review – Page 41 – American ME and CFS Society

Evidence for the presence of immune dysfunction in chronic fatigue syndrome

Chronic fatigue syndrome is a medically unexplained ailment characterized by new onset of fatigue accompanied by rheumatological, infectious, and neuropsychiatric symptoms. Because the ailment often begins suddenly with a flu-like presentation, early pathophysiological ideas as to cause included viral infection and immune activation. When early reports identified putative immunological abnormalities in this illness, it was given the name of chronic fatigue and immune dysfunction syndrome, or CFIDS.

The purpose of this review is to evaluate the immunological literature to determine if strong evidence to support this notion exists. We collected and reviewed 239 published papers, of which only 72 fulfilled a set of criteria for use in this review. For this review, we developed the following criteria: papers had to be published in the peer review literature; patients had to be from a group with substantial fatigue lasting at least 6 months (the vast majority fulfilled either the 1988 or the 1994 case definition of chronic fatigue syndrome [CFS]); papers had to compare CFS patients to healthy controls; and actual data had to be shown with evidence of testing for statistical significance. So, for example, when a paper reported no difference between patients and controls for some immunological variables but actual data were not included, we did not include it. Also, if a report compared patient data to normative values rather than to the study’s own control group, we did not include it.

You can read the rest of this article here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC120010/

Source: Natelson BH, Haghighi MH, Ponzio NM. Evidence for the presence of immune dysfunction in chronic fatigue syndrome. Clin Diagn Lab Immunol. 2002 Jul;9(4):747-52. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC120010/ (Full article)

Review: behavioural interventions show the most promise for chronic fatigue syndrome

Comment on: Interventions for the treatment and management of chronic fatigue syndrome: a systematic review. [JAMA. 2001]

QUESTION: In patients with chronic fatigue syndrome (CFS), what is the effectiveness of evaluated interventions?

Data sources: Published and unpublished studies in any language were identified by searching 19 databases, including Medline, EMBASE/Excerpta Medica, PsycLIT, ERIC, Current Contents, and the Cochrane Library (to 2000); the internet was searched using a meta-search engine; references of retrieved articles were scanned; and individuals and organisations were contacted through a website dedicated to this review and through members of 2 advisory panels.

Study selection: Studies were selected if they were randomised controlled trials (RCTs) or controlled clinical trials of any intervention used in the treatment or management of CFS in adults or children. Studies in which diagnoses were based on another syndrome with criteria similar to CFS, such as myalgic encephalomyelitis, chronic fatigue immune deficiency syndrome, or chronic Epstein-Barr virus infection, were included, but studies of fibromyalgia were not.

Data extraction: Data were extracted on study validity (randomisation and allocation concealment [RCTs], control group appropriateness and adjustment for confounders [controlled studies], baseline comparability of groups, blinding, follow up, drop outs, objectivity of outcome assessment, analysis, sample size, and cointerventions); intervention; diagnostic criteria; duration of follow up; and outcomes (psychological, physical, quality of life and health status, physiological, and resource use).

Main results: 44 studies (n=2801; age range 11–87 y, 71% women) were included (32 studies of adults, 1 of children, and 2 of adults and children; 9 studies did not give age information). 31 different interventions were grouped by type of intervention (behavioural, immunological, pharmacological, supplements, complementary or alternative, and other interventions). 36 studies were RCTs. 18 trials (41%) showed an overall beneficial effect of the intervention (≥1 clinical outcome improved). The results from the RCTs are shown in the table. Cognitive behavioural therapy (CBT) and graded exercise therapy (GET) had beneficial effects. Overall evidence from the other interventions was inconclusive.

Source: Kinsella P. Review: behavioural interventions show the most promise for chronic fatigue syndrome. Evid Based Nurs. 2002 Apr;5(2):46. http://ebn.bmj.com/content/5/2/46.long (Full article)

The case definition of chronic fatigue syndrome

Abstract:

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.

