Tag: 2021

Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) differ for triggers, mode of start, associated symptoms, evolution, and biochemical traits. Therefore, serious attempts are underway to partition them into subgroups useful for a personalized medicine approach to the disease. Here, we investigated clinical and biochemical traits in 40 ME/CFS patients and 40 sex- and age-matched healthy controls. Particularly, we analyzed serum levels of some cytokines, Fatty Acid Binding Protein 2 (FAPB-2), tryptophan, and some of its metabolites via serotonin and kynurenine.
ME/CFS patients were heterogeneous for genetic background, trigger, start mode, symptoms, and evolution. ME/CFS patients had higher levels of IL-17A (p = 0.018), FABP-2 (p = 0.002), and 3-hydroxykynurenine (p = 0.037) and lower levels of kynurenine (p = 0.012) and serotonin (p = 0.045) than controls. Changes in kynurenine and 3-hydroxykynurenine were associated with increased kynurenic acid/kynurenine and 3-hydroxykynurenine/kynurenine ratios, indirect measures of kynurenine aminotransferases and kynurenine 3-monooxygenase enzymatic activities, respectively. No correlation was found among cytokines, FABP-2, and tryptophan metabolites, suggesting that inflammation, anomalies of the intestinal barrier, and changes of tryptophan metabolism may be independently associated with the pathogenesis of the disease.
Interestingly, patients with the start of the disease after infection showed lower levels of kynurenine (p = 0.034) than those not starting after an infection. Changes in tryptophan metabolites and increased IL-17A levels in ME/CFS could both be compatible with anomalies in the sphere of energy metabolism. Overall, clinical traits together with serum biomarkers related to inflammation, intestine function, and tryptophan metabolism deserve to be further considered for the development of personalized medicine strategies for ME/CFS.
Source: Manuela Simonato, Stefano Dall’Acqua, Caterina Zilli, Stefania Sut, Romano Tenconi, Nicoletta Gallo, Paolo Sfriso, Leonardo Sartori, Francesco Cavallin, Ugo Fiocco, Paola Cogo, Paolo Agostinis, Anna Aldovini, Daniela Bruttomesso, Renzo Marcolongo, Stefano Comai, and Aldo Baritussio. Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Biomedicines 2021, 9(11), 1724; https://doi.org/10.3390/biomedicines9111724 (registering DOI) https://www.mdpi.com/2227-9059/9/11/1724/htm (Full text)

Factors related to educational adaptations and social life at school experienced by young people with CFS/ME: a qualitative study

Abstract:

Objectives: To explore factors perceived as positive or negative among young people with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) in relation to school and everyday life.

Design: A qualitative study with semistructured individual interviews performed at the local hospital or at the informants’ homes between September 2017 and January 2018, with an additional telephone interview to collect data on experiences from the COVID-19 pandemic, conducted in September 2020. Data were analysed using a grounded theory approach.

Setting: The informants were recruited from two university hospitals that offer interdisciplinary assessments of young people with CFS/ME from various parts of Norway.

Participants: Five males and 13 females aged 13-21 years with CFS/ME diagnosed 3-56 months prior to the interviews participated.

Results: The informants were concerned about a lack of educational adaptations and missed social life at school. Educational and social adaptations could improve schooling and health among young people with CFS/ME. Negative experiences were related to a lack of knowledge about CFS/ME among school personnel and young people’s difficulties to limit activities. Online teaching as experienced during the COVID-19 pandemic was described as positive both for education and social life.

Conclusions: Young people with CFS/ME can benefit from better educational adaptations and increased social interaction with peers. From the participants’ view, factors that limit learning and socialisation include a lack of knowledge about CFS/ME among teachers and school personnel, expectations from teachers of doing more than they could manage at school, feeling alone coping with the disease and not recognising their own limitations regarding what they are able to do. Suggested factors perceived to enhance learning and socialisation were a better understanding of the disease among school personnel and peers, suitable educational adaptations and being able to socialise with peers.

