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Chronic Fatigue Syndrome: HELP
Articles from Bergen, NO
Based on 30 articles published since 2010
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These are the 30 published articles about Fatigue Syndrome, Chronic that originated from Bergen, NO during 2010-2020.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Fatigue in psoriasis: a phenomenon to be explored. 2015

Skoie, I M / Ternowitz, T / Jonsson, G / Norheim, K / Omdal, R. ·Department of Dermatology, Stavanger University Hospital, Stavanger, Norway. · Department of Medical Biochemistry, Stavanger University Hospital, Stavanger, Norway. · Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway. · Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway. ·Br J Dermatol · Pubmed #25557165.

ABSTRACT: Fatigue is a prevalent and substantial phenomenon in many patients with chronic inflammatory diseases, often rated by patients as the most troublesome symptom and aspect of their disease. It frequently interferes with physical and social functions and may lead to social withdrawal, long-standing sick leave and disability. Although psychological and somatic factors such as depression, sleep disorders, pain and anaemia influence fatigue, the underlying pathophysiological mechanisms by which fatigue is generated and regulated are largely unknown. Increasing evidence points towards a genetic and molecular basis for fatigue as part of the innate immune system and cellular stress responses. Few studies have focused on fatigue in dermatological diseases. Most of these studies describe fatigue as a phenomenon related to psoriatic arthritis and describe the beneficial effects of biological agents on fatigue observed in clinical studies. It is therefore possible that this problem has been underestimated and deserves more attention in the dermatological community. In this review, we provide a definition and explanation for chronic fatigue, describe some commonly used instruments for measuring fatigue, and present hypothetical biological mechanisms with an emphasis on activation of the innate immune system and oxidative stress. An overview of relevant clinical studies covering the theme 'psoriasis and fatigue' is given.

2 Review [Exercise therapy for patients with chronic fatigue syndrome]. 2011

Larun, Lillebeth / Malterud, Kirsti. ·Allmennmedisinsk forskningsenhet i Bergen, Uni helse, Kalfarveien 31, Bergen. ela@nokc.no ·Tidsskr Nor Laegeforen · Pubmed #21304571.

ABSTRACT: BACKGROUND: Post-exertional fatigue is the main symptom of chronic fatigue syndrome. Evidence-based guidelines recommend cognitive behavioral therapy and graded exercise therapy. In this article, we present a systematic review of outcome studies and discuss procedures for individualized exercise therapy for patients with chronic fatigue syndrome. MATERIAL AND METHODS: The effect of exercise treatment for these patients was assessed through a meta-analysis of randomized controlled trials which were identified through a systematic literature review. Effect size was calculated for fatigue, pain and health-related quality of life and the GRADE system was used to estimate the documentation level (quality of the evidence and strength of the recommendations). RESULTS: Seven outcome studies were included in the meta-analysis. They demonstrated that exercise therapy seems to reduce fatigue, but the results were inconclusive for pain and health-related quality of life. The documentation level is moderate to low and further research can modify the results in positive or negative directions. We found no indications of adverse effects of individualized exercise programs which were adapted to the patients' functional level and included adequate follow-up. INTERPRETATION: In light of general knowledge about positive health effects of exercise therapy and empirically based hypotheses about disease mechanisms in chronic fatigue syndrome, we conclude that further research has a high probability of confirming recommendations on individualized exercise therapy to these patients.

3 Review [Chronic muscular pain is not unexplainable]. 2010

Malterud, Kirsti. ·Allmennmedisinsk forskningsenhet Bergen, Unifob Helse, Kalfarveien 31, 5018 Bergen, Norway. kirsti.malterud@isf.uib.no ·Tidsskr Nor Laegeforen · Pubmed #21139661.

ABSTRACT: BACKGROUND: Patients with chronic muscular pain suffer from extensive symptoms although test results are normal. Symptoms considered as "unexplained" are not necessarily unexplainable. Recent research provides relevant frameworks for understanding the interaction of bodily and mental processes and life conditions. Such perspectives can be used as a point of departure for understanding and change of conditions shaping vulnerability and resistance. MATERIAL AND METHODS: The article presents a summary of theoretical perspectives, empirical findings, and clinical experience, with a discussion of how this body of knowledge can be applied in clinical practice. RESULTS: Distress can lead to dysregulation through spinal sensitization and sustained arousal. Psychoneuroimmunology describes how subjective experience, emotions, cognitive functions, the nervous system and physiological stress reactions interact to restore balance through complex signal systems. Responses are influenced by emotional and cognitive processes, dependent on individual vulnerability and strength. Phenomenology focuses on life circumstances, meaning, and interpretation of bodily signals. Through acknowledging patients' experiences doctors can shift the attention from shame to coping. INTERPRETATION: Chronic muscular pain can be explained by the interaction between body, mind and life circumstances. Searching for simple causalities and consistent findings will provide no benefit. Instead, we should encourage coping strategies with the capacity of breaking vicious circles that maintain symptoms.

4 Clinical Trial Immunosignature Analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). 2019

Günther, Oliver P / Gardy, Jennifer L / Stafford, Phillip / Fluge, Øystein / Mella, Olav / Tang, Patrick / Miller, Ruth R / Parker, Shoshana M / Johnston, Stephen A / Patrick, David M. ·Günther Analytics, Vancouver, BC, Canada. · British Columbia Centre for Disease Control, Vancouver, BC, Canada. · School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada. · Biodesign Institute, Arizona State University, Phoenix, AZ, USA. · Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway. · Sidra Medical and Research Centre, Doha, Qatar. · Centre for Health Evaluation and Outcome Sciences, St. Paul's Hospital, Vancouver, BC, Canada. · British Columbia Centre for Disease Control, Vancouver, BC, Canada. david.patrick@ubc.ca. · School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada. david.patrick@ubc.ca. ·Mol Neurobiol · Pubmed #30298340.