Source: Tan EM, Sugiura K, Gupta S. The case definition of chronic fatigue syndrome. J Clin Immunol. 2002 Jan;22(1):8-12. http://www.ncbi.nlm.nih.gov/pubmed/11958593

Chronic fatigue syndrome: evaluation and treatment

Abstract:

Severe fatigue is a common complaint among patients. Often, the fatigue is transient or can be attributed to a definable organic illness. Some patients present with persistent and disabling fatigue, but show no abnormalities on physical examination or screening laboratory tests. In these cases, the diagnosis of chronic fatigue syndrome (CFS) should be considered. CFS is characterized by debilitating fatigue with associated myalgias, tender lymph nodes, arthralgias, chills, feverish feelings, and postexertional malaise. Diagnosis of CFS is primarily by exclusion with no definitive laboratory test or physical findings. Medical research continues to examine the many possible etiologic agents for CFS (infectious, immunologic, neurologic, and psychiatric), but the answer remains elusive. It is known that CFS is a heterogeneous disorder possibly involving an interaction of biologic systems. Similarities with fibromyalgia exist and concomitant illnesses include irritable bowel syndrome, depression, and headaches. Therefore, treatment of CFS may be variable and should be tailored to each patient. Therapy should include exercise, diet, good sleep hygiene, antidepressants, and other medications, depending on the patient’s presentation.

Comment in:

Differential diagnosis for chronic fatigue syndrome. [Am Fam Physician. 2003]

Chronic fatigue syndrome and depression. [Am Fam Physician. 2002]

Source: Craig T, Kakumanu S. Chronic fatigue syndrome: evaluation and treatment. Am Fam Physician. 2002 Mar 15;65(6):1083-90. http://www.aafp.org/afp/2002/0315/p1083.html (Full article)

Annotation: Chronic Fatigue Syndrome in children and adolescents

Abstract:

BACKGROUND: Over the past two decades Chronic Fatigue Syndrome (CFS) of childhood has gained increasing prominence. A number of clinical reports and case-control studies have examined the nature of the disorder, its associations, response to treatment and outcome.

METHOD: A review of publications on childhood CFS was undertaken and reference to work on adult CFS made. Most studies on childhood CFS have been on markedly affected children attending specialist pediatric clinics and very little is known about the condition as it presents in the community or to general medical services.

RESULTS: The main symptom is fatigue in association with a variety of physical symptoms and with marked and prolonged functional impairment. CFS is commonly reported as being brought on by acute infections. Co-morbid psychiatric (usually mood) disorders are present in at least a half. Personality problems and health attitudes have been described as possible predisposing and maintaining factors. Clinical reports indicate that family work focused on engagement and on a rehabilitation programme (including graded increasing activity and treatment of psychiatric co-morbidity) can help even the more severely impaired children. Recovery may be expected in over two-thirds.

CONCLUSIONS: CFS presents as a distinct, markedly impairing disorder of childhood. In its severe form, it is often associated with mood disorders. Further research into milder forms and into the efficacy of different treatment interventions is specially needed.

Source: Garralda ME1, Rangel L. Annotation: Chronic Fatigue Syndrome in children and adolescents. J Child Psychol Psychiatry. 2002 Feb;43(2):169-76. http://www.ncbi.nlm.nih.gov/pubmed/11902596

Defining and managing chronic fatigue syndrome

Abstract:

Objectives: Objectives of this evidence report are to summarize research evidence regarding the case definitions, prevalence, natural history and therapy of chronic fatigue syndrome (CFS).

Search Strategy: English and non-English citations were identified through July 2000 from four electronic bibliographic databases (MEDLINE, The Cochrane Library, PsycINFO, EMBASE), CFS Internet sites, the Journal of Chronic Fatigue Syndrome, references of pertinent articles, textbooks, and experts. The electronic search was updated through October 2000 using PubMed; experts identified relevant citations up to January 2001.

Selection Criteria: Published and unpublished studies that were conducted after 1980 and that involved adults with CFS were reviewed.

Data Collection and Analysis: Two reviewers (physician, psychometrician, research methodologist, and/or nurse) independently abstracted data from the selected studies. Data were synthesized descriptively, emphasizing the quality and methodologic design of studies. Meta-analyses were not done because of marked heterogeneity of study designs.

