Etiology of chronic fatigue syndrome: testing popular hypotheses using a national birth cohort study

Abstract:

OBJECTIVE: To review the etiology of chronic fatigue syndrome (CFS) and test hypotheses relating to immune system dysfunction, physical deconditioning, exercise avoidance, and childhood illness experiences, using a large prospective birth cohort.

METHODS: A total of 4779 participants from the Medical Research Council’s National Survey of Health and Development were prospectively followed for the first 53 years of their life with >20 separate data collections. Information was collected on childhood and parental health, atopic illness, levels of physical activity, fatigue, and participant’s weight and height at multiple time points. CFS was identified through self-report during a semistructured interview at age 53 years with additional case notes review.

RESULTS: Of 2983 participants assessed at age 53 years, 34 (1.1%, 95% Confidence Interval 0.8-1.5) reported a diagnosis of CFS. Those who reported CFS were no more likely to have suffered from childhood illness or atopy. Increased levels of exercise throughout childhood and early adult life and a lower body mass index were associated with an increased risk of later CFS. Participants who later reported CFS continued to exercise more frequently even after they began to experience early symptoms of fatigue.

CONCLUSIONS: Individuals who exercise frequently are more likely to report a diagnosis of CFS in later life. This may be due to the direct effects of this behavior or associated personality factors. Continuing to be active despite increasing fatigue may be a crucial step in the development of CFS.

 

Source: Harvey SB, Wadsworth M, Wessely S, Hotopf M. Etiology of chronic fatigue syndrome: testing popular hypotheses using a national birth cohort study. Psychosom Med. 2008 May;70(4):488-95. doi: 10.1097/PSY.0b013e31816a8dbc. Epub 2008 Mar 31. https://www.ncbi.nlm.nih.gov/pubmed/18378866

 

Health-related quality of life in chronic fatigue syndrome: predictors of physical functioning and psychological distress

Abstract:

This study investigated health-related quality of life (HRQoL; physical functioning and psychological distress) in an Australian chronic fatigue syndrome (CFS) population. The aims of the study were to compare HRQoL in those with CFS to the normal population, and to investigate the extent to which sociodemographic (age, gender, partner status, education), illness-related (illness duration, symptom frequency), and fatigue severity (physical, mental) variables predicted HRQoL.

A total of 139 people meeting CFS criteria completed questionnaires. HRQoL was assessed using standardised measures of distress and physical functioning. Compared with norms, those with CFS obtained significantly lower scores on all physical functioning areas, whereas 63% of participants reported clinically significant psychological distress.

Hierarchical regression analyses indicated that physical fatigue severity and symptom frequency were the strongest predictors of deficits in physical domain HRQoL. Physical HRQoL outcomes were also predicted by mental fatigue severity, older age, and female gender. All predictors were unrelated to psychological distress apart from weak positive associations with physical fatigue and symptom frequency.

Results identify a potent set of predictors of HRQoL and show that CFS has a pervasive negative impact on quality of life, particularly physical and psychological functioning.

 

Source: Lowry TJ, Pakenham KI. Health-related quality of life in chronic fatigue syndrome: predictors of physical functioning and psychological distress. Psychol Health Med. 2008 Mar;13(2):222-38. Doi: 10.1080/13548500701335698. https://www.ncbi.nlm.nih.gov/pubmed/18350466

 

Acute phase phospholipids related to the cardiolipin of mitochondria in the sera of patients with chronic fatigue syndrome (CFS), chronic Ciguatera fish poisoning (CCFP), and other diseases attributed to chemicals, Gulf War, and marine toxins

Abstract:

This study examined 328 CFS sera in a study with 17 CCFP, 8 Gulf War Veterans (GWV), 24 Prostate Cancer (PC), and 52 normal sera in the modified Membrane Immunobead Assay (MIA) procedure for CTX. Three hundred and twenty-eight CFS patients’ sera were examined by the modified MIA with purified MAb-CTX and 91.2% gave a titre > or =1:40. 76% of the 17 CCFP sera samples and 100% of the 8 GWV sera samples also had a titre > or =1:40. 92.3% of 52 normal sera showed titres of 1:20 or less, while 4 gave titres of > or =1:40.