ABSTRACT: A random-sequence peptide microarray can interrogate serum antibodies in a broad, unbiased fashion to generate disease-specific immunosignatures. This approach has been applied to cancer detection, diagnosis of infections, and interrogation of vaccine response. We hypothesized that there is an immunosignature specific to ME/CFS and that this could aid in the diagnosis. We studied two subject groups meeting the Canadian Consensus Definition of ME/CFS. ME/CFS (n = 25) and matched control (n = 25) sera were obtained from a Canadian study. ME/CFS (n = 25) sera were obtained from phase 1/2 Norwegian trials (NCT01156909). Sera from six healthy controls from the USA were included in the analysis. Canadian cases and controls were tested for a disease immunosignature. By combining results from unsupervised and supervised analyses, a candidate immunosignature with 654 peptides was able to differentiate ME/CFS from controls. The immunosignature was tested and further refined using the Norwegian and USA samples. This resulted in a 256-peptide immunosignature with the ability to separate ME/CFS cases from controls in the international data sets. We were able to identify a 256-peptide signature that separates ME/CFS samples from healthy controls, suggesting that the hit-and-run hypothesis of immune dysfunction merits further investigation. By extending testing of both our signature and one previously reported in the literature to larger cohorts, and further interrogating the specific peptides we and others have identified, we may deepen our understanding of the origins of ME/CFS and work towards a clinically meaningful diagnostic biomarker.

5 Clinical Trial B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. 2015

Fluge, Øystein / Risa, Kristin / Lunde, Sigrid / Alme, Kine / Rekeland, Ingrid Gurvin / Sapkota, Dipak / Kristoffersen, Einar Kleboe / Sørland, Kari / Bruland, Ove / Dahl, Olav / Mella, Olav. ·Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway. · Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Haukeland University Hospital, Bergen, Norway. · Department of Immunology and Transfusion Medicine, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Haukeland University Hospital, Bergen, Norway. · Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway; Department of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. · Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Haukeland University Hospital, Bergen, Norway. ·PLoS One · Pubmed #26132314.

ABSTRACT: BACKGROUND: Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS. METHODS: In this single-center, open-label, one-armed phase II study (NCT01156909), 29 patients were included for treatment with rituximab (500 mg/m2) two infusions two weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months, and with follow-up for 36 months. FINDINGS: Major or moderate responses, predefined as lasting improvements in self-reported Fatigue score, were detected in 18 out of 29 patients (intention to treat). Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment. For these 18 patients, the mean response durations within the 156 weeks study period were 105 weeks in 14 major responders, and 69 weeks in four moderate responders. At end of follow-up (36 months), 11 out of 18 responding patients were still in ongoing clinical remission. For major responders, the mean lag time from first rituximab infusion until start of clinical response was 23 weeks (range 8-66). Among the nine patients from the placebo group in the previous randomized study with no significant improvement during 12 months follow-up after saline infusions, six achieved a clinical response before 12 months after rituximab maintenance infusions in the present study. Two patients had an allergic reaction to rituximab and two had an episode of uncomplicated late-onset neutropenia. Eight patients experienced one or more transient symptom flares after rituximab infusions. There was no unexpected toxicity. CONCLUSION: In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed patterns of delayed responses and relapse after B-cell depletion and regeneration, a three times higher disease prevalence in women than in men, and a previously demonstrated increase in B-cell lymphoma risk for elderly ME/CFS patients, suggest that ME/CFS may be a variant of an autoimmune disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT01156909.

6 Clinical Trial Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. 2011

Fluge, Øystein / Bruland, Ove / Risa, Kristin / Storstein, Anette / Kristoffersen, Einar K / Sapkota, Dipak / Næss, Halvor / Dahl, Olav / Nyland, Harald / Mella, Olav. ·Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway. oystein.fluge@gmail.com ·PLoS One · Pubmed #22039471.

ABSTRACT: BACKGROUND: Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients. METHODS AND FINDINGS: In this double-blind, placebo-controlled phase II study (NCT00848692), 30 CFS patients were randomised to either Rituximab 500 mg/m(2) or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV) was not detected in any of the patients. The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003). Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8-44). Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed), with differences between the Rituximab and Placebo groups between 6-10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening. CONCLUSION: The delayed responses starting from 2-7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses. The present findings will impact future research efforts in CFS. TRIAL REGISTRATION: ClinicalTrials.gov NCT00848692.

7 Article From IBS to ME - The dysbiotic march hypothesis. 2020

Berstad, Arnold / Hauso, Olav / Berstad, Ketil / Berstad, Johanna E R. ·University of Bergen, Norway. · Volda, Norway. · The Norwegian Medicines Manual, Oslo, Norway. Electronic address: k-bers@online.no. · Unit of Oral and Maxillofacial Surgery, Department of Head and Neck Surgery, Division for Head, Neck and Reconstructive Surgery, Oslo University Hospital, National Hospital, Oslo, Norway. ·Med Hypotheses · Pubmed #32126475.

ABSTRACT: Irritable bowel syndrome (IBS) is often associated with other unexplained complaints like chronic fatigue syndrome (CFS), fibromyalgia and myalgic encephalopathy (ME). The pathogenesis of the relationship is unknown. Intestinal dysbiosis may be a common abnormality, but based on 1100 consecutive IBS patients examined over a nine years period, we hypothesize that the development of the disease, often from IBS to ME, actually manifests a "dysbiotic march". In analogy with "the atopic march" in allergic diseases, we suggest "a dysbiotic march" in IBS; initiated by extensive use of antibiotics during childhood, often before school age. Various abdominal complaints including IBS may develop soon thereafter, while systemic symptom like CFS, fibromyalgia and ME may appear years later.

8 Article Searching for Serum Antibodies to Neuronal Proteins in Patients With Myalgic Encephalopathy/Chronic Fatigue Syndrome. 2019

Giannoccaro, Maria Pia / Cossins, Judith / Sørland, Kari / Fluge, Øystein / Vincent, Angela. ·Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. Electronic address: mpgiannoccaro@gmail.com. · Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. · Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway. ·Clin Ther · Pubmed #31053295.

ABSTRACT: PURPOSE: A role for the immune system in causing myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is long suspected, but few studies have looked for specific autoantibodies that might contribute to the symptoms. Our aim was to look for evidence of antibodies to neuronal proteins in patients with ME/CSF. METHODS: Sera samples from 50 patients and 50 healthy individuals were sent coded to the Neuroimmunology Laboratory in Oxford. Screening for antibody binding to neuronal tissue was performed on brain tissue and neuronal cultures. Specific serum antibodies were assessed by antigen-specific cell-based assays and radioimmunoassays. After antibody testing, the associations between seropositive status and clinical data were investigated. FINDINGS: Overall, 8 patients and 11 participants were found to have some serum immunoreactivity toward neuronal or neuromuscular junction proteins, but only 1 patient and 2 participants had specific serum antibodies. Nevertheless, seropositive status in patients with ME was associated with shorter duration since onset and a more severe disease. IMPLICATIONS: The results indicate no overall increased frequency of antibodies to neuronal proteins in ME/CSF and no evidence of a specific antibody that might be causative or contribute to clinical features in patients. However, the association of seropositive status with shorter duration of disease and more severe symptoms suggests a possible role of antibodies at onset in some patients and should be the focus of future studies.

