Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model

Abstract:

Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease.

A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension.

A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS.

Source: Jonas Blomberg, Gerhard Gottfries, Amal Elfaitouri, Muhammad Rizwan and Anders Rosén. Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model. Hypothesis and Theory Article, Front. Immunol., 15 February 2018 | https://doi.org/10.3389/fimmu.2018.00229 (Full article)

Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a heterogeneous syndrome in which patients often experience severe fatigue and malaise following exertion. Immune and cardiovascular dysfunction have been postulated to play a role in the pathophysiology. We therefore, examined whether cytokine profiling or cardiovascular testing following exercise would differentiate patients with ME/CFS.

Twenty-four ME/CFS patients were matched to 24 sedentary controls and underwent cardiovascular and circulating immune profiling. Cardiovascular analysis included echocardiography, cardiopulmonary exercise and endothelial function testing. Cytokine and growth factor profiles were analyzed using a 51-plex Luminex bead kit at baseline and 18 hours following exercise. Cardiac structure and exercise capacity were similar between groups.

Sparse partial least square discriminant analyses of cytokine profiles 18 hours post exercise offered the most reliable discrimination between ME/CFS and controls (κ = 0.62(0.34,0.84)). The most discriminatory cytokines post exercise were CD40L, platelet activator inhibitor, interleukin 1-β, interferon-α and CXCL1. In conclusion, cytokine profiling following exercise may help differentiate patients with ME/CFS from sedentary controls.

Source: Kegan J. Moneghetti, Mehdi Skhiri, Kévin Contrepois, Yukari Kobayashi, Holden Maecker, Mark Davis, Michael Snyder, Francois Haddad & Jose G. Montoya. Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Scientific Reports volume 8, Article number: 2779 (2018). doi:10.1038/s41598-018-20941-w. Received:02 November 2017. Accepted:26 January 2018. Published online:09 February 2018. https://www.nature.com/articles/s41598-018-20941-w (Full article)

On chronic fatigue syndrome and nosological categories

Abstract:

Chronic fatigue syndrome (CFS) is a heterogeneous disease which presents with pronounced disabling fatigue, sleep disturbances, and cognitive impairment that negatively affects patients’ functional capability. CFS remains a poorly defined entity and its etiology is still in question. CFS is neither a novel diagnosis nor a new medical condition. From as early as the eighteenth century, a constellation of perplexing symptoms was observed that resembled symptoms of CFS. Commencing with “febricula” and ending with CFS, many names for the disease were proposed including neurocirculatory asthenia, atypical poliomyelitis, Royal Free disease, effort syndrome, Akureyri disease, Tapanui disease, chronic Epstein-Barr virus syndrome, and myalgic encephalitis. To date, it remains unclear whether CFS has an autoimmune component or is a condition that precedes a full-blown autoimmune disease.

Research suggests that CFS may overlap with other diseases including postural orthostatic tachycardia syndrome (POTS), autoimmune syndrome induced by adjuvants (ASIA), and Sjögren’s syndrome. Additionally, it has been postulated that the earliest manifestations of some autoimmune diseases can present with vague non-specific symptoms similar to CFS. Sometimes only when exposed to a secondary stimulus (e.g., antigen) which could accelerate the natural course of the disease would an individual develop the classic autoimmune disease. Due to the similarity of symptoms, it has been postulated that CFS could simply be an early manifestation of an autoimmune disease. This paper will provide a historical background review of this disease and a discussion of CFS as an entity overlapping with multiple other conditions.

Source: Sharif K, Watad A, Bragazzi NL, Lichtbroun M, Martini M, Perricone C, Amital H, Shoenfeld Y. On chronic fatigue syndrome and nosological categories. Clin Rheumatol. 2018 Feb 7. doi: 10.1007/s10067-018-4009-2. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29417255

Time to Reject the PACE Study

Abstract:

The PACE trial investigated the efficacy of graded exercise therapy and cognitive behavioral therapy for ME/CFS. The design and the implementation of the study were flawed, and the conclusions are contradicted by the data. It is time to reject the study.

https://www.researchgate.net/publication/320101462_Time_to_Reject_the_PACE_Study [Full article].

