2015 – Page 8 – American ME and CFS Society

Reflections on the Institute of Medicine’s systemic exertion intolerance disease

Abstract:

The Institute of Medicine (IOM) in the United States has recently proposed that the term systemic exertion intolerance disease (SEID) replace chronic fatigue syndrome. In addition, the IOM proposed a new case definition for SEID, which includes substantial reductions or impairments in the ability to engage in pre illness activities, unrefreshing sleep, postexertional malaise, and either cognitive impairment or orthostatic intolerance.

Unfortunately, these recommendations for a name change were not vetted with patient and professional audiences, and the new criteria were not evaluated with data sets of patients and controls. A recent poll suggests that the majority of patients reject this new name. In addition, studies have found that prevalence rates will dramatically increase with the new criteria, particularly due to the ambiguity revolving around exclusionary illnesses. Findings suggest that the new criteria select more patients who have less impairment and fewer symptoms than several other criteria. The implications of these findings are discussed in the current review.

Source: Jason LA, Sunnquist M, Brown A, McManimen S, Furst J. Reflections on the Institute of Medicine’s systemic exertion intolerance disease. Pol Arch Med Wewn. 2015;125(7-8):576-81. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826027/ (Full article)

Induction Murine Models of Chronic Fatigue Syndrome by Brucella abortus Antigen Injections: Is Anemia Induced or Not?

Abstract:

To investigate whether Brucella abortus (BA) antigen injections lead to anemia, and to establish an appropriate Chronic Fatigue Syndrome (CFS) animal model by BA injections, 6 repeated injections of BA antigen were fulfilled every 2 weeks. At a high dose of 1∗10(10) particles/mouse, anemia was induced within 2 weeks and then recovered a lot at the end of the research, while at a moderate dose of 1∗10(8) (3 injections) shifting to 1∗10(9)/mouse (3 injections) anemia was absent. In both groups running wheel activity remained very low even 6 weeks after the last injection.

Source: Moriya J, He Q, Uenishi H, Akazawa S, Yamakawa J, Kobayashi J, Ishigaki Y. Induction Murine Models of Chronic Fatigue Syndrome by Brucella abortus Antigen Injections: Is Anemia Induced or Not? Biomed Res Int. 2015;2015:191489. doi: 10.1155/2015/191489. Epub 2015 Jun 11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480237/ (Full article)

Oral Colostrum Macrophage-activating Factor for Serious Infection and Chronic Fatigue Syndrome: Three Case Reports

Abstract:

BACKGROUND: Gc protein-derived macrophage-activating factor (GcMAF) immunotherapy has been steadily advancing over the last two decades. Oral colostrum macrophage-activating factor (MAF) produced from bovine colostrum has shown high macrophage phagocytic activity. GcMAF-based immunotherapy has a wide application for use in treating many diseases via macrophage activation or for use as supportive therapy.

RESULTS: Three case studies demonstrate that oral colostrum MAF can be used for serious infection and chronic fatigue syndrome (CFS) without adverse effects.

CONCLUSION: We demonstrate that colostrum MAF shows promising clinical results in patients with infectious diseases and for symptoms of fatigue, which is common in many chronic diseases.

Source: Inui T, Kubo K, Kuchiike D, Uto Y, Nishikata T, Sakamoto N, Mette M. Oral Colostrum Macrophage-activating Factor for Serious Infection and Chronic Fatigue Syndrome: Three Case Reports. Anticancer Res. 2015 Aug;35(8):4545-9. https://www.ncbi.nlm.nih.gov/pubmed/26168499

Modeling diurnal hormone profiles by hierarchical state space models

Abstract:

Adrenocorticotropic hormone (ACTH) diurnal patterns contain both smooth circadian rhythms and pulsatile activities. How to evaluate and compare them between different groups is a challenging statistical task. In particular, we are interested in testing (1) whether the smooth ACTH circadian rhythms in chronic fatigue syndrome and fibromyalgia patients differ from those in healthy controls and (2) whether the patterns of pulsatile activities are different. In this paper, a hierarchical state space model is proposed to extract these signals from noisy observations. The smooth circadian rhythms shared by a group of subjects are modeled by periodic smoothing splines. The subject level pulsatile activities are modeled by autoregressive processes. A functional random effect is adopted at the pair level to account for the matched pair design. Parameters are estimated by maximizing the marginal likelihood. Signals are extracted as posterior means. Computationally efficient Kalman filter algorithms are adopted for implementation. Application of the proposed model reveals that the smooth circadian rhythms are similar in the two groups but the pulsatile activities in patients are weaker than those in the healthy controls.