9 Article B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. 2019

Fluge, Øystein / Rekeland, Ingrid G / Lien, Katarina / Thürmer, Hanne / Borchgrevink, Petter C / Schäfer, Christoph / Sørland, Kari / Aßmus, Jörg / Ktoridou-Valen, Irini / Herder, Ingrid / Gotaas, Merethe E / Kvammen, Øivind / Baranowska, Katarzyna A / Bohnen, Louis M L J / Martinsen, Sissel S / Lonar, Ann E / Solvang, Ann-Elise H / Gya, Arne E S / Bruland, Ove / Risa, Kristin / Alme, Kine / Dahl, Olav / Mella, Olav. ·Haukeland University Hospital, Bergen, Norway (Ø.F., I.G.R., K.S., J.A., I.K., O.B., K.R., K.A.). · Oslo University Hospital, Oslo, Norway (K.L., I.H., S.S.M.). · Notodden Hospital, Notodden, Norway (H.T., A.E.L.). · St. Olavs Hospital, Trondheim, Norway (P.C.B., M.E.G., Ø.K., K.A.B., A.H.S.). · University Hospital of Northern Norway, Tromsø, Norway (C.S., L.M.B., A.E.G.). · Haukeland University Hospital and University of Bergen, Bergen, Norway (O.D., O.M.). ·Ann Intern Med · Pubmed #30934066.

ABSTRACT: Background: Previous phase 2 trials indicated benefit from B-lymphocyte depletion in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Objective: To evaluate the effect of the monoclonal anti-CD20 antibody rituximab versus placebo in patients with ME/CFS. Design: Randomized, placebo-controlled, double-blind, multicenter trial. (ClinicalTrials.gov: NCT02229942). Setting: 4 university hospitals and 1 general hospital in Norway. Patients: 151 patients aged 18 to 65 years who had ME/CFS according to Canadian consensus criteria and had had the disease for 2 to 15 years. Intervention: Treatment induction with 2 infusions of rituximab, 500 mg/m2 of body surface area, 2 weeks apart, followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9, and 12 months (n = 77), or placebo (n = 74). Measurements: Primary outcomes were overall response rate (fatigue score ≥4.5 for ≥8 consecutive weeks) and repeated measurements of fatigue score over 24 months. Secondary outcomes included repeated measurements of self-reported function over 24 months, components of the Short Form-36 Health Survey and Fatigue Severity Scale over 24 months, and changes from baseline to 18 months in these measures and physical activity level. Between-group differences in outcome measures over time were assessed by general linear models for repeated measures. Results: Overall response rates were 35.1% in the placebo group and 26.0% in the rituximab group (difference, 9.2 percentage points [95% CI, -5.5 to 23.3 percentage points]; P = 0.22). The treatment groups did not differ in fatigue score over 24 months (difference in average score, 0.02 [CI, -0.27 to 0.31]; P = 0.80) or any of the secondary end points. Twenty patients (26.0%) in the rituximab group and 14 (18.9%) in the placebo group had serious adverse events. Limitation: Self-reported primary outcome measures and possible recall bias. Conclusion: B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS. Primary Funding Source: The Norwegian Research Council, Norwegian Regional Health Trusts, Kavli Trust, MEandYou Foundation, and Norwegian ME Association.

10 Article Rituximab Serum Concentrations and Anti-Rituximab Antibodies During B-Cell Depletion Therapy for Myalgic Encephalopathy/Chronic Fatigue Syndrome. 2019

Rekeland, Ingrid G / Fluge, Øystein / Alme, Kine / Risa, Kristin / Sørland, Kari / Mella, Olav / de Vries, Annick / Schjøtt, Jan. ·Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway. Electronic address: ingrid.gurvin.rekeland@helse-bergen.no. · Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway. · Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Norway. · Sanquin Diagnostic Services, Amsterdam, The Netherlands. · Section of Clinical Pharmacology, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Norway. ·Clin Ther · Pubmed #30502905.

ABSTRACT: PURPOSE: Previous Phase II trials indicated clinical benefit from B-cell depletion using the monoclonal anti-CD20 antibody rituximab in patients with myalgic encephalopathy/chronic fatigue syndrome (ME/CFS). The association between rituximab serum concentrations and the effect and clinical relevance of antidrug antibodies (ADAs) against rituximab in ME/CFS is unknown. We retrospectively measured rituximab concentrations and ADAs in serum samples from patients included in an open-label Phase II trial with maintenance rituximab treatment (KTS-2-2010) to investigate possible associations with clinical improvement and clinical and biochemical data. METHODS: Patients with ME/CFS fulfilling the Canadian criteria received rituximab (500 mg/m FINDINGS: There were no significant differences in mean serum rituximab concentrations between 14 patients experiencing clinical improvement versus 9 patients with no improvement. Female patients had higher mean serum rituximab concentrations than male patients at 3 months (P = 0.05). There was a significant negative correlation between B-cell numbers in peripheral blood at baseline and rituximab serum concentration at 3 months (r = -0.47; P = 0.03). None of the patients had ADAs at any time point. IMPLICATIONS: Clinical improvement of patients with ME/CFS in the KTS-2-2010 trial was not related to rituximab serum concentrations or ADAs. This finding is also in line with a recent randomized trial questioning the efficacy of rituximab in ME/CFS. Rituximab concentrations and ADAs still offer supplemental information when interpreting the results of these trials.

11 Article A 4-Day Mindfulness-Based Cognitive Behavioral Intervention Program for CFS/ME. An Open Study, With 1-Year Follow-Up. 2018

Stubhaug, Bjarte / Lier, Haldis O / Aßmus, Jörg / Rongve, Arvid / Kvale, Gerd. ·Department of Research and Innovation, Fonna Hospital Trust, Haugesund, Norway. · Department of Clinical Medicine (K1), Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway. · Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway. · Department of Mental Health, Haukeland University Hospital, Bergen, Norway. · OCD-team, Haukeland University Hospital, Bergen, Norway. ·Front Psychiatry · Pubmed #30618889.