In addition, 41 sera were examined for Anti-Cardiolipin (aCL) by a commercial ELISA procedure with 87.8% demonstrating IgM, IgM+IgA, or IgM+IgG aCL antibodies. These results showed mostly the IgM aCL antibody alone in the sera samples. In addition, 41 serum samples were examined for aCL, with 37 showing positive for aCL, representing 90.2% positive for the three disease categories examined: CFS, CCFP and GWV. Examination for antiMitochondrial-M2 autoantibody (aM-M2) in 28 patients (CFS (18), CCFP (5), and GWV (5)) was negative for aM-M2.

Inhibition analysis with antigens, CTX, CFS “Acute Phase Lipids”, commercial Cardiolipin (CL) and 1,2-Dipalmitoyl-sn-Glycero-3-[Phospho-L-Serine] (PS) and antibodies, MAb-CTX and aCL from patients’ serum show that the phospholipids in CL and CTX are antigenically indistinguishable with antibodies MAb-CTX and CFS-aCL. Preliminary chemical analyses have shown the lipids to be phospholipids associated with CL of the mitochondria.

We designate this “Acute Phase Lipid” comparable to “Acute Phase Proteins” (C-reactive protein (CRP) and Serum Amyloid A (SAA)) in inflammatory conditions.

(Copyright ) 2008 Wiley-Liss, Inc.

 

Source: Hokama Y, Empey-Campora C, Hara C, Higa N, Siu N, Lau R, Kuribayashi T, Yabusaki K. Acute phase phospholipids related to the cardiolipin of mitochondria in the sera of patients with chronic fatigue syndrome (CFS), chronic Ciguatera fish poisoning (CCFP), and other diseases attributed to chemicals, Gulf War, and marine toxins. J Clin Lab Anal. 2008;22(2):99-105. doi: 10.1002/jcla.20217. https://www.ncbi.nlm.nih.gov/pubmed/18348309

 

Effectiveness of distant healing for patients with chronic fatigue syndrome: a randomised controlled partially blinded trial (EUHEALS)

Abstract:

BACKGROUND: Distant healing, a form of spiritual healing, is widely used for many conditions but little is known about its effectiveness.

METHODS: In order to evaluate distant healing in patients with a stable chronic condition, we randomised 409 patients with chronic fatigue syndrome (CFS) from 14 private practices for environmental medicine in Germany and Austria in a two by two factorial design to immediate versus deferred (waiting for 6 months) distant healing. Half the patients were blinded and half knew their treatment allocation. Patients were treated for 6 months and allocated to groups of 3 healers from a pool of 462 healers in 21 European countries with different healing traditions. Change in Mental Health Component Summary (MHCS) score (SF-36) was the primary outcome and Physical Health Component Summary score (PHCS) the secondary outcome.

RESULTS: This trial population had very low quality of life and symptom scores at entry. There were no differences over 6 months in post-treatment MHCS scores between the treated and untreated groups. There was a non-significant outcome (p = 0.11) for healing with PHCS (1.11; 95% CI -0.255 to 2.473 at 6 months) and a significant effect (p = 0.027) for blinding; patients who were unblinded became worse during the trial (-1.544; 95% CI -2.913 to -0.176). We found no relevant interaction for blinding among treated patients in MHCS and PHCS. Expectation of treatment and duration of CFS added significantly to the model.

CONCLUSIONS: In patients with CFS, distant healing appears to have no statistically significant effect on mental and physical health but the expectation of improvement did improve outcome.

Copyright (c) 2008 S. Karger AG, Basel.