Source: Similä WA, Nøst TH, Helland IB, Rø TB. Factors related to educational adaptations and social life at school experienced by young people with CFS/ME: a qualitative study. BMJ Open. 2021 Nov 18;11(11):e051094. doi: 10.1136/bmjopen-2021-051094. PMID: 34794992. https://pubmed.ncbi.nlm.nih.gov/34794992/

Post-COVID syndrome: the aftershock of SARS-CoV-2

Introduction:

Significant time has passed since the coronavirus disease of 2019 (COVID-19) pandemic outbreak, which led to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection in hundreds of millions of individuals all around the globe. Accumulation evidence along the pandemic raised an association between the SARS-CoV-2 and autoimmunity (1). SARS-CoV-2 infected patients have a high presence of various autoantibodies (1). Moreover, numerous cases of new-onset of autoimmune-related disorders had been documented following the infection, including both organ-specific and systemic autoimmune diseases (1).

Recent studies focused on analyzing recovered COVID-19 patients demonstrate a broad spectrum of persistent and systemic symptoms, which had got the novel terms of “post-COVID syndrome”, “long COVID” and “chronic COVID-19” (2). This new disorder had led to the understanding that the absence of SARS-CoV-2 following COVID-19 does not necessarily mean full recovery (2).

Studies conducted follow-ups on COVID-19 patients indicate that 50-80% of symptomatic COVID-19 patients who recovered report non-specific symptoms, most commonly fatigue, headache, dyspnea, anosmia, and memory complaint (3–5). An Italian study that examined patients after a mean of 60 days from the first COVID-19 symptom on-set had found only 12.6% of the patients completely recovered; 55% had three or more symptoms, and worsened quality of life was observed among 44% of patients (3). Intriguingly, a systematic review and meta-analysis reported more than 50 possible long-term effects of the SAR-CoV-2 infection (6). The chronic phase of COVID-19 is also presented in objective findings; for example, a study conducted in Germany had found that 78% of recently recovered symptomatic COVID-19 patients had at least one chronic symptom; the most common abnormality was myocardial inflammation (60%) (4).

In this issue of the journal, Bertin D et al. documented a case of post-COVID syndrome with a one-year follow-up. This case describes persistent anti-cardiolipin IgG autoantibodies and eosinopenia with ongoing neurologic symptoms, demonstrating the long-term disease course of COVID-19 in many patients. Anti-cardiolipin autoantibodies and eosinopenia were defined as independent factors associated with COVID-19 severity, indicating their active involvement in the progression of the disease (7,8). Additional studies that included follow-up on recovered COVID-19 patients describe similar findings: patients report respiratory, neurologic, and non-specific symptoms, accompanied by the presents of autoantibodies (6). Interestingly, in a one-year prospective cohort study, neurocognitive symptoms frequency were found significantly higher in patients with ANA titer of ≥1:160 in comparison to <1:160 at 12 months post–COVID-19 symptom onset (9). It should be emphasized that the development of autoantibodies, which appears to be common following symptomatic SARS-CoV-2 infection, could act as the preclinical stage of many autoimmune diseases. Thus, the long-term autoimmune implications of SARS-CoV-2 could be severe.

Involvement of the autonomic nervous system dysfunction in post-COVID syndrome

Many viruses are well known to contribute to autoimmunity in genetically pre dispositioned individuals, such as those with human leukocyte antigen B27 (10). SARS-CoV-2 had been associated with numerous autoantibodies (1); some are believed to be the basis of the severe forms of COVID-19 (11). Furthermore, these autoantibodies, along with others, could lead to the multi-organ involvement of post-COVID syndrome, which manifests as broad and unspecific symptoms (6). Autoantibodies against the autonomic nervous system compounds are believed to be an incremental part of the post-COVID syndrome etiology. A study that included post-COVID syndrome patients had unidentified in all the subjects between 2 and 7 different functionally active autoantibodies that acted as receptor agonists, such as β2-adrenoceptor, α1-adrenoceptor, and angiotensin II receptor type 1 receptor (12). Functionally active autoantibodies such as those were present in several neurological and cardiac disorders, which might clarify the onset of neurological and cardiovascular symptoms of the post-COVID syndrome (12).

