From BMC Immunology, 10 March 2016 (open access journal).
Illness progression in chronic fatigue syndrome: a shifting immune baseline
Lindsey Russell(1,†), Gordon Broderick(1,2,3,†), Renee Taylor(4), Henrique Fernandes(1), Jeanna Harvey (2,5), Zachary Barnes(1,2,3), AnneLiese Smylie(1), Fanny Collado(2), Elizabeth G. Balbin(1), Ben Z. Katz(6), Nancy G. Klimas (2,3) and Mary Ann Fletcher (2,3).
†) Contributed equally to study.
1) Department of Medicine, University of Alberta
2) Miami Veterans Affairs Medical Center
3) Institute for Neuro-immune Medicine, Nova Southeastern University
4) Department of Occupational Therapy, University of Illinois at Chicago
5) Department of Medicine, University of Miami
6) Division of Infectious Diseases, Ann & Robert H Lurie Children’s Hospital of Chicago
Abstract
BACKGROUND
Validation of biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) across data sets has proven disappointing. As immune signature may be affected by many factors, our objective was to explore the shift in discriminatory cytokines across ME/CFS subjects separated by duration of illness.
METHODS
Cytokine expression collected at rest across multiple studies for female ME/CFS subjects (i) 18 years or younger, ill for 2 years or less (n = 18), (ii) 18–50 years of age, ill for 7 years (n = 22), and (iii) age 50 years or older (n = 28), ill for 11 years on average. Control subjects were matched for age and body mass index (BMI). Data describing the levels of 16 cytokines using a chemiluminescent assay was used to support the identification of separate linear classification models for each subgroup. In order to isolate the effects of duration of illness alone, cytokines that changed significantly with age in the healthy control subjects were excluded a priori.
RESULTS
Optimal selection of cytokines in each group resulted in subsets of IL-1α, 6, 8, 15 and TNFα. Common to any 2 of 3 groups were IL-1α, 6 and 8. Setting these 3 markers as a triple screen and adjusting their contribution according to illness duration sub-groups produced ME/CFS classification accuracies of 75–88 %. The contribution of IL-1α, higher in recently ill adolescent ME/CFS subjects was progressively less important with duration. While high levels of IL-8 screened positive for ME/CFS in the recently afflicted, the opposite was true for subjects ill for more than 2 years. Similarly, while low levels of IL-6 suggested early ME/CFS, the reverse was true in subjects over 18 years of age ill for more than 2 years.
CONCLUSIONS
These preliminary results suggest that IL-1α, 6 and 8 adjusted for illness duration may serve as robust biomarkers, independent of age, in screening for ME/CFS.
Sophie Loup, the ME Association's research assistant, writes in her latest lay summary: This North American cytokine study published on 10 March 2016 is only an exploratory first analysis. The results need to be validated in a larger, more varied cohort before these cytokines can be considered as clinical biomarkers of ME/CFS.
Lay summary
Researchers have been looking for reliable indicators of ME/CFS to help with the screening of patients. Because markers in the immune system can be affected by many factors and because the characteristics of ME/CFS vary between patients in terms of age, illness duration and menopausal status, the identification of illness indicators is difficult.
Previous research suggests that ME/CFS may be characterised by imbalance in immune and hormonal functions and that certain cytokine profiles are characteristic of this persistent imbalance. Cytokines are small proteins that are made by cells and affect the behaviour of other cells. They are an important part of the immune system. Therefore this study explores the shifts in certain cytokines across ME/CFS patients with different illness durations to see if specific cytokines can be used as indicators of ME/CFS.
The authors of this North American study published on 10 March 2016 recruited women with ME/CFS meeting the Fukuda criteria across three studies in the US and divided them into three groups: (i) 18 year old or younger, ill for two years or less (18 participants), (ii) 18-50 year old, ill for seven years on average (22 participants), and (iii) 50 year old or older, ill for 11 years on average (28 participants). Control subjects were matched for age and body mass index (BMI).
The authors looked at a number of cytokines, and excluded those that changed significantly with age and BMI in the healthy controls. They identified the cytokines IL-1α, 6 and 8 as common to any two of the three groups of participants. These may be broadly applicable as illness markers for ME/CFS but their contribution varies based on duration of illness and perhaps other related factors. The contribution of IL-1α was higher in recently ill adolescents and decreased with duration of illness. High levels of IL-8 were found in the recently affected, but not in subjects ill for more than two years. Low levels of IL-6 suggested early ME/CFS, but the reverse was true for participants over 18 year old and ill for more than two years.
The results of the study suggest that IL-1α, 6 and 8, adjusted for illness duration, may serve as biomarkers for screening for ME/CFS, independent of age. However this study is only an exploratory first analysis. The results need to be further validated in a larger and more varied cohort before the three cytokines can be used in clinical settings.
From the Journal of Gastroenterology and Hepatology Research, published online on 22 March 2016 (full text available).
Putative Prophylaxes of Aloe Vera Juice with L-arginine to Chronic Fatigue Syndrome
Akira Yagi, Suzuka Ataka
Akira Yagi is Emeritus Professor, Fukuyama University, Hiroshima, Japan.
Suzuka Ataka is Associate Professor, Department of Geriatrics and Neurology, Osaka City University Medical School, Japan.
Their paper acknowledges the support of Forever Living Product Japan for supplying aloe vera juice and L-arginine supplement “and totaling (sic) of questionnaire”.
Abstract
L-Arginine is one of the most metabolically versatile amino acids. Several in vitro/in vivo experiments have indicated that exogenous L-arginine intake has multiple beneficial pharmacological and pharmaco-kinetic effects. Such effects include reduction in the risk of vascular and heart diseases and chronic fatigue syndrome.
The effects of a dietary supplementation of aloe vera juice with L-arginine to chronic fatigue syndrome were demonstrated and a questionnaire was given to adult subjects. The questionnaire included 10 points regarding their mental, circulatory and muscle functions. Table 1 and 2 summarize the most noteworthy information on supplementation of aloe vera juice with L-arginine.
The demonstrated benefits of aloe vera juice with L-arginine show promises to chronic fatigue syndrome in adult subjects.
Very impressed with the first paper. The authors have somehow managed to pin down hard data in spite of shifting immune signatures in different ME patients over time. We have seen many similar papers over the years, but I don’t think anyone else has managed to achieve this? Perhaps its to do with how the study was designed? Even more impressed by Sophie’s analysis which was so clearly written (equally hard to achieve in the muddied field of ME research!) Thank you. Begs the question why more researchers can’t use a straightforward language in the first place instead of an overly academic one?! (ps, I used to work as a nurse)!
Hear, hear, to all that, Jackie.
Tony
I’ll echo the above comments. Well done to Sophie. Much easier to understand.
Thank you