Source: Liu Z, Guo W. Modeling diurnal hormone profiles by hierarchical state space models. Stat Med. 2015 Oct 30;34(24):3223-34. doi: 10.1002/sim.6579. Epub 2015 Jul 7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592415/ (Full article)

The Health-Related Quality of Life for Patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS)

Abstract:

INTRODUCTION: Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a common, severe condition affecting 0.2 to 0.4 per cent of the population. Even so, no recent international EQ-5D based health-related quality of life (HRQoL) estimates exist for ME/CFS patients. The main purpose of this study was to estimate HRQoL scores using the EQ-5D-3L with Danish time trade-off tariffs. Secondary, the aims were to explore whether the results are not influenced by other conditions using regression, to compare the estimates to 20 other conditions and finally to present ME/CFS patient characteristics for use in clinical practice.

MATERIAL AND METHODS: All members of the Danish ME/CFS Patient Association in 2013 (n=319) were asked to fill out a questionnaire including the EQ-5D-3L. From these, 105 ME/CFS patients were identified and gave valid responses. Unadjusted EQ-5D-3L means were calculated and compared to the population mean as well as to the mean of 20 other conditions. Furthermore, adjusted estimates were calculated using ordinary least squares (OLS) regression, adjusting for gender, age, education, and co-morbidity of 18 self-reported conditions. Data from the North Denmark Health Profile 2010 was used as population reference in the regression analysis (n=23,392).

RESULTS: The unadjusted EQ-5D-3L mean of ME/CFS was 0.47 [0.41-0.53] compared to a population mean of 0.85 [0.84-0.86]. The OLS regression estimated a disutility of -0.29 [-0.21;-0.34] for ME/CFS patients in this study. The characteristics of ME/CFS patients are different from the population with respect to gender, relationship, employment etc.

CONCLUSION: The EQ-5D-3L-based HRQoL of ME/CFS is significantly lower than the population mean and the lowest of all the compared conditions. The adjusted analysis confirms that poor HRQoL of ME/CFS is distinctly different from and not a proxy of the other included conditions. However, further studies are needed to exclude the possible selection bias of the current study.

Source: Falk Hvidberg M, Brinth LS, Olesen AV, Petersen KD, Ehlers L. The Health-Related Quality of Life for Patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS). PLoS One. 2015 Jul 6;10(7):e0132421. doi: 10.1371/journal.pone.0132421. ECollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492975/ (Full article)

Accurate diagnosis of myalgic encephalomyelitis and chronic fatigue syndrome based upon objective test methods for characteristic symptoms

Abstract:

Although myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are considered to be synonymous, the definitional criteria for ME and CFS define two distinct, partially overlapping, clinical entities. ME, whether defined by the original criteria or by the recently proposed criteria, is not equivalent to CFS, let alone a severe variant of incapacitating chronic fatigue.

Distinctive features of ME are: muscle weakness and easy muscle fatigability, cognitive impairment, circulatory deficits, a marked variability of the symptoms in presence and severity, but above all, post-exertional “malaise”: a (delayed) prolonged aggravation of symptoms after a minor exertion. In contrast, CFS is primarily defined by (unexplained) chronic fatigue, which should be accompanied by four out of a list of 8 symptoms, e.g., headaches.

Due to the subjective nature of several symptoms of ME and CFS, researchers and clinicians have questioned the physiological origin of these symptoms and qualified ME and CFS as functional somatic syndromes. However, various characteristic symptoms, e.g., post-exertional “malaise” and muscle weakness, can be assessed objectively using well-accepted methods, e.g., cardiopulmonary exercise tests and cognitive tests. The objective measures acquired by these methods should be used to accurately diagnose patients, to evaluate the severity and impact of the illness objectively and to assess the positive and negative effects of proposed therapies impartially.

Source: Twisk FN. Accurate diagnosis of myalgic encephalomyelitis and chronic fatigue syndrome based upon objective test methods for characteristic symptoms. World J Methodol. 2015 Jun 26;5(2):68-87. doi: 10.5662/wjm.v5.i2.68. ECollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482824/ (Full article)

Health related quality of life in adolescents with chronic fatigue syndrome: a cross-sectional study

Abstract:

AIM: To study health related quality of life (HRQOL) and depressive symptoms in adolescents with chronic fatigue syndrome (CFS) and to investigate in which domains their HRQOL and depressive symptoms differ from those of healthy adolescents.

BACKGROUND AND OBJECTIVE: Several symptoms such as disabling fatigue, pain and depressive symptoms affect different life domains of adolescents with CFS. Compared to adolescents with other chronic diseases, young people with CFS are reported to be severely impaired, both physiologically and mentally. Despite this, few have investigated the HRQOL in this group.

METHOD: This is a cross-sectional study on HRQOL including 120 adolescents with CFS and 39 healthy controls (HC), between 12 and 18 years. The Pediatric Quality of Life Inventory™, 4.0 (PedsQL) was used to assess HRQOL. The Mood and Feelings Questionnaire assessed depressive symptoms. Data were collected between March 2010 and October 2012 as part of the NorCAPITAL project (Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial). Linear and logistic regression models were used in analysis, and all tests were two-sided.