 

Source: Walach H, Bosch H, Lewith G, Naumann J, Schwarzer B, Falk S, Kohls N, Haraldsson E, Wiesendanger H, Nordmann A, Tomasson H, Prescott P, Bucher HC. Effectiveness of distant healing for patients with chronic fatigue syndrome: a randomised controlled partially blinded trial (EUHEALS). Psychother Psychosom. 2008;77(3):158-66. doi: 10.1159/000116609. Epub 2008 Feb 14. https://www.ncbi.nlm.nih.gov/pubmed/18277062

 

Immunoassay with cytomegalovirus early antigens from gene products p52 and CM2 (UL44 and UL57) detects active infection in patients with chronic fatigue syndrome

Abstract:

AIMS: To investigate whether the use of recombinant early antigens for detection of antibodies to human cytomegalovirus (HCMV) gene products CM(2) (UL44, UL57) and p52 (UL44) is specific in the diagnosis and differentiation of active HCMV infection in a subset of patients with chronic fatigue syndrome (CFS), a diagnosis which is often missed by the current ELISA assay that uses crude viral lysate antigen.

METHODS: At a single clinic from 1999 to 2001, a total of 4774 serological tests were performed in 1135 patients with patients using two immunoassays, Copalis and ELISA. The Copalis immunoassay utilised HCMV early gene products of UL44 and UL57 recombinant antigens for detection of HCMV IgM antibody, and viral capsid antigen for detection of HCMV IgG antibody. The ELISA immunoassay utilised viral crude lysate as antigen for detection of both HCMV IgG and IgM.

RESULTS: 517 patients (45.6%) were positive for HCMV IgG by both assays. Of these, 12 (2.2%) were positive for HCMV(V) IgM serum antibody by HCMV ELISA assay, and 61 (11.8%) were positive for IgM HCMV serum antibody by Copalis assay. The Copalis assay that uses HCMV early recombinant gene products CM(2) (UL44, UL57) and p52 (UL44) in comparison with ELISA was 98% specific.

CONCLUSIONS: Immunoassays that use early antigen recombinant HCMV CM(2) and p52 are five times more sensitive than HCMV ELISA assay using viral lysate, and are specific in the detection and differentiation of active HCMV infection in a subset of patients with CFS.

 

Source: Beqaj SH, Lerner AM, Fitzgerald JT. Immunoassay with cytomegalovirus early antigens from gene products p52 and CM2 (UL44 and UL57) detects active infection in patients with chronic fatigue syndrome. J Clin Pathol. 2008 May;61(5):623-6. Epub 2007 Nov 23. https://www.ncbi.nlm.nih.gov/pubmed/18037660

 

The relationship between prior psychiatric disorder and chronic fatigue: evidence from a national birth cohort study

Abstract:

BACKGROUND: Increased rates of psychiatric disorder have previously been reported in those diagnosed with chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME), although the direction of causation in this relationship has not been established. We aimed to test the hypothesis that individuals with self-reported CFS/ME have increased levels of psychiatric disorder prior to the onset of their fatigue symptoms.

METHOD: A total of 5,362 participants were prospectively followed with various measures of personality, psychiatric disorder and fatigue levels collected over the first 43 years of their life. CFS/ME was identified through self-report during a semi-structured interview at age 53 years.

RESULTS: Thirty-four (1.1%) of the 3,035 subjects assessed at age 53 years reported a diagnosis of CFS/ME. CFS/ME was more common among females, but there was no association between CFS/ME and either social class, social mobility or educational level. Those with psychiatric illness between the ages of 15 and 36 years were more likely to report CFS/ME later in life with an odds ratio (OR, adjusted for sex) of 2.65 [95% confidence interval (CI) 1.26-5.57, p=0.01]. Increased levels of psychiatric illness, in particular depression and anxiety, were present prior to the occurrence of fatigue symptoms. There was a dose-response relationship between the severity of psychiatric symptoms and the likelihood of later CFS/ME. Personality factors were not associated with a self-reported diagnosis of CFS/ME.

