Pathogenesis – Page 7 – American ME and CFS Society

Epstein-Barr virus (EBV) reactivation and therapeutic inhibitors

Abstract:

Epstein-Barr virus (EBV) is a ubiquitous human virus which infects almost all humans during their lifetime and following the acute phase, persists for the remainder of the life of the individual. EBV infects B lymphocytes leading to their immortalisation, with persistence of the EBV genome as an episome. In the latent phase, EBV is prevented from reactivating through efficient cytotoxic cellular immunity.

EBV reactivates (lytic phase) under conditions of psychological stress with consequent weakening of cellular immunity, and EBV reactivation has been shown to occur in a subset of individuals with each of a variety of cancers, autoimmune diseases, the autoimmune-like disease, chronic fatigue syndrome/myalgic encephalitis and under other circumstances such as being an inpatient in an intensive care unit.

Chronic EBV reactivation is an important mechanism in the pathogenesis of many such diseases, yet is rarely tested for in immunocompetent individuals. This review summarises the pathogenesis of EBV infection, EBV reactivation and its role in disease, and methods which may be used to detect it. Known inhibitors of EBV reactivation and replication are discussed, including drugs licensed for treatment of other herpesviruses, licensed or experimental drugs for various other indications, compounds at an early stage of drug development and nutritional constituents such as vitamins and dietary supplements.

Source: Kerr JR. Epstein-Barr virus (EBV) reactivation and therapeutic inhibitors. J Clin Pathol. 2019 Jul 17. pii: jclinpath-2019-205822. doi: 10.1136/jclinpath-2019-205822. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31315893

Chronic fatigue syndrome patients have alterations in their oral microbiome composition and function

Abstract:

Host-microbe interactions have been implicated in the pathogenesis of chronic fatigue syndrome (CFS), but whether the oral microbiome is altered in CFS patients is unknown. We explored alterations of the oral microbiome in Chinese Han CFS patients using 16S rRNA gene sequencing and alterations in the functional potential of the oral microbiome using PICRUSt.

We found that Shannon and Simpson diversity indices were not different in CFS patients compared to healthy controls, but the overall oral microbiome composition was different (MANOVA, p < 0.01). CFS patients had a higher relative abundance of Fusobacteria compared with healthy controls. Further, the genera Leptotrichia, Prevotella, and Fusobacterium were enriched and Haemophilus, Veillonella, and Porphyromonas were depleted in CFS patients compared to healthy controls. Functional analysis from inferred metagenomes showed that bacterial genera altered in CFS patients were primarily associated with amino acid and energy metabolism.

Our findings demonstrate that the oral microbiome in CFS patients is different from healthy controls, and these differences lead to shifts in functional pathways with implications for CFS pathogenesis. These findings increase our understanding of the relationship between the oral microbiota and CFS, which will advance our understanding of CFS pathogenesis and may contribute to future improvements in treatment and diagnosis.

Source: Wang T, Yu L, Xu C, Pan K, Mo M, Duan M, Zhang Y, Xiong H. Chronic fatigue syndrome patients have alterations in their oral microbiome composition and function. PLoS One. 2018 Sep 11;13(9):e0203503. doi:
10.1371/journal.pone.0203503. eCollection 2018. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203503 (Full article)

Reduced glycolytic reserve in isolated natural killer cells from Myalgic encephalomyelitis/chronic fatigue syndrome patients: A preliminary investigation

Abstract:

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is medically unexplained post-exertional fatigue associated with significant reduction in natural killer cell (NK) cytotoxicity activity. Cytotoxic activity relies on glycolytic flux and mitochondrial respiration to fulfill energetic cellular demands. While mitochondrial dysfunction has been reported in ME/CFS patients, no previous investigation has examined the bioenergetic profile of isolated NK cells from ME/CFS patients.

OBJECTIVE: This study was to determine the metabolic function in resting NK cells from ME/CFS patients.

METHOD: Six ME/CFS patients (aged 50.33±4.95) were age and sex-matched with non-fatigued healthy controls (aged 50.00±5.04). Mitochondrial stress tests measured parameters of mitochondrial function in the NK cells including basal respiration, ATP production, proton leak, maximal respiration, spare respiratory capacity and bioenergetic health index. Glycolytic stress tests measured parameters of glycolytic function such as glycolytic reserve, glycolysis and glycolytic capacity in isolated NK cells from ME/CFS patients and healthy controls using an extracellular flux analyzer, Seahorse XFp.

RESULT: There was a significant reduction of glycolytic reserve in resting NK cells from ME/CFS patients (0.6±0.07 mpH/ min) compared with healthy control (2.25±1.3 mpH/min). Mitochondrial respiration in resting NK cells did not approach statistical significance between ME/CFS patients and healthy controls.

CONCLUSION: These findings suggest resting NK cells from ME/CFS patients have reduced ability to increase glycolytic flux to respond to high energetic demands for ATP production. Hence, the reduced glycolytic reserves we have identified in isolated resting isolated NK cells should be further investigated to assist in understanding ME/CFS pathogenesis.