ABSTRACT:

12 Article Unperturbed Cytotoxic Lymphocyte Phenotype and Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. 2017

Theorell, Jakob / Bileviciute-Ljungar, Indre / Tesi, Bianca / Schlums, Heinrich / Johnsgaard, Mette Sophie / Asadi-Azarbaijani, Babak / Bolle Strand, Elin / Bryceson, Yenan T. ·Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden. · Department of Rehabilitation Medicine, Karolinska Institutet, Stockholm, Sweden. · Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden. · Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital Solna, Stockholm, Sweden. · Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institute, Karolinska University Hospital Solna, Stockholm, Sweden. · Balderklinikken, Oslo, Norway. · Division of Medicine, CFS/ME Centre, Oslo University Hospital, Oslo, Norway. · VID Specialized University, Oslo, Norway. · Norwegian National Advisory Unit on CFS/ME, Oslo University Hospital, Oslo, Norway. · Department of Clinical Science, University of Bergen, Bergen, Norway. ·Front Immunol · Pubmed #28694809.

ABSTRACT: Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a debilitating disorder linked to diverse intracellular infections as well as physiological stress. Cytotoxic lymphocytes combat intracellular infections. Their function is attenuated by stress. Despite numerous studies, the role of cytotoxic lymphocytes in ME/CFS remains unclear. Prompted by advances in the understanding of defects in lymphocyte cytotoxicity, the discovery of adaptive natural killer (NK) cell subsets associated with certain viral infections, and compelling links between stress, adrenaline, and cytotoxic lymphocyte function, we reassessed the role of cytotoxic lymphocytes in ME/CFS. Forty-eight patients from two independent cohorts fulfilling the Canada 2003 criteria for ME/CFS were evaluated with respect to cytotoxic lymphocyte phenotype and function. Results were compared to values from matched healthy controls. Reproducible differences between patients and controls were not found in cytotoxic lymphocyte numbers, cytotoxic granule content, activation status, exocytotic capacity, target cell killing, or cytokine production. One patient expressed low levels of perforin, explained by homozygosity for the

13 Article Giardia-specific cellular immune responses in post-giardiasis chronic fatigue syndrome. 2017

Hanevik, Kurt / Kristoffersen, Einar / Mørch, Kristine / Rye, Kristin Paulsen / Sørnes, Steinar / Svärd, Staffan / Bruserud, Øystein / Langeland, Nina. ·Department of Clinical Science, Lab-building 8.floor, University of Bergen, N-5021, Bergen, Norway. kurt.hanevik@med.uib.no. · Center for Tropical Infectious Diseases, Haukeland University Hospital, Bergen, Norway. kurt.hanevik@med.uib.no. · Department of Clinical Science, Lab-building 8.floor, University of Bergen, N-5021, Bergen, Norway. · Department of immunology and transfusion medicine, Haukeland University Hospital, Bergen, Norway. · Center for Tropical Infectious Diseases, Haukeland University Hospital, Bergen, Norway. · Department of Cell and Molecular biology, Uppsala University, Uppsala, Sweden. ·BMC Immunol · Pubmed #28129747.

ABSTRACT: BACKGROUND: The role of pathogen specific cellular immune responses against the eliciting pathogen in development of post-infectious chronic fatigue syndrome (PI-CFS) is not known and such studies are difficult to perform. The aim of this study was to evaluate specific anti-Giardia cellular immunity in cases that developed CFS after Giardia infection compared to cases that recovered well. Patients reporting chronic fatigue in a questionnaire study three years after a Giardia outbreak were clinically evaluated five years after the outbreak and grouped according to Fukuda criteria for CFS and idiopathic chronic fatigue. Giardia specific immune responses were evaluated in 39 of these patients by proliferation assay, T cell activation and cytokine release analysis. 20 Giardia exposed non-fatigued individuals and 10 healthy unexposed individuals were recruited as controls. RESULTS: Patients were clinically classified into CFS (n = 15), idiopathic chronic fatigue (n = 5), fatigue from other causes (n = 9) and recovered from fatigue (n = 10). There were statistically significant antigen specific differences between these Giardia exposed groups and unexposed controls. However, we did not find differences between the Giardia exposed fatigue classification groups with regard to CD4 T cell activation, proliferation or cytokine levels in 6 days cultured PBMCs. Interestingly, sCD40L was increased in patients with PI-CFS and other persons with fatigue after Giardia infection compared to the non-fatigued group, and correlated well with fatigue levels at the time of sampling. CONCLUSION: Our data show antigen specific cellular immune responses in the groups previously exposed to Giardia and increased sCD40L in fatigued patients.

14 Article Comorbidities treated in primary care in children with chronic fatigue syndrome / myalgic encephalomyelitis: A nationwide registry linkage study from Norway. 2016

Bakken, Inger J / Tveito, Kari / Aaberg, Kari M / Ghaderi, Sara / Gunnes, Nina / Trogstad, Lill / Magnus, Per / Stoltenberg, Camilla / Håberg, Siri E. ·Norwegian Institute of Public Health, PO Box 4404, Nydalen, Oslo, 0403, Norway. inger.johanne.bakken@fhi.no. · Norwegian Institute of Public Health, PO Box 4404, Nydalen, Oslo, 0403, Norway. · The National Center for Epilepsy, Oslo University Hospital, Oslo, Norway. · Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway. ·BMC Fam Pract · Pubmed #27590471.

ABSTRACT: BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a complex condition. Causal factors are not established, although underlying psychological or immunological susceptibility has been proposed. We studied primary care diagnoses for children with CFS/ME, with children with another hospital diagnosis (type 1 diabetes mellitus [T1DM]) and the general child population as comparison groups. METHODS: All Norwegian children born 1992-2012 constituted the study sample. Children with CFS/ME (n = 1670) or T1DM (n = 4937) were identified in the Norwegian Patient Register (NPR) (2008-2014). Children without either diagnosis constituted the general child population comparison group (n = 1337508). We obtained information on primary care diagnoses from the Norwegian Directorate of Health. For each primary care diagnosis, the proportion and 99 % confidence interval (CI) within the three groups was calculated, adjusted for sex and age by direct standardization. RESULTS: Children with CFS/ME were more often registered with a primary care diagnosis of weakness/general tiredness (89.9 % [99 % CI 88.0 to 91.8 %]) than children in either comparison group (T1DM: 14.5 % [99 % CI: 13.1 to 16.0 %], general child population: 11.1 % [99 % CI: 11.0 to 11.2 %]). Also, depressive disorder and anxiety disorder were more common in the CFS/ME group, as were migraine, muscle pain, and infections. In the 2 year period prior to the diagnoses, infectious mononucleosis was registered for 11.1 % (99 % CI 9.1 to 13.1 %) of children with CFS/ME and for 0.5 % (99 % CI (0.2 to 0.8 %) of children with T1DM. Of children with CFS/ME, 74.6 % (1292/1670) were registered with a prior primary care diagnosis of weakness / general tiredness. The time span from the first primary care diagnosis of weakness / general tiredness to the specialist health care diagnosis of CFS/ME was 1 year or longer for 47.8 %. CONCLUSIONS: This large nationwide registry linkage study confirms that the clinical picture in CFS/ME is complex. Children with CFS/ME were frequently diagnosed with infections, supporting the hypothesis that infections may be involved in the causal pathway. The long time span often observed from the first diagnosis of weakness / general tiredness to the diagnosis of CFS/ME might indicate that the treatment of these patients is sometimes not optimal.