RESULTS: Adolescents with CFS reported significantly lower overall HRQOL compared to HCs. When controlling for gender differences, CFS patients scored 44 points lower overall HRQOL on a scale from 0-100 compared to HCs. The domains with the largest differences were interference with physical health (B = -59, 95 % CI -54 to -65) and school functioning (B = -52, 95 % CI -45 to -58). Both depressive symptoms and being a patient were independently associated with lower levels of HRQOL

CONCLUSION: The difference in HRQOL between CFS patients and healthy adolescents was even larger than we expected. The large sample of adolescents with CFS in our study confirms previous findings from smaller studies, and emphasizes that CFS is a seriously disabling condition that has a strong impact on their HRQOL. Even though depressive symptoms were found in the group of patients, they could not statistically explain the poor HRQOL.

Source: Winger A, Kvarstein G, Wyller VB, Ekstedt M, Sulheim D, Fagermoen E, Småstuen MC, Helseth S. Health related quality of life in adolescents with chronic fatigue syndrome: a cross-sectional study. Health Qual Life Outcomes. 2015 Jul 3;13:96. doi: 10.1186/s12955-015-0288-3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490669/ (Full article)

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

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.

Source: Fluge Ø, Risa K, Lunde S, Alme K, Rekeland IG, Sapkota D, Kristoffersen EK, Sørland K, Bruland O, Dahl O, Mella O. B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. PLoS One. 2015 Jul 1;10(7):e0129898. doi: 10.1371/journal.pone.0129898. ECollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488509/ (Full article)

Hybrid facial image feature extraction and recognition for non-invasive chronic fatigue syndrome diagnosis

Abstract:

Due to an absence of reliable biochemical markers, the diagnosis of chronic fatigue syndrome (CFS) mainly relies on the clinical symptoms, and the experience and skill of the doctors currently. To improve objectivity and reduce work intensity, a hybrid facial feature is proposed.

First, several kinds of appearance features are identified in different facial regions according to clinical observations of traditional Chinese medicine experts, including vertical striped wrinkles on the forehead, puffiness of the lower eyelid, the skin colour of the cheeks, nose and lips, and the shape of the mouth corner. Afterwards, such features are extracted and systematically combined to form a hybrid feature.

We divide the face into several regions based on twelve active appearance model (AAM) feature points, and ten straight lines across them. Then, Gabor wavelet filtering, CIELab color components, threshold-based segmentation and curve fitting are applied to extract features, and Gabor features are reduced by a manifold preserving projection method. Finally, an AdaBoost based score level fusion of multi-modal features is performed after classification of each feature.

Despite that the subjects involved in this trial are exclusively Chinese, the method achieves an average accuracy of 89.04% on the training set and 88.32% on the testing set based on the K-fold cross-validation. In addition, the method also possesses desirable sensitivity and specificity on CFS prediction.

Source: Chen Y, Liu W, Zhang L, Yan M, Zeng Y. Hybrid facial image feature extraction and recognition for non-invasive chronic fatigue syndrome diagnosis. Comput Biol Med. 2015 Sep;64:30-9. doi: 10.1016/j.compbiomed.2015.06.005. Epub 2015 Jun 15. https://www.ncbi.nlm.nih.gov/pubmed/26117650

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

Abstract:

Recent evidence suggests immune and inflammatory alterations are important in chronic fatigue syndrome (CFS). This study was done to explore the association of functionally important genetic variants in inflammation and immune pathways with CFS. Peripheral blood DNA was isolated from 50 CFS and 121 non-fatigued (NF) control participants in a population-based study. Genotyping was performed with the Affymetrix Immune and Inflammation Chip that covers 11K single nucleotide polymorphisms (SNPs) following the manufacturer’s protocol.

Genotyping accuracy for specific genes was validated by pyrosequencing. Golden Helix SVS software was used for genetic analysis. SNP functional annotation was done using SPOT and GenomePipe programs. CFS was associated with 32 functionally important SNPs: 11 missense variants, 4 synonymous variants, 11 untranslated regulatory region (UTR) variants and 6 intronic variants. Some of these SNPs were in genes within pathways related to complement cascade (SERPINA5, CFB, CFH, MASP1 and C6), chemokines (CXCL16, CCR4, CCL27), cytokine signaling (IL18, IL17B, IL2RB), and toll-like receptor signaling (TIRAP, IRAK4).

Of particular interest is association of CFS with two missense variants in genes of complement activation, rs4151667 (L9H) in CFB and rs1061170 (Y402H) in CFH. A 5′ UTR polymorphism (rs11214105) in IL18 also associated with physical fatigue, body pain and score for CFS case defining symptoms. This study identified new associations of CFS with genetic variants in pathways including complement activation providing additional support for altered innate immune response in CFS. Additional studies are needed to validate the findings of this exploratory study.

Published by Elsevier Inc.

Source: Rajeevan MS, Dimulescu I, Murray J, Falkenberg VR, Unger ER. Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome. Hum Immunol. 2015 Aug;76(8):553-60. doi: 10.1016/j.humimm.2015.06.014. Epub 2015 Jun 24. https://www.ncbi.nlm.nih.gov/pubmed/26116897