CONCLUSIONS: This temporal, dose-response relationship suggests that psychiatric disorders, or shared risk factors for psychiatric disorders, are likely to have an aetiological role in some cases of CFS/ME.

 

Source: Harvey SB, Wadsworth M, Wessely S, Hotopf M. The relationship between prior psychiatric disorder and chronic fatigue: evidence from a national birth cohort study. Psychol Med. 2008 Jul;38(7):933-40. Epub 2007 Nov 2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3196526/ (Full article)

 

Hematologic and urinary excretion anomalies in patients with chronic fatigue syndrome

Abstract:

Patients with chronic fatigue syndrome (CFS) have a broad and variable spectrum of signs and symptoms with variable onsets. This report outlines the results of a single-blind, cross-sectional research project that extensively investigated a large cohort of 100 CFS patients and 82 non fatigued control subjects with the aim of performing a case-control evaluation of alterations in standard blood parameters and urinary amino and organic acid excretion profiles.

Blood biochemistry and full blood counts were unremarkable and fell within normal laboratory ranges. However, the case-control comparison of the blood cell data revealed that CFS patients had a significant decrease in red cell distribution width and increases in mean platelet volume, neutrophil counts, and the neutrophil-lymphocyte ratio.

Evaluation of the urine excretion parameters also revealed a number of anomalies. The overnight urine output and rate of amino acid excretion were both reduced in the CFS group (P < 0.01). Significant decreases in the urinary excretion of asparagine (P < 0.0001), phenylalanine (P < 0.003), the branch chain amino acids (P < 0.005), and succinic acid (P < 0.0001), as well as increases in 3-methylhistidine (P < 0.05) and tyrosine (P < 0.05) were observed.

It was concluded that the urinary excretion and blood parameters data supported the hypothesis that alterations in physiologic homeostasis exist in CFS patients.

 

Source: Niblett SH, King KE, Dunstan RH, Clifton-Bligh P, Hoskin LA, Roberts TK, Fulcher GR, McGregor NR, Dunsmore JC, Butt HL, Klineberg I, Rothkirch TB. Hematologic and urinary excretion anomalies in patients with chronic fatigue syndrome. Exp Biol Med (Maywood). 2007 Sep;232(8):1041-9. https://www.ncbi.nlm.nih.gov/pubmed/17720950

 

Chronic fatigue syndrome treated by acupuncture and moxibustion in combination with psychological approaches in 310 cases

Abstract:

OBJECTIVE: To observe clinical therapeutic effect of acupuncture and moxibustion combined with a psychological approach on chronic fatigue syndrome (CFS).

METHODS: The treatment was given by acupuncture plus moxibustion combined with a psychological approach based on differentiation of symptoms and signs in 310 cases.

RESULTS: Of 310 cases observed, 275 cases (88.7%) were clinically cured, 28 cases (9%) improved, and 7 cases (2.3%) failed.

CONCLUSION: Acupuncture plus moxibustion combined with a psychological approach is an effective therapy for CFS.

 

Source: Guo J.Chronic fatigue syndrome treated by acupuncture and moxibustion in combination with psychological approaches in 310 cases. J Tradit Chin Med. 2007 Jun;27(2):92-5. http://www.journaltcm.com/modules/Journal/contents/stories/072/3.pdf (Full article)

 

Complementary and alternative medical therapy utilization by people with chronic fatiguing illnesses in the United States

Abstract:

BACKGROUND: Chronic fatiguing illnesses, including chronic fatigue syndrome (CFS), pose a diagnostic and therapeutic challenge. Previous clinical reports addressed the utilization of health care provided to patients with CFS by a variety of practitioners with other than allopathic training, but did not examine the spectrum of complementary and alternative medicine (CAM) therapies used. This study was designed to measure CAM therapy use by persons with fatiguing illnesses in the United States population.