15 Article Serum BAFF and APRIL Levels, T-Lymphocyte Subsets, and Immunoglobulins after B-Cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Myalgic Encephalopathy/Chronic Fatigue Syndrome. 2016

Lunde, Sigrid / Kristoffersen, Einar K / Sapkota, Dipak / Risa, Kristin / Dahl, Olav / Bruland, Ove / Mella, Olav / Fluge, Øystein. ·Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway. · Department of Immunology and Transfusion Medicine, Haukeland University Hospital, Bergen, Norway. · Department of Clinical Science, University of Bergen, Haukeland University Hospital, Bergen, Norway. · Department of Clinical Medicine, University of Bergen, Haukeland University Hospital, Bergen, Norway. · Department of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. ·PLoS One · Pubmed #27536947.

ABSTRACT: Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We have previously suggested clinical benefit from B-cell depletion using the monoclonal anti-CD20 antibody rituximab in a randomized and placebo-controlled study. Prolonged responses were then demonstrated in an open-label phase-II study with maintenance rituximab treatment. Using blood samples from patients in the previous two clinical trials, we investigated quantitative changes in T-lymphocyte subsets, in immunoglobulins, and in serum levels of two B-cell regulating cytokines during follow-up. B-lymphocyte activating factor of the tumor necrosis family (BAFF) in baseline serum samples was elevated in 70 ME/CFS patients as compared to 56 healthy controls (p = 0.011). There were no significant differences in baseline serum BAFF levels between patients with mild, moderate, or severe ME/CFS, or between responders and non-responders to rituximab. A proliferation-inducing ligand (APRIL) serum levels were not significantly different in ME/CFS patients compared to healthy controls at baseline, and no changes in serum levels were seen during follow-up. Immunophenotyping of peripheral blood T-lymphocyte subsets and T-cell activation markers at multiple time points during follow-up showed no significant differences over time, between rituximab and placebo groups, or between responders and non-responders to rituximab. Baseline serum IgG levels were significantly lower in patients with subsequent response after rituximab therapy compared to non-responders (p = 0.03). In the maintenance study, slight but significant reductions in mean serum immunoglobulin levels were observed at 24 months compared to baseline; IgG 10.6-9.5 g/L, IgA 1.8-1.5 g/L, and IgM 0.97-0.70 g/L. Although no functional assays were performed, the lack of significant associations of T- and NK-cell subset numbers with B-cell depletion, as well as the lack of associations to clinical responses, suggest that B-cell regulatory effects on T-cell or NK-cell subsets are not the main mechanisms for the observed improvements in ME/CFS symptoms observed in the two previous trials. The modest increase in serum BAFF levels at baseline may indicate an activated B-lymphocyte system in a subgroup of ME/CFS patients.

16 Article Investigation of suspected chronic fatigue syndrome/myalgic encephalopathy. 2016

Owe, Jone Furlund / Næss, Halvor / Gjerde, Ivar Otto / Bødtker, Jørn Eilert / Tysnes, Ole-Bjørn. ·Nevrologisk avdeling Haukeland universitetssykehus. · Nevrologisk avdeling Haukeland universitetssykehus og Universitet i Bergen. · Klinikk for psykosomatisk medisin, Haukeland universitetssykehus. ·Tidsskr Nor Laegeforen · Pubmed #26860382.

ABSTRACT: BACKGROUND: Chronic fatigue is a frequently occurring problem in both the primary and specialist health services. The Department of Neurology at Haukeland University Hospital has established a standard assessment for patients referred with suspected CFS/ME. This study reports diagnoses and findings upon assessment, and considers the benefit of supplementary examinations. MATERIAL AND METHOD: Diagnoses and findings from examinations of 365 patients assessed for suspected CFS/ME are retrospectively reported. RESULTS: A total of 48 patients (13.2%) were diagnosed with CFS/ME, while a further 18 patients (4.9%) were diagnosed with post-infectious fatigue. Mental and behavioural disorders were diagnosed in 169 patients (46.3%), and these represented by far the largest group. Serious, but unrecognised somatic illness was discovered in two patients, while changes of uncertain significance were identified by MRI and lumbar puncture in a few patients. INTERPRETATION: Fatigue is a frequently occurring symptom in the population. Thorough somatic and psychiatric investigation is necessary before referral to the specialist health services. Mental disorders and reactions to life crises are common and important differential diagnoses for CFS/ME. Long waiting times in the specialist health services may result in delayed diagnosis for these patients.

17 Article Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. 2016

Loebel, Madlen / Grabowski, Patricia / Heidecke, Harald / Bauer, Sandra / Hanitsch, Leif G / Wittke, Kirsten / Meisel, Christian / Reinke, Petra / Volk, Hans-Dieter / Fluge, Øystein / Mella, Olav / Scheibenbogen, Carmen. ·Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany. Electronic address: madlen.loebel@charite.de. · Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany. · CellTrend GmbH, Luckenwalde, Brandenburg, Germany. · Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany; Labor Berlin GmbH, Immunology Department, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany. · Department of Nephrology, Charité University Medicine Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Germany. · Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Germany. · Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway. · Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway. ·Brain Behav Immun · Pubmed #26399744.