Main Results: There are four well-recognized case definitions of CFS, and the Centers for Disease Control and Prevention (CDC) is spearheading the development of a fifth. Definitions, developed primarily by expert knowledge and consensus, have evolved over time. A few comparative research studies support the concept of a condition, characterized by prolonged fatigue and impaired ability to function, which is captured by the case definitions. The superiority of one case definition over another is not well established. The validity of any definition is difficult to establish because there are no clear biologic markers for CFS, and no effective treatments specific only to CFS have been identified.

Findings from surveys show that the prevalence of CFS in community populations is probably less than 1% and in primary care populations less than 3%. The reliability of these estimates is limited, because surveys used different case definitions and varied assessment and reporting methods, and sometimes had poor response rates.

Precise estimates of recovery, improvement, and/or relapse from CFS are not possible because there are few natural history studies and those that are available have involved selected referral populations or have used varying case definitions and followup methods.

Source: Mulrow CD, Ramirez G, Cornell JE, Allsup K. Defining and managing chronic fatigue syndrome. Evid Rep Technol Assess (Summ). 2001 Sep;(42):1-4. http://www.ncbi.nlm.nih.gov/books/NBK33797/ (Full article)

Neuroendocrine mechanisms in fibromyalgia-chronic fatigue

Abstract:

Fibromyalgia and chronic fatigue syndrome are poorly understood disorders that share similar demographic and clinical characteristics. Because of the clinical similarities between both disorders it was suggested that they share a common pathophysiological mechanism, namely, central nervous system dysfunction.

This chapter presents data demonstrating neurohormonal abnormalities, abnormal pain processing and autonomic nervous system dysfunction in fibromyalgia and chronic fatigue syndrome. The possible contribution of the central nervous system dysfunction to the development and symptomatology of these conditions is discussed. The chapter concludes by reviewing the effect of current treatments and emerging therapeutic modalities in fibromyalgia and chronic fatigue syndrome.

Source: Buskila D, Press J. Neuroendocrine mechanisms in fibromyalgia-chronic fatigue. Best Pract Res Clin Rheumatol. 2001 Dec;15(5):747-58. http://www.ncbi.nlm.nih.gov/pubmed/11812019

The neuroendocrinology of chronic fatigue syndrome and fibromyalgia

Abstract:

BACKGROUND: Disturbance of the HPA axis may be important in the pathophysiology of chronic fatigue syndrome (CFS) and fibromyalgia. Symptoms may be due to: (1) low circulating cortisol; (2) disturbance of central neurotransmitters; or (3) disturbance of the relationship between cortisol and central neurotransmitter function. Accumulating evidence of the complex relationship between cortisol and 5-HT function, make some form of hypothesis (3) most likely. We review the methodology and results of studies of the HPA and other neuroendocrine axes in CFS.

METHOD: Medline, Embase and Psychlit were searched using the Cochrane Collaboration strategy. A search was also performed on the King’s College CFS database, which includes over 3000 relevant references, and a citation analysis was run on the key paper (Demitrack et al. 1991).

RESULTS: One-third of the studies reporting baseline cortisol found it to be significantly low, usually in one-third of patients. Methodological differences may account for some of the varying results. More consistent is the finding of reduced HPA function, and enhanced 5-HT function on neuroendocrine challenge tests. The opioid system, and arginine vasopressin (AVP) may also be abnormal, though the growth hormone (GH) axis appears to be intact, in CFS.

CONCLUSIONS: The significance of these changes, remains unclear. We have little understanding of how neuroendocrine changes relate to the experience of symptoms, and it is unclear whether these changes are primary, or secondary to behavioural changes in sleep or exercise. Longitudinal studies of populations at risk for CFS will help to resolve these issues.

Source: Parker AJ, Wessely S, Cleare AJ. The neuroendocrinology of chronic fatigue syndrome and fibromyalgia. Psychol Med. 2001 Nov;31(8):1331-45. http://www.ncbi.nlm.nih.gov/pubmed/11722149

Interventions for the treatment and management of chronic fatigue syndrome: a systematic review

Erratum in: JAMA 2002 Mar 20;287(11):1401.

Abstract:

CONTEXT: A variety of interventions have been used in the treatment and management of chronic fatigue syndrome (CFS). Currently, debate exists among health care professionals and patients about appropriate strategies for management.