This is a translation of an article that was published in slightly shortened form in Läkartidningen, Stockholm, Sweden, on 28 September 2017. http://www.lakartidningen.se/

Link to the shortened article in Swedish: http://www.lakartidningen.se/Opinion/De-batt/2017/09/Dags-att-forkasta-PACE-studien/

Source: Helmfrid S, Edsberg J. Dags att förkasta PACE-studien. Lakartid-ningen. 2017;114:ETLE.

The international collaborative on fatigue following infection (COFFI)

Abstract:

Background: The purpose of the Collaborative on Fatigue Following Infection (COFFI) is for investigators of post-infection fatigue (PIF) and other syndromes to collaborate on these enigmatic and poorly understood conditions by studying relatively homogeneous populations with known infectious triggers. Utilising COFFI, pooled data and stored biosamples will support both epidemiological and laboratory research to better understand the etiology and risk factors for development and progression of PIF.

Methods: COFFI consists of prospective cohorts from the UK, Netherlands, Norway, USA, New Zealand and Australia, with some cohorts closed and some open to recruitment. The 9 cohorts closed to recruitment total over 3000 participants, including nearly 1000 with infectious mononucleosis (IM), > 500 with Q fever, > 800 with giardiasis, > 600 with campylobacter gastroenteritis (CG), 190 with Legionnaires disease and 60 with Ross River virus. Follow-ups have been at least 6 months and up to 10 years. All studies use the Fukuda criteria for defining chronic fatigue syndrome (CFS).

Results: Preliminary analyses indicated that risk factors for non-recovery from PIF included lower physical fitness, female gender, severity of the acute sickness response, and autonomic dysfunction.

Conclusions: COFFI (https://internationalcoffi.wordpress.com/) is an international collaboration which should be able to answer questions based on pooled data that are not answerable in the individual cohorts. Possible questions may include the following: Do different infections trigger different PIF syndromes (e.g. CFS vs. irritable bowel syndrome)?; What are longitudinal predictors of PIF and its severity?

Source: Ben Z Katz, Simon M Collin, Gabrielle Murphy, Rona Moss-Morris, Vegard Bruun Wyller, Knut-Arne Wensaas, Jeannine L.A. Hautvast, Chantal P Bleeker-Rovers, Ute Vollmer-Conna, Dedra Buchwald, Renée Taylor, Paul Little, Esther Crawley, Peter D White & Andrew Lloyd. The international collaborative on fatigue following infection (COFFI). Fatigue: Biomedicine, Health & Behavior Vol. 0, Iss. 0, 2018. http://www.tandfonline.com/doi/abs/10.1080/21641846.2018.1426086?journalCode=rftg20

A Molecular Neurobiological Approach to Understanding the Aetiology of Chronic Fatigue Syndrome (Myalgic Encephalomyelitis or Systemic Exertion Intolerance Disease) with Treatment Implications

Abstract:

Currently, a psychologically based model is widely held to be the basis for the aetiology and treatment of chronic fatigue syndrome(CFS)/myalgic encephalomyelitis (ME)/systemic exertion intolerance disease (SEID). However, an alternative, molecular neurobiological approach is possible and in this paper evidence demonstrating a biological aetiology for CFS/ME/SEID is adduced from a study of the history of the disease and a consideration of the role of the following in this disease: nitric oxide and peroxynitrite, oxidative and nitrosative stress, the blood-brain barrier and intestinal permeability, cytokines and infections, metabolism, structural and chemical brain changes, neurophysiological changes and calcium ion mobilisation. Evidence is also detailed for biologically based potential therapeutic options, including: nutritional supplementation, for example in order to downregulate the nitric oxide-peroxynitrite cycle to prevent its perpetuation; antiviral therapy; and monoclonal antibody treatment. It is concluded that there is strong evidence of a molecular neurobiological aetiology, and so it is suggested that biologically based therapeutic interventions should constitute a focus for future research into CFS/ME/SEID.