ABSTRACT: Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in CFS point to an autoimmune disease directed against neurotransmitter receptors. Autoantibodies against G-protein coupled receptors were shown to play a pathogenic role in several autoimmune diseases. Here, serum samples from a patient cohort from Berlin (n=268) and from Bergen with pre- and post-treatment samples from 25 patients treated within the KTS-2 rituximab trial were analysed for IgG against human α and β adrenergic, muscarinic (M) 1-5 acetylcholine, dopamine, serotonin, angiotensin, and endothelin receptors by ELISA and compared to a healthy control cohort (n=108). Antibodies against β2, M3 and M4 receptors were significantly elevated in CFS patients compared to controls. In contrast, levels of antibodies against α adrenergic, dopamine, serotonin, angiotensin, and endothelin receptors were not different between patients and controls. A high correlation was found between levels of autoantibodies and elevated IgG1-3 subclasses, but not with IgG4. Further patients with high β2 antibodies had significantly more frequently activated HLA-DR+ T cells and more frequently thyreoperoxidase and anti-nuclear antibodies. In patients receiving rituximab maintenance treatment achieving prolonged B-cell depletion, elevated β2 and M4 receptor autoantibodies significantly declined in clinical responder, but not in non-responder. We provide evidence that 29.5% of patients with CFS had elevated antibodies against one or more M acetylcholine and β adrenergic receptors which are potential biomarkers for response to B-cell depleting therapy. The association of autoantibodies with immune markers suggests that they activate B and T cells expressing β adrenergic and M acetylcholine receptors. Dysregulation of acetylcholine and adrenergic signalling could also explain various clinical symptoms of CFS.

18 Article The relationship between irritable bowel syndrome, functional dyspepsia, chronic fatigue and overactive bladder syndrome: a controlled study 6 years after acute gastrointestinal infection. 2015

Persson, Robert / Wensaas, Knut-Arne / Hanevik, Kurt / Eide, Geir Egil / Langeland, Nina / Rortveit, Guri. ·Research Unit for General Practice, Uni Research Health, Bergen, Norway. persson.robert@gmail.com. · Research Unit for General Practice, Uni Research Health, Bergen, Norway. awensaas@online.no. · Department of Clinical Science, University of Bergen, Bergen, Norway. kurt.hanevik@med.uib.no. · Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway. geir.egil.eide@helse-bergen.no. · Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway. geir.egil.eide@helse-bergen.no. · Department of Clinical Science, University of Bergen, Bergen, Norway. nina.langeland@mofa.uib.no. · Department of Medicine, Haukeland University Hospital, Bergen, Norway. nina.langeland@mofa.uib.no. · Research Unit for General Practice, Uni Research Health, Bergen, Norway. guri.rortveit@isf.uib.no. · Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway. guri.rortveit@isf.uib.no. ·BMC Gastroenterol · Pubmed #26058591.

ABSTRACT: BACKGROUND: To investigate in a cohort with previous gastrointestinal infection and a control group the prevalence of overactive bladder syndrome (OAB), and how it was associated with three other functional disorders; irritable bowel syndrome (IBS), functional dyspepsia (FD) and chronic fatigue (CF). METHODS: Controlled historic cohort study including 724 individuals with laboratory confirmed giardiasis six years earlier, and 847 controls matched by gender and age. Prevalence and odds ratios (OR) with 95 % confidence intervals (CI) were calculated. RESULTS: The prevalence of OAB was 18.7 % (134/716) in the exposed group and 13.6 % (113/833) in the control group (p = 0.007). The association between OAB and IBS was strong in the control group (OR: 2.42; 95 % CI: 1.45 to 4.04), but insignificant in the Giardia exposed (OR: 1.29; 95 % CI: 0.88 to 1.88). The association between OAB and FD was weak in both groups. CF was strongly associated with OAB (OR: 2.73; 95 % CI: 1.85 to 4.02 in the exposed and OR: 2.79; 95 % CI: 1.69 to 4.62 in the controls), and this association remained when comorbid conditions were excluded. CONCLUSIONS: Sporadic IBS was associated with increased risk of OAB, whereas post-infectious IBS was not. An apparent association between OAB and previous Giardia infection can be ascribed to comorbid functional disorders.

19 Article Longitudinal follow-up of employment status in patients with chronic fatigue syndrome after mononucleosis. 2014

Nyland, Morten / Naess, Halvor / Birkeland, Jon Steinar / Nyland, Harald. ·Institute of Clinical Medicine, University of Bergen, Bergen, Norway. · Institute of Clinical Medicine, University of Bergen, Bergen, Norway Department of Neurology, Haukeland University Hospital, Bergen, Norway. · Department of Neurology, Haukeland University Hospital, Bergen, Norway. ·BMJ Open · Pubmed #25428629.

ABSTRACT: OBJECTIVE: To examine the effect of early clinical and demographic factors on occupational outcome, return to work or awarded permanent disability pension in young patients with chronic fatigue syndrome (CFS). DESIGN: Longitudinal cohort study. INTERVENTION: A written self-management programme including a description of active coping strategies for daily life was provided. SETTING, PARTICIPANTS: Patients with CFS after mononucleosis were evaluated at Department of Neurology, Haukeland University Hospital during 1996-2006 (contact 1). In 2009 self-report questionnaires were sent to all patients (contact 2). PRIMARY AND SECONDARY OUTCOME MEASURES: Primary measure was employment status at contact 2. Secondary measures included clinical symptoms, and Fatigue Severity Scale (FSS) scores on both contacts, and Work and Social Adjustment Scale (WSAS) at contact 2. RESULTS: Of 111 patients at contact 1, 92 (83%) patients returned the questionnaire at contact 2. Mean disease duration at contact 1 was 4.7 years and at contact 2 11.4 years. At contact 1, 9 (10%) were part-time or full-time employed. At contact 2, 49 (55%) were part-time or full-time employed. Logical regression analysis showed that FSS≥5 at contact 2 was associated with depression, arthralgia and long disease duration (all at contact 1). CONCLUSIONS: About half of younger patients with CFS with long-term incapacity for work experienced marked improvement including full-time or part-time employment showing better outcomes than expected. Risk factors for transition to permanent disability were depression, arthralgia and disease duration.