OBJECTIVE: To assess the effectiveness of all interventions that have been evaluated for use in the treatment or management of CFS in adults or children.

DATA SOURCES: Nineteen specialist databases were searched from inception to either January or July 2000 for published or unpublished studies in any language. The search was updated through October 2000 using PubMed. Other sources included scanning citations, Internet searching, contacting experts, and online requests for articles.

STUDY SELECTION: Controlled trials (randomized or nonrandomized) that evaluated interventions in patients diagnosed as having CFS according to any criteria were included. Study inclusion was assessed independently by 2 reviewers. Of 350 studies initially identified, 44 met inclusion criteria, including 36 randomized controlled trials and 8 controlled trials.

DATA EXTRACTION: Data extraction was conducted by 1 reviewer and checked by a second. Validity assessment was carried out by 2 reviewers with disagreements resolved by consensus. A qualitative synthesis was carried out and studies were grouped according to type of intervention and outcomes assessed.

DATA SYNTHESIS: The number of participants included in each trial ranged from 12 to 326, with a total of 2801 participants included in the 44 trials combined. Across the studies, 38 different outcomes were evaluated using about 130 different scales or types of measurement. Studies were grouped into 6 different categories. In the behavioral category, graded exercise therapy and cognitive behavioral therapy showed positive results and also scored highly on the validity assessment. In the immunological category, both immunoglobulin and hydrocortisone showed some limited effects but, overall, the evidence was inconclusive. There was insufficient evidence about effectiveness in the other 4 categories (pharmacological, supplements, complementary/alternative, and other interventions).

CONCLUSIONS: Overall, the interventions demonstrated mixed results in terms of effectiveness. All conclusions about effectiveness should be considered together with the methodological inadequacies of the studies. Interventions which have shown promising results include cognitive behavioral therapy and graded exercise therapy. Further research into these and other treatments is required using standardized outcome measures.

Comment in:

Measuring the quality of trials of treatments for chronic fatigue syndrome. [JAMA. 2001]

Chronic fatigue syndrome–trials and tribulations. [JAMA. 2001]

Review: behavioural interventions show the most promise for chronic fatigue syndrome. [Evid Based Nurs. 2002]

Review: behavioral interventions show the most promise for the chronic fatigue syndrome. [ACP J Club. 2002]

Review: cognitive behavioural therapy and graded exercise show the most promise for chronic fatigue syndrome. [Evid Based Ment Health. 2002]

Source: Whiting P, Bagnall AM, Sowden AJ, Cornell JE, Mulrow CD, Ramírez G. Interventions for the treatment and management of chronic fatigue syndrome: a systematic review. JAMA. 2001 Sep 19;286(11):1360-8. http://www.ncbi.nlm.nih.gov/pubmed/11560542

Chronic fatigue syndrome: neurological findings may be related to blood–brain barrier permeability

Abstract:

Despite volumes of international research, the etiology of chronic fatigue syndrome (CFS) remains elusive. There is, however, considerable evidence that CFS is a disorder involving the central nervous system (CNS).

It is our hypothesis that altered permeability of the blood-brain barrier (BBB) may contribute to ongoing signs and symptoms found in CFS. To support this hypothesis we have examined agents that can increase the blood-brain barrier permeability (BBBP) and those that may be involved in CFS.

The factors which can compromise the normal BBBP in CFS include viruses, cytokines, 5-hydroxytryptamine, peroxynitrite, nitric oxide, stress, glutathione depletion, essential fatty acid deficiency, and N-methyl-D-aspartate overactivity. It is possible that breakdown of normal BBBP leads to CNS cellular dysfunction and disruptions of neuronal transmission in CFS. Abnormal changes in BBBP have been linked to a number of disorders involving the CNS; based on review of the literature we conclude that the BBB integrity in CFS warrants investigation.

Source: Bested AC, Saunders PR, Logan AC. Chronic fatigue syndrome: neurological findings may be related to blood–brain barrier permeability. Med Hypotheses. 2001 Aug;57(2):231-7. http://www.ncbi.nlm.nih.gov/pubmed/11461179