Source: Monro JA, Puri BK. A Molecular Neurobiological Approach to Understanding the Aetiology of Chronic Fatigue Syndrome (Myalgic Encephalomyelitis or Systemic Exertion Intolerance Disease) with Treatment Implications. Mol Neurobiol. 2018 Feb 6. doi: 10.1007/s12035-018-0928-9. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29411266

Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons

Abstract:

BACKGROUND: Preliminary evidence suggests that the enteric microbiota may play a role in the expression of neurological symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Overlapping symptoms with the acute presentation of D-lactic acidosis has prompted the use of antibiotic treatment to target the overgrowth of species within the Streptococcus genus found in commensal enteric microbiota as a possible treatment for neurological symptoms in ME/CFS.

METHODS: An open-label, repeated measures design was used to examine treatment efficacy and enable sex comparisons. Participants included 44 adult ME/CFS patients (27 females) from one specialist medical clinic with Streptococcus viable counts above 3.00 × 105 cfu/g (wet weight of faeces) and with a count greater than 5% of the total count of aerobic microorganisms. The 4-week treatment protocol included alternate weeks of Erythromycin (400 mg of erythromycin as ethyl succinate salt) twice daily and probiotic (D-lactate free multistrain probiotic, 5 × 1010 cfu twice daily). 2 × 2 repeated measures ANOVAs were used to assess sex-time interactions and effects across pre- and post-intervention for microbial, lactate and clinical outcomes. Ancillary non-parametric correlations were conducted to examine interactions between change in microbiota and clinical outcomes.

RESULTS: Large treatment effects were observed for the intention-to-treat sample with a reduction in Streptococcus viable count and improvement on several clinical outcomes including total symptoms, some sleep (less awakenings, greater efficiency and quality) and cognitive symptoms (attention, processing speed, cognitive flexibility, story memory and verbal fluency). Mood, fatigue and urine D:L lactate ratio remained similar across time. Ancillary results infer that shifts in microbiota were associated with more of the variance in clinical changes for males compared with females.

CONCLUSIONS: Results support the notion that specific microorganisms interact with some ME/CFS symptoms and offer promise for the therapeutic potential of targeting gut dysbiosis in this population. Streptococcus spp. are not the primary or sole producers of D-lactate. Further investigation of lactate concentrations are needed to elucidate any role of D-lactate in this population. Concurrent microbial shifts that may be associated with clinical improvement (i.e., increased Bacteroides and Bifidobacterium or decreased Clostridium in males) invite enquiry into alternative strategies for individualised treatment.

Trial Registration Australian and New Zealand Clinical Trial Registry (ACTRN12614001077651) 9th October 2014. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366933&isReview=true.

Source: Wallis A, Ball M, Butt H, Lewis DP, McKechnie S, Paull P, Jaa-Kwee A, Bruck D. Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons. J Transl Med. 2018 Feb 6;16(1):24. doi: 10.1186/s12967-018-1392-z. https://www.ncbi.nlm.nih.gov/pubmed/29409505

Cardiovascular characteristics of chronic fatigue syndrome

Abstract:

Patients with chronic fatigue syndrome (CFS) commonly exhibit orthostatic intolerance. Abnormal sympathetic predominance in the autonomic cardiovascular response to gravitational stimuli was previously described in numerous studies. The aim of the current study was to describe cardiological and clinical characteristics of Italian patients with CFS. All of the patients were of Caucasian ethnicity and had been referred to our center, the Cardiology Department of the University Hospital of Pavia (Pavia, Italy) with suspected CFS. A total of 44 patients with suspected CFS were included in the present study and the diagnosis was confirmed in 19 patients according to recent clinical guidelines.