20 Article Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012. 2014

Bakken, Inger Johanne / Tveito, Kari / Gunnes, Nina / Ghaderi, Sara / Stoltenberg, Camilla / Trogstad, Lill / Håberg, Siri Eldevik / Magnus, Per. ·Norwegian Institute of Public Health, PO Box 4404, Nydalen, N-0403, Oslo, Norway. inger.johanne.bakken@fhi.no. · The Norwegian Medical Association, Oslo, Norway. kari.tveito@legeforeningen.no. · Norwegian Institute of Public Health, PO Box 4404, Nydalen, N-0403, Oslo, Norway. nina.gunnes@fhi.no. · Norwegian Institute of Public Health, PO Box 4404, Nydalen, N-0403, Oslo, Norway. sara.ghaderi@fhi.no. · Norwegian Institute of Public Health, PO Box 4404, Nydalen, N-0403, Oslo, Norway. camilla.stoltenberg@fhi.no. · Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway. camilla.stoltenberg@fhi.no. · Norwegian Institute of Public Health, PO Box 4404, Nydalen, N-0403, Oslo, Norway. lill.iren.trogstad@fhi.no. · Norwegian Institute of Public Health, PO Box 4404, Nydalen, N-0403, Oslo, Norway. sirieldevik.haberg@fhi.no. · Norwegian Institute of Public Health, PO Box 4404, Nydalen, N-0403, Oslo, Norway. per.magnus@fhi.no. ·BMC Med · Pubmed #25274261.

ABSTRACT: BACKGROUND: The aim of the current study was to estimate sex- and age-specific incidence rates of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) using population-based registry data. CFS/ME is a debilitating condition with large impact on patients and their families. The etiology is unknown, and the distribution of the disease in the general population has not been well described. METHODS: Cases of CFS/ME were identified in the Norwegian Patient Register (NPR) for the years 2008 to 2012. The NPR is nationwide and contains diagnoses assigned by specialist health care services (hospitals and outpatient clinics). We estimated sex- and age-specific incidence rates by dividing the number of new cases of CFS/ME in each category by the number of person years at risk. Incidence rate ratios were estimated by Poisson regression with sex, age categories, and year of diagnosis as covariates. RESULTS: A total of 5,809 patients were registered with CFS/ME during 2008 to 2012. The overall incidence rate was 25.8 per 100,000 person years (95% confidence interval (CI): 25.2 to 26.5). The female to male incidence rate ratio of CFS/ME was 3.2 (95% CI: 3.0 to 3.4). The incidence rate varied strongly with age for both sexes, with a first peak in the age group 10 to 19 years and a second peak in the age group 30 to 39 years. CONCLUSIONS: Early etiological clues can sometimes be gained from examination of disease patterns. The strong female preponderance and the two age peaks suggest that sex- and age-specific factors may modulate the risk of CFS/ME.

21 Article Prevalence and predictors of recovery from chronic fatigue syndrome in a routine clinical practice. 2014

Flo, Elisabeth / Chalder, Trudie. ·Norwegian Competence Center for Sleep Disorders, Haukeland University Hospital, Bergen, Norway; Centre for Elderly and Nursing Home Medicine, Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway. Electronic address: elisabeth.flo@psykp.uib.no. · Institute of Psychiatry, King's College London, London, United Kingdom. ·Behav Res Ther · Pubmed #25222752.

ABSTRACT: Cognitive behavioural therapy (CBT) is one of the treatments of choice for patients with chronic fatigue syndrome (CFS). However, the factors that predict recovery are unknown. The objective of this study was to ascertain the recovery rate among CFS patients receiving CBT in routine practice and to explore possible predictors of recovery. Recovery was defined as no longer meeting Oxford or CDC criteria for CFS measured at 6 months follow-up. A composite score representing full recovery additionally included the perception of improvement, and normal population levels of fatigue and of physical functioning. Logistic regression was used to examine predictors of recovery. Predictors included age, gender, cognitive and behavioural responses to symptoms, work and social adjustment, beliefs about emotions, perfectionism, anxiety and depression at baseline. At 6 months follow-up 37.5% of the patients no longer met either the Oxford or the CDC criteria for CFS while 18.3% were fully recovered. Multivariate analyses showed that worse scores on the work and social adjustment scale, unhelpful beliefs about emotions, high levels of depression and older age were associated with reduced odds for recovery. Recovery rates in this routine practice were comparable to previous RCTs. There was a wide spectrum of significant predictors for recovery.

22 Article Irritable bowel syndrome and chronic fatigue 6 years after giardia infection: a controlled prospective cohort study. 2014

Hanevik, Kurt / Wensaas, Knut-Arne / Rortveit, Guri / Eide, Geir Egil / Mørch, Kristine / Langeland, Nina. ·Department of Clinical Science, University of Bergen. · Research Unit for General Practice, Uni Research Health. · Research Unit for General Practice, Uni Research Health Department of Global Public Health and Primary Care, University of Bergen. · Department of Global Public Health and Primary Care, University of Bergen Centre for Clinical Research. · National Centre for Tropical Infectious Diseases, Department of Medicine, Haukeland University Hospital, Bergen, Norway. ·Clin Infect Dis · Pubmed #25115874.

ABSTRACT: BACKGROUND: Functional gastrointestinal disorders and fatigue may follow acute infections. This study aimed to estimate the persistence, prevalence, and risk of irritable bowel syndrome and chronic fatigue 6 years after Giardia infection. METHODS: We performed a controlled prospective study of a cohort of 1252 individuals who had laboratory-confirmed Giardia infection during a waterborne outbreak in 2004. In total, 748 cohort cases (exposed) and 878 matched controls responded to a postal questionnaire 6 years later (in 2010). Responses were compared to data from the same cohort 3 years before (in 2007). RESULTS: The prevalences of irritable bowel syndrome (39.4%) by Rome III criteria and chronic fatigue (30.8%) in the exposed group 6 years after giardiasis were significantly elevated compared with controls, with adjusted relative risks (RRs) of 3.4 (95% confidence interval [CI], 2.9-3.9) and 2.9 (95% CI, 2.3-3.4), respectively. In the exposed group, the prevalence of irritable bowel syndrome decreased by 6.7% (RR, 0.85 [95% CI, .77-.93]), whereas the prevalence of chronic fatigue decreased by 15.3% from 3 to 6 years after Giardia infection (RR, 0.69 [95% CI, .62-.77]). Giardia exposure was a significant risk factor for persistence of both conditions, and increasing age was a risk factor for persisting chronic fatigue. CONCLUSIONS: Giardia infection in a nonendemic setting is associated with an increased risk for irritable bowel syndrome and chronic fatigue 6 years later. The prevalences of both conditions decrease over time, indicating that this intestinal protozoan parasite may elicit very long-term, but slowly self-limiting, complications.