Source: Nguyen T, Staines D, Johnston S, Marshall-Gradisnik S. Reduced glycolytic reserve in isolated natural killer cells from Myalgic encephalomyelitis/chronic fatigue syndrome patients: A preliminary investigation. Asian Pac J Allergy Immunol. 2018 Jul 8. doi: 10.12932/AP-011117-0188. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29981562

The “Biology-First” Hypothesis: Functional disorders may begin and end with biology-A scoping review

Abstract:

While it is generally accepted that gastrointestinal infections can cause functional disturbances in the upper and lower gastrointestinal tract-known as postinfectious irritable bowel syndrome (PI-IBS) and functional dyspepsia (PI-FD)-it has still not been widely recognized that such an infection can also initiate functional non-intestinal diseases, and that non-intestinal infections can provoke both intestinal and non-intestinal functional disturbances. We conducted a scoping review of the respective literature and-on the basis of these data-hypothesize that medically unexplained functional symptoms and syndromes following an infection may have a biological (genetic, endocrine, microbiological) origin, and that psychological and social factors, which may contribute to the disease “phenotype,” are secondary to this biological cause. If this holds true, then the search for psychological and social theories and factors to explain why one patient develops a chronic functional disorder while another does not is-at least for postinfectious states-misleading and detracts from exploring and identifying the true origins of these essentially biological disorders. The biopsychosocial model may, as the term implies, always begin with biology, also for functional (somatoform) disorders.

Source: Enck P, Mazurak N. The “Biology-First” Hypothesis: Functional disorders may begin and end with biology-A scoping review. Neurogastroenterol Motil. 2018 Jun 28:e13394. doi: 10.1111/nmo.13394. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29956418

Rheumatism and chronic fatigue, the two facets of post-chikungunya disease: the TELECHIK cohort study on Reunion island

Abstract:

Prolonged fatigue is increasingly reported among chikungunya virus (CHIKV)-infected populations. We investigated the relationships between CHIKV exposure, long-lasting rheumatic musculoskeletal pain (LRMSP) and chronic fatigue. 1094 participants (512 CHIKV seropositive and 582 seronegative) of the TELECHIK population-based cohort were analysed considering the duration of the manifestations throughout an average 2-year follow-up.

Weighted prevalence rates and prevalence ratios for LRMSP, idiopathic chronic fatigue (ICF), and chronic fatigue syndrome (CFS)-like illness, both latter syndromes adapted from Centers for Disease Control (CDC)-1994/Fukuda criteria, were compared. Population attributable fractions (PAF) were estimated to assess the contribution of CHIKV infection to each of the three phenotypes.

Among 362 adult subjects who had reported either rheumatic pain or fatigue at the onset of the infection, weighted prevalence rates of LRMSP, ICF and CFS-like illness were respectively of 32.9%, 38.7% and 23.9%, and of 8.7%, 8.5% and 7.4% among initially asymptomatic peers (P < 0.01, respectively). Each of the three outcomes was highly attributable to chikungunya (PAF of 43.2%, 36.2% and 41.0%, respectively).

In the sub-cohort of CHIKV-infected subjects, LRMSP, ICF and CFS-like illness, which overlapped in 70%, accounted for 53% of the chronic manifestations. In addition to rheumatic disease, chronic fatigue could be considered in caring for patients with chronic chikungunya disease.

Source: Duvignaud A, Fianu A, Bertolotti A, Jaubert J, Michault A, Poubeau P, Fred A, Méchain M, Gaüzère BA, Favier F, Malvy D, Gérardin P. Rheumatism and chronic fatigue, the two facets of post-chikungunya disease: the TELECHIK cohort study on Reunion island. Epidemiol Infect. 2018 Feb 28:1-9. doi: 10.1017/S0950268818000031. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29486812

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)

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)

Prevalence of Irritable Bowel Syndrome and Chronic Fatigue 10 Years after Giardia Infection

Abstract:

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is a complication that can follow gastrointestinal infection, but it is not clear if patients also develop chronic fatigue. We investigated the prevalence and odds ratio of IBS and chronic fatigue 10 years after an outbreak of Giardia lamblia, compared with a control cohort, and changes in prevalence over time.

METHODS: We performed a prospective follow-up study of 1252 laboratory-confirmed cases of giardiasis (exposed), which developed in Bergen, Norway in 2004. Statistics Norway provided us with information from 2504 unexposed individuals from Bergen, matched by age and sex (controls). Questionnaires were mailed to participants 3, 6, and 10 years after the outbreak. Results from the 3- and 6-year follow-up analyses have been published previously. We report the 10-year data and changes in prevalence among time points, determined by logistic regression using generalized estimating equations.