The characteristics at baseline of the population confirm findings from various previous reports regarding the prevalence in females with a female to male ratio of 4:1, the age of onset of the pathology and the presence of previous infection by the Epstein-Barr virus, cytomegalovirus and other human herpesviruses. Despite the current data indicating that the majority of the cardiological parameters investigated are not significantly different in patients with and without CFS, a significant association between the disease and low levels of blood pressure was identified. Other pilot studies revealed a higher prevalence of hypotension and orthostatic intolerance in patients with CFS. Furthermore, many of the CFS symptoms, including fatigue, vertigo, decreased concentration, tremors and nausea, may be explained by hypotension.

Source: Bozzini S, Albergati A, Capelli E, Lorusso L, Gazzaruso C, Pelissero G, Falcone C. Cardiovascular characteristics of chronic fatigue syndrome. Biomed Rep. 2018 Jan;8(1):26-30. doi: 10.3892/br.2017.1024. Epub 2017 Nov 28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772628/ (Full article)

Rethinking childhood adversity in chronic fatigue syndrome

Abstract:

Background: Previous studies have consistently shown increased rates of childhood adversity in chronic fatigue syndrome (CFS). However, such aetiopathogenic studies of CFS are potentially confounded by co-morbidity and misdiagnosis particularly with depression.

Purpose: We examined the relationship between rates of childhood adversity using two complimentary approaches (1) a sample of CFS patients who had no lifetime history of depression and (2) a modelling approach.

Methods: Childhood trauma questionnaire (CTQ) administered to a sample of 52 participants with chronic fatigue syndrome and 19 controls who did not meet criteria for a psychiatric disorder (confirmed using the Structured Clinical Interview for DSM-IV). Subsequently, Mediation Analysis (Baye’s Rules) was used to establish the risk childhood adversity poses for CFS with and without depression.

Results: In a cohort of CFS patients with depression comprehensively excluded, CTQ scores were markedly lower than in all previous studies and, in contrast to these previous studies, not increased compared with healthy controls. Post-hoc analysis showed that CTQ scores correlated with the number of depressive symptoms during the lifetime worst period of low mood. The probability of developing CFS given a history of childhood trauma is 4%, a two-fold increased risk compared to the general population. However, much of this risk is mediated by the concomitant development of major depression.

Conclusions: The data suggests that previous studies showing a relationship between childhood adversity and CFS may be attributable to the confounding effects of co-morbid or misdiagnosed depressive disorder.

Abbreviations: CFS: Chronic fatigue syndrome; CTQ: Childhood trauma questionnaire; MDD: Major depressive disorder; CA: Childhood adversity; P: Probability.

Source: Clark JE, Davidson SL, Maclachlan L, Newton JL, Watson S. Rethinking childhood adversity in chronic fatigue syndrome. Fatigue. 2017 Oct 10;6(1):20-29. doi: 10.1080/21641846.2018.1384095. eCollection 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774185/ (Full article)

Chronic fatigue syndrome in Chinese middle-school students

Abstract:

The objective of the present study was to determine the prevalence of chronic fatigue syndrome (CFS) and its associated factors in middle-school students in Suzhou, China. From September 2010 to January 2011, across-sectional study was conducted in junior- and senior middle-school students aged 10 to 18 years using a battery of confidential questionnaires. Our results indicate that 18,139 completed the questionnaires effectively, of whom 163 (0.9%) met the definition of CFS, with senior high-school students and male students predominating. The prevalence of CFS in the middle-school students increased steadily with age. The main symptoms of CFS in these students included being afraid of going to school, despondency, and irritability in addition to those specified in the Centers for Disease Control and Prevention (CDC). Our study shows that CFS is prevalent among Chinese teenagers, and requiring proper intervention and treatment.

Source: Shi J, Shen J, Xie J, Zhi J, Xu Y. Chronic fatigue syndrome in Chinese middle-school students. Medicine (Baltimore). 2018 Jan;97(4):e9716. doi: 10.1097/MD.0000000000009716. https://journals.lww.com/md-journal/fulltext/2018/01260/Chronic_fatigue_syndrome_in_Chinese_middle_school.37.aspx (Full article)