23 Article Chronic fatigue syndrome 5 years after giardiasis: differential diagnoses, characteristics and natural course. 2013

Mørch, Kristine / Hanevik, Kurt / Rivenes, Ann C / Bødtker, Jørn E / Næss, Halvor / Stubhaug, Bjarte / Wensaas, Knut-Arne / Rortveit, Guri / Eide, Geir E / Hausken, Trygve / Langeland, Nina. ·National Centre for Tropical Infectious Diseases, Department of Medicine, Haukeland University Hospital, Bergen, Norway. kristine.morch@helse-bergen.no ·BMC Gastroenterol · Pubmed #23399438.

ABSTRACT: BACKGROUND: A high prevalence of chronic fatigue has previously been reported following giardiasis after a large waterborne outbreak in Bergen, Norway in 2004. The aim of this study was to describe and evaluate differential diagnoses and natural course of fatigue five years after giardiasis among patients who reported chronic fatigue three years after the infection. METHODS: Patients who three years after Giardia infection met Chalder's criteria for chronic fatigue (n=347) in a questionnaire study among all patients who had laboratory confirmed giardiasis during the Bergen outbreak (n=1252) were invited to participate in this study five years after the infection (n=253). Structured interviews and clinical examination were performed by specialists in psychiatry, neurology and internal medicine/infectious diseases. Fukuda et al's 1994 criteria were used to diagnose chronic fatigue syndrome (CFS) and idiopathic chronic fatigue (ICF). Self-reported fatigue recorded with Chalder Fatigue Questionnaire three and five years after infection were compared. RESULTS: 53 patients were included. CFS was diagnosed in 41.5% (22/53) and ICF in 13.2% (7/53). Chronic fatigue caused by other aetiology was diagnosed in 24.5% (13/53); five of these patients had sleep apnoea/hypopnoea syndrome, six had depression and five anxiety disorder, and among these two had more than one diagnosis. Fatigue had resolved in 20.8% (11/53). Self-reported fatigue score in the cohort was significantly reduced at five years compared to three years (p<0.001). CONCLUSION: The study shows that Giardia duodenalis may induce CFS persisting as long as five years after the infection. Obstructive sleep apnoea/hypopnoea syndrome, depression and anxiety were important differential diagnoses, or possibly comorbidities, to post-infectious fatigue in this study. Improvement of chronic fatigue in the period from three to five years after giardiasis was found.

24 Article Immunophenotyping in post-giardiasis functional gastrointestinal disease and chronic fatigue syndrome. 2012

Hanevik, Kurt / Kristoffersen, Einar K / Sørnes, Steinar / Mørch, Kristine / Næss, Halvor / Rivenes, Ann C / Bødtker, Jørn E / Hausken, Trygve / Langeland, Nina. ·Institute of Medicine, University of Bergen, Bergen N-5021, Norway. kurt.hanevik@med.uib.no ·BMC Infect Dis · Pubmed #23061432.

ABSTRACT: BACKGROUND: A Giardia outbreak was associated with development of post-infectious functional gastrointestinal disorders (PI-FGID) and chronic fatigue syndrome (PI-CFS). Markers of immune dysfunction have given conflicting results in CFS and FGID patient populations. The aim of this study was to evaluate a wide selection of markers of immune dysfunction in these two co-occurring post-infectious syndromes. METHODS: 48 patients, reporting chronic fatigue in a questionnaire study, were clinically evaluated five years after the outbreak and grouped according to Fukuda criteria for CFS (n=19) and idiopathic chronic fatigue (n=5) and Rome II criteria for FGIDs (n=54). 22 Giardia exposed non-fatigued individuals and 10 healthy unexposed individuals were recruited as controls. Peripheral blood lymphocyte subsets were analyzed by flow cytometry. RESULTS: In peripheral blood we found significantly higher CD8 T-cell levels in PI-FGID, and significantly lower NK-cell levels in PI-CFS patients. Severity of abdominal and fatigue symptoms correlated negatively with NK-cell levels. A tendency towards lower T-cell CD26 expression in FGID was seen. CONCLUSION: Patients with PI-CFS and/or PI-FGID 5 years after Giardia lamblia infection showed alterations in NK-cell and CD8-cell populations suggesting a possible immunological abnormality in these conditions. We found no significant changes in other markers examined in this well-defined group of PI-CFS and PI-FGID elicited by a gastrointestinal infection. Controlling for co-morbid conditions is important in evaluation of CFS-biomarkers.

25 Article Chronic fatigue syndrome after Giardia enteritis: clinical characteristics, disability and long-term sickness absence. 2012

Naess, Halvor / Nyland, Morten / Hausken, Trygve / Follestad, Inghild / Nyland, Harald I. ·Institute of Clinical Medicine, Department of Neurology, and Unit for Gastroenterology, Department for Medicine, Haukeland University Hospital, Bergen, Norway. halvor.naess@haukeland.no ·BMC Gastroenterol · Pubmed #22316329.

ABSTRACT: BACKGROUND: A waterborne outbreak of Giardia lamblia gastroenteritis led to a high prevalance of long-lasting fatigue and abdominal symptoms. The aim was to describe the clinical characteristics, disability and employmentloss in a case series of patients with Chronic Fatigue Syndrome (CFS) after the infection. METHODS: Patients who reported persistent fatigue, lowered functional capacity and sickness leave or delayed education after a large community outbreak of giardiasis enteritis in the city of Bergen, Norway were evaluated with the established Centers for Disease Control and Prevention criteria for CFS. Fatigue was self-rated by the Fatigue Severity Scale (FSS). Physical and mental health status and functional impairment was measured by the Medical Outcome Severity Scale-short Form-36 (SF-36). The Hospital Anxiety and Depression Scale (HADS) was used to measure co-morbid anxiety and depression. Inability to work or study because of fatigue was determined by sickness absence certified by a doctor. RESULTS: A total of 58 (60%) out of 96 patients with long-lasting post-infectious fatigue after laboratory confirmed giardiasis were diagnosed with CFS. In all, 1262 patients had laboratory confirmed giardiasis. At the time of referral (mean illness duration 2.7 years) 16% reported improvement, 28% reported no change, and 57% reported progressive course with gradual worsening. Mean FSS score was 6.6. A distinctive pattern of impairment was documented with the SF-36. The physical functioning, vitality (energy/fatigue) and social functioning were especially reduced. Long-term sickness absence from studies and work was noted in all patients. CONCLUSION: After giardiasis enteritis at least 5% developed clinical characteristics and functional impairment comparable to previously described post-infectious fatigue syndrome.

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