmune Autonomic Dysfunction Syndromes: Potential Involvement and Pathophysiology Related to Complex Regional Pain Syndrome,Fibromyalgia, Chronic Fatigue Syndrome,Silicone Breast Implant–Related Symptoms and Post-COVID Syndrome

The pathophysiological mechanisms involved in chronic disorders such as complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant–related symptoms, and post-COVID syndrome have not been clearly defined. The course of the pain in some of the syndromes, the absence of evident tissue damage, and the predominance of alterations in the autonomic nervous system are shared similarities between them. The production of autoantibodies following a trigger in the syndromes was previously described, for instance, trauma in complex regional pain syndrome, infectious agents in fibromyalgia, chronic fatigue syndrome, and post-COVID syndrome, and the immune stimulation by silicone in women with breast implants. In fact, the autoantibodies produced were shown to be directed against the autonomic nervous system receptors, leading to the amplification of the perception of pain alongside various clinical symptoms seen during the clinical course of the syndromes. Therefore, we viewed autoantibodies targeting the autonomic nervous system resulting in autonomic dysfunction as likely the most comprehensive explanation of the pathophysiology of the disorders mentioned. Based on this, we aimed to introduce a new concept uniting complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant–related symptoms, and post-COVID syndrome, namely “autoimmune autonomic dysfunction syndromes”. Due to its etiological, pathophysiological, and clinical implications, the suggested term would be more precise in classifying the syndromes under one title. The new title would doubtlessly facilitate both laboratory and clinical studies aimed to improve diagnosis and make treatment options more directed and precise.     

Immunological Response in Chronic Fatigue Syndrome Following a Graded Exercise Test to Exhaustion

This study was conducted to evaluate the immunological response to an exhaustive treadmill exercise test in 20 female chronic fatigue syndrome patients compared to 14 matched sedentary controls. Venipuncture was performed at baseline and 4 min, 1 hr, and 24 hr postexercise. White blood cells were labeled for monoclonal antibody combinations and were quantified by FACsan. Cytokines were assayed utilizing quantitative RT/PCR. No group difference was seen in (28.6 ± 1.6 vs 30.9 ± 1.2 ml · kg^–1 · min^–1; P > 0.05). However, 24 hr after exercise the patients' fatigue levels were significantly increased (P < 0.05). The counts of WBC, CD3⁺CD8⁺ cells, CD3⁺CD4⁺ cells, T cells, B cells, natural killer cells, and IFN- changed across time (P's < 0.01). No group differences were seen for any of the immune variables at baseline or after exercise (P's > 0.05). The immune response of chronic fatigue syndrome patients to exhaustive exercise is not significantly different from that of healthy nonphysically active controls.     

Chronic Fatigue Exhibits Heterogeneous Autoimmunity Characteristics Which Reflect Etiology

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is considered to be associated with post-viral complications and mental stress, but the role of autoimmunity also remains promising. A comparison of autoimmune profiles in chronic fatigue of different origin may bring insights on the pathogenesis of this disease. Thirty-three patients with CFS/ME were divided into three subgroups. The first group included Herpesviridae carriers (group V), the second group included stress-related causes of chronic fatigue (distress, group D), and the third group included idiopathic CFS/ME (group I). Were evaluated thirty-six neural and visceral autoantigens with the ELISA ELI-test (Biomarker, Russia) and compared to 20 healthy donors, either without any fatigue (group H), or “healthy but tired” (group HTd) with episodes of fatigue related to job burnout not fitting the CFS/ME criteria. β2-glycoprotein-I autoantibodies were increased in CFS/ME patients, but not in healthy participants, that alludes the link between CFS/ME and antiphospholipid syndrome (APS) earlier suspected by Berg et al. (1999). In CFS/ME patients, an increase in levels of autoantibodies towards the non-specific components of tissue debris (double-stranded DNA, collagen) was shown. Both CFS and HTd subgroups had elevated level of autoantibodies against serotonin receptors, glial fibrillary acidic protein and protein S100. Only group V showed an elevation in the autoantibodies towards voltage-gated calcium channels, and only group D had elevated levels of dopamine-, glutamate- and GABA-receptor autoantibodies, as well as NF200-protein autoantibodies. Therefore, increased autoimmune reactions to the multiple neural antigens and to adrenal medullar antigen, but not to other tissue-specific somatic ones were revealed. An increase in autoantibody levels towards some neural and non-tissue-specific antigens strongly correlated with a CFS/ME diagnosis. Autoimmune reactions were described in all subtypes of the clinically significant chronic fatigue. Visceral complaints in CFS/ME patients may be secondary to the neuroendocrine involvement and autoimmune dysautonomia. CFS may be closely interrelated with antiphospholipid syndrome, that requires further study.     