METHODS: During a random-digit dialing survey to estimate the prevalence of CFS-like illness in urban and rural populations from different geographic regions of the United States, we queried the utilization of CAM including manipulation or body-based therapies, alternative medical systems, mind-body, biologically-based, and energy modalities.

RESULTS: Four hundred forty fatigued and 444 non-fatigued persons from 2,728 households completed screening. Fatigued subjects included 53 persons with prolonged fatigue, 338 with chronic fatigue, and 49 with CFS-like illness. Mind-body therapy (primarily personal prayer and prayer by others) was the most frequently used CAM across all groups. Among women, there was a significant trend of increasing overall CAM use across all subgroups (p-trend = 0.003). All categories of CAM use were associated with significantly poorer physical health scores, and all but one (alternative medicine systems) were associated with significantly poorer mental health scores. People with CFS-like illness were significantly more likely to use body-based therapy (chiropractic and massage) than non-fatigued participants (OR = 2.52, CI = 1.32, 4.82). Use of body-based therapies increased significantly in a linear trend across subgroups of non-fatigued, prolonged fatigued, chronic fatigued, and CFS-like subjects (p-trend = 0.002). People with chronic fatigue were also significantly more likely to use body-based therapy (OR = 1.52, CI = 1.07, 2.16) and mind-body (excluding prayer) therapy than non-fatigued participants (OR = 1.73, CI = 1.20 – 2.48).

CONCLUSION: Utilization of CAM was common in fatiguing illnesses, and was largely accounted for by the presence of underlying conditions and poor physical and mental health. Compared to non-fatigued persons, those with CFS-like illness or chronic fatigue were most likely to use body-based and mind-body therapies. These observations have important implications for provider education programs and development of intervention strategies for CFS.

 

Source: Jones JF, Maloney EM, Boneva RS, Jones AB, Reeves WC. Complementary and alternative medical therapy utilization by people with chronic fatiguing illnesses in the United States. BMC Complement Altern Med. 2007 Apr 25;7:12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1878505/ (Full article)

 

Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS, also called myalgic encephalomyelitis /encephalopathy or ME) is a debilitating condition with no known cause or cure. Improvement may occur with medical care and additional therapies of pacing, cognitive behavioural therapy and graded exercise therapy. The latter two therapies have been found to be efficacious in small trials, but patient organisations surveys have reported adverse effects. Although pacing has been advocated by patient organisations, it lacks empirical support. Specialist medical care is commonly provided but its efficacy when given alone is not established. This trial compares the efficacy of the additional therapies when added to specialist medical care against specialist medical care alone.

METHODS: 600 patients, who meet operationalised diagnostic criteria for CFS, will be recruited from secondary care into a randomised trial of four treatments, stratified by current co morbid depressive episode and different CFS/ME criteria. The four treatments are standardised specialist medical care either given alone, or with adaptive pacing therapy or cognitive behaviour therapy or graded exercise therapy. Supplementary therapies will involve fourteen sessions over 23 weeks and a booster session at 36 weeks. Outcome will be assessed at 12, 24, and 52 weeks after randomisation. Two primary outcomes of self-rated fatigue and physical function will assess differential effects of each treatment on these measures. Secondary outcomes include adverse events and reactions, subjective measures of symptoms, mood, sleep and function and objective measures of physical activity, fitness, cost-effectiveness and cost-utility. The primary analysis will be based on intention to treat and will use logistic regression models to compare treatments. Secondary outcomes will be analysed by repeated measures analysis of variance with a linear mixed model. All analyses will allow for stratification factors. Mediators and moderators will be explored using multiple linear and logistic regression techniques with interactive terms, with the sample split into two to allow validation of the initial models. Economic analyses will incorporate sensitivity measures.

DISCUSSION: The results of the trial will provide information about the benefits and adverse effects of these treatments, their cost-effectiveness and cost-utility, the process of clinical improvement and the predictors of efficacy.

 

Source: White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007 Mar 8;7:6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2147058/