RESULTS: The prevalence of IBS 10 years after the outbreak was 43% (n=248) among 576 exposed individuals and 14% (n=94) among 685 controls (adjusted odds ratio for development of IBS in exposed individuals, 4.74; 95% CI, 3.61-6.23). At this time point, the prevalence of chronic fatigue was 26% (n=153) among 587 exposed individuals and 11% (n=73) among 692 controls (adjusted odds ratio, 3.01; 95% CI, 2.22-4.08). The prevalence of IBS among exposed persons did not change significantly from 6 years after infection (40%) to 10 years after infection (43%; adjusted odds ratio for the change 1.03; 95% CI, 0.87-1.22). However, the prevalence of chronic fatigue decreased from 31% at 6 years after infection to 26% at 10 years after infection (adjusted odds ratio for the change 0.74; 95% CI, 0.61-0.90).

CONCLUSION: The prevalence of IBS did not change significantly from 6 years after an outbreak of Giardia lamblia infection in Norway to 10 years after. However, the prevalence of chronic fatigue decreased significantly from 6 to 10 years afterward. IBS and chronic fatigue were still associated with giardiasis 10 years after the outbreak.

Source: Litleskare S, Rortveit G, Eide GE, Hanevik K, Langeland N, Wensaas KA. Prevalence of Irritable Bowel Syndrome and Chronic Fatigue 10 Years after Giardia Infection. Clin Gastroenterol Hepatol. 2018 Jan 25. pii: S1542-3565(18)30088-0. doi: 10.1016/j.cgh.2018.01.022. [Epub ahead of print]

Improvement of severe myalgic encephalomyelitis/chronic fatigue syndrome symptoms following surgical treatment of cervical spinal stenosis

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a potentially disabling disorder. Little is known about the contributors to severe forms of the illness. We describe three consecutive patients with severe ME/CFS whose symptoms improved after recognition and surgical management of their cervical spinal stenosis.

Methods: All patients satisfied clinical criteria for ME/CFS and orthostatic intolerance, and were later found to have cervical spinal stenosis. Overall function was assessed before and after surgery using the Karnofsky score and the SF-36 physical function subscale score.

Results: Neurological findings included > 3+ deep tendon reflexes in 2 of 3, a positive Hoffman sign in 2 of 3, tremor in 2 of 3, and absent gag reflex in 1 of 3. The cervical spine canal diameter in the three patients ranged from 6 to 8.5 mm. One had congenital cervical stenosis with superimposed spondylosis, and two had single- or two-level spondylosis. Anterior cervical disc replacement surgery in two patients and a hybrid anterior cervical disc fusion and disc replacement in the third was associated with a marked improvement in myelopathic symptoms, resolution of lightheadedness and hemodynamic dysfunction, improvement in activity levels, and improvement in global ME/CFS symptoms.

Conclusions: The prompt post-surgical restoration of more normal function suggests that cervical spine stenosis contributed to the pathogenesis of refractory ME/CFS and orthostatic symptoms. The improvements following surgery emphasize the importance of a careful search for myelopathic examination findings in those with ME/CFS, especially when individuals with severe impairment are not responding to treatment.

Source: Rowe, P.C., Marden, C.L., Heinlein, S. et al. J Transl Med (2018) 16: 21. https://doi.org/10.1186/s12967-018-1397-7

Tenuous link between chronic fatigue syndrome and pyruvate dehydrogenase deficiency

Abstract:

Researchers studying the energy metabolism of patients with chronic fatigue syndrome have reached the conclusion that these patients have impaired pyruvate dehydrogenase function, but their measurements are not consistent with the changes we see in patients with primary genetic pyruvate dehydrogenase deficiency.

A cross-sectional study published in December 2016 found a change in the pattern of amino acids in the plasma of patients with chronic fatigue syndrome. Gene expression in white blood cells and energy metabolism in muscle cells was also found to have changed (1). The authors interpret the results as an expression of functional inhibition of the enzyme pyruvate dehydrogenase, and they postulate dysregulation of the enzyme complex as a possible key factor in the pathogenesis associated with chronic fatigue syndrome.

The study received extensive media coverage (2, 3), and the link to pyruvate dehydrogenase is published without reservations as an established fact (4, 5). At our laboratory we are now receiving samples for metabolic screening from patients with suspected fatigue syndrome. On the basis of my own experience with biochemical diagnostic workup for pyruvate dehydrogenase deficiency, I would like to point out weaknesses in the study that should have prompted much greater caution in the conclusions.

Source: Bliksrud YT. Tenuous link between chronic fatigue syndrome and pyruvate dehydrogenase deficiency. Tidsskr Nor Laegeforen. 2017 Nov 28;137(23-24). doi: 10.4045/tidsskr.17.0948. Print 2017 Dec 12. [Article in English, Norwegian] http://tidsskriftet.no/en/2017/12/debatt/tenuous-link-between-chronic-fatigue-syndrome-and-pyruvate-dehydrogenase-deficiency (Full article)