慢性疲劳发生过程中小鼠血清皮质酮的动态变化

目的通过观察小鼠血清皮质酮（corticosterone,CorT）的动态变化,探讨在亚健康状态中慢性疲劳的发生发展机制。方法昆明小鼠120只,完全随机分为10组,分别为：正常对照0、4、9、16、23d组和模型：0、4、9、16、23d组,每组12只。正常组小鼠自由饮食,模型各组小鼠置于水深为0.5cm的塑料盒内18h/d。负7%体重力竭游泳以检测疲劳程度,放射免疫法检测血清CorT含量。结果正常组小鼠在实验过程中体重有上升的趋势但差异无统计学意义（P〉0.05）;游泳时间逐渐下降,从第9天起差异有统计学意义（P〈0.05）;皮质醇无明显变化（P〉0.05）。模型组小鼠随着造模时间的延长体重显著减轻（P〈0.01）;力竭游泳时间显著下降,第4天起差异有统计学意义（P〈0.01）;血清CorT第4天开始升高,第16天达分泌高峰（P〈0.01）,随后逐渐下降,但各时间点与正常对照组比较仍显著升高（P〈0.05）。结论随着小鼠疲劳的加重,血清CorT呈现出先升高后降低的动态变化,提示肾上腺皮质代偿性功能亢进后有功能衰退的趋势,可能是慢性疲劳发生发展及转归机制之一。     

慢性疲劳综合征患者外周血淋巴细胞亚群及CD25^＋调节性T细胞表达的研究

研究慢性疲劳综合征（CFS）患者外周血淋巴细胞亚群及CD25＋调节性T细胞的表达情况。使用流式细胞仪检测84例CFS患者（CFS组）、50例健康体检者（健康对照组）外周血淋巴细胞亚群（T细胞、CD4＋T细胞、CD8＋T细胞、B细胞、NK细胞）及CD25＋调节性T细胞的表达情况。结果显示,CFS组与健康对照组的T细胞、CD8＋T细胞百分率以及CD4＋/CD8＋比值无显著差别（P〉0.05）;而CFS组NK细胞、CD4＋T细胞及CD25＋调节性T细胞百分率显著增高,B细胞百分率显著降低（P〈0.05）。结论：慢性疲劳综合征患者外周血淋巴细胞各亚群比例异常,提示其免疫功能失衡,而CD25＋T调节性细胞可能在该病进程中有重要意义。     

Lower serum zinc in Chronic Fatigue Syndrome (CFS): relationships to immune dysfunctions and relevance for the oxidative stress status in CFS

The present study examines serum zinc concentrations in patients with chronic fatigue syndrome (CFS) versus normal volunteers. Serum zinc levels were determined by means of an atomic absorption method. We found that serum zinc was significantly lower in the CFS patients than in the normal controls. There was a trend toward a significant negative correlation between serum zinc and the severity of CFS and there was a significant and negative correlation between serum zinc and the subjective experience of infection. We found that serum zinc was significantly and negatively correlated to the increase in the alpha2 protein fraction and positively correlated to decreases in the expression of mitogen-induced CD69+ (a T cell activation marker) on CD3+ as well as CD3+CD8+ T cells. These results show that CFS is accompanied by a low serum zinc status and that the latter is related to signs of inflammation and defects in early T cell activation pathways. Since zinc is a strong anti-oxidant, the present results further support the findings that CFS is accompanied by increased oxidative stress. The results of these reports suggest that some patients with CFS should be treated with specific antioxidants, including zinc supplements.     

Influences of Transportation on Health Decision-Making and Self-Management Behaviors among Older Adults with Chronic Conditions

Although transportation has been established as a facilitator/barrier to health self-management, little is known about how the context of transportation shapes health self-management behaviors and decision-making among older adults with chronic conditions. This study interviewed 37 older adults with chronic conditions in Florida to examine their perspectives about how transportation influences their chronic care self-management. The data were systematically analyzed for themes. The thematic findings revealed how transportation intersected with participants' everyday experiences with chronic health self-management, how they evaluated transportation as part of the process of making decisions about health, and how creative problem-solving about transportation became an additional health self-management activity for addressing their complex needs. These findings suggest that the context of transportation goes beyond a basic facilitator/barrier for health and enhance our understanding about how transportation services and policies may be changed to better address the needs of older adults with chronic conditions.     

Fatigue Severity, Attributions, Medical Utilization, and Symptoms in Persons with Chronic Fatigue

This study examined the roles of ethnicity, gender, and socioeconomic status (SES) in predicting fatigue severity, symptoms, medical utilization, and attributions among a sample of individuals with chronic fatigue. Using path analysis, a model was tested and revised. In the new model, gender predicted fatigue, ethnicity predicted attributions, fatigue predicted medical utilization and attributions, and attributions predicted medical utilization. Women reported more fatigue and were more likely to feel that stress and depression were causing their fatigue. Higher-SES participants were more likely to cite stress and overwork as causing their fatigue. Latinos reported more physical symptoms than African Americans and Whites. The implications of these results are discussed.     

Neutrophil apoptosis: impact of granulocyte macrophage colony stimulating factor on cell survival and viability in chronic kidney disease and hemodialysis patients

Introduction

Altered neutrophil apoptosis might be responsible for recurrent bacterial infections encountered in hemodialysis (HD) and chronic kidney disease (CKD) patients. This work was designed to assess the neutrophil apoptotic activity and the impact of implementation of granulocyte macrophage colony stimulating factor (GM-CSF), as a survival factor, on neutrophil apoptosis among these patients.

Material and methods

Twenty-five patients on regular HD along with 34 CKD patients on conservative treatment, as well as 15 healthy controls, were investigated for apoptotic rate via assessment of neutrophil expression of Annexin-V by flow cytometry, before and after 20 h culture in absence and presence of GM-CSF. Neutrophil viability was determined using light microscopy. The preservation of neutrophil activation in these patients was analyzed by flow cytometric CD18 neutrophil expression. Chronic inflammatory state was evaluated by estimating C-reactive protein (CRP) and soluble intercellular adhesion molecule-1 (sICAM-1). Obtained data were statistically analyzed.

Results

Compared to controls, both HD and CKD groups had a significant increase of Annexin-V and CD18 expression and significant decrease in neutrophil viability. Culture of their neutrophils with GM-CSF showed significant decrease of apoptosis accompanied by improvement of neutrophil viability compared to their cultured cells without GM-CSF. These patients also showed significant elevation of CRP and sICAM-1.

Conclusions

Granulocyte macrophage colony stimulating factor demonstrated an evident impact on improving in vitro neutrophil survival and viability in HD and CKD patients. Therefore, this may represent promising preventive and/or therapeutic strategies against infection frequently observed in these patients and causing morbidity and mortality.     

Serological and virological investigation of the role of the herpesviruses EBV,CMV and HHV‐6 in post‐infective fatigue syndrome

Multiple previous studies have sought evidence for ongoing, active infection with, or reactivation of, Herpesviruses in patients with chronic fatigue syndrome (CFS), with conflicting results. This study aimed to clarify this by studying 20 patients enrolled in a well‐characterized model of the onset and evolution of CFS, the prospective cohort of the Dubbo Infection Outcomes Study (DIOS). The patients selected for examination included five CFS patients with primary Epstein–Barr virus (EBV) infection; five CFS patients with acute viral infection not caused by EBV; and 10 matched controls with prompt resolution of primary EBV infection. Serum samples from three timepoints were assayed using a comprehensive range of serological assays for EBV, HHV‐6, and CMV. Viral genomes were assessed using quantitative PCR assays. All patients were seropositive for HHV‐6, and 10 were seropositive for CMV at infection baseline (five patients and five controls). Low titer CMV IgM antibodies were found at infection baseline in two of these cases and three control patients. HHV‐6 IgG antibody titers were highest at infection baseline but did not differ between the CFS cases and the control patients. There were increases in EBV IgG VCA p18, EBNA‐1 IgG, and EA IgG titers over time, but these did not differ between CFS cases and control patients. EBV and HHV6 DNA levels were at control levels in a minority of samples, and CMV was undetectable in all samples. These data do not support the hypothesis of ongoing or reactivated EBV, HHV‐6, or CMV infection in the pathogenesis of CFS. J. Med. Virol. 82:1684–1688, 2010. 2010 Wiley‐Liss, Inc.