Post-COVID patients commonly have a clinical presentation similar to the encephalomyelitis/chronic fatigue syndrome (ME/CFS): severe fatigue, sleep disorders, cognition impairments, and different manifestations of autonomic dysfunction exacerbated in physical exercise (6,13–15). ME/CFS has an autoimmune etiology, which can be demonstrated by high titers of autoantibodies against autonomic receptors, such as beta-adrenergic and muscarinic receptors (16,17). These autoantibodies, similar to those found in patients with post-COVID symptoms, lead to unspecific symptoms due to autonomic nervous system dysregulation. In addition to ME/CFS, many features of the post-COVID syndrome are shared with fibromyalgia patients. It had been shown that 189/616 (30.7%) of COVID-19 recovered patients satisfied the American College of Rheumatology criteria for fibromyalgia, 43.4% of which were men (18).

Therapeutic options and vaccination

ME/CFS and fibromyalgia have solid evidence of dysregulated immune involvement (16,17,19). Moreover, current studies suggest that immunosuppression, such as monoclonal anti-CD20 antibody and cyclophosphamide, may benefit patients suffering from ME/CFS (20,21). Such immunosuppressive therapeutic options can assist in the depletion of B cells, thus reducing the functionally active autoantibodies linked to autonomic dysfunction. Beneficial effects had also been demonstrated by the use of anti-ß2 adrenergic receptor-binding immunoadsorption (22). It should be emphasized that such treatment can diminish other pathogenic antibodies that the medical community had not yet recognized. Due to the possible involvement of autoantibodies against the autonomic nervous system in the post-COVID syndrome, similar immunosuppressive options in these patients may be effective, thereby should be investigated.

Most individuals infected by SARS-CoV-2 are asymptomatic or experience mild symptoms (23,24). While the frequency of post-COVID syndrome in such individuals is still uncertain, it seems to be much lower than in symptomatic patients (9). Thus, avoiding COVID-19 with SARS-CoV-2 vaccination could prominently assist in preventing long-term symptoms of COVID-19, lower the prevalence of post-COVID syndrome and help overcome the pandemic. Nonetheless, even with the ongoing heist mass vaccination programs, the COVID-19 pandemic will leave its mark.

Conclusion

Due to the accumulating evidence of persistent post-infectious symptoms reported by numerous recovered patients, the focus of the medical and research communities might need to start shifting focus from the acute phase of COVID-19 to the chronic manifestations of the SARS-CoV-2 infection, referred to as by “post-COVID syndrome”. Post-COVID syndrome presents as non-specific symptoms, most commonly fatigue, headache, dyspnea, anosmia, and memory complaint, which is suspiciously similar to the infection-induced myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (15,18). As current studies suggest an involvement of immune-related dysfunction in the development of post-COVID syndrome, immunosuppressive therapeutic options could be beneficial in parallel to heist SARS-CoV-2 vaccination of the population (15,20,21).

References

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Article Info

Publication History

Accepted: November 9, 2021
Received: November 9, 2021

Publication stage

In Press Journal Pre-Proof

Identification

DOI: https://doi.org/10.1016/j.ijid.2021.11.020

Copyright

© 2021 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

The Emerging Role of Gut Microbiota in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Current Evidence and Potential Therapeutic Applications

Abstract:

The well-known symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are chronic pain, cognitive dysfunction, post-exertional malaise and severe fatigue. Another class of symptoms commonly reported in the context of ME/CFS are gastrointestinal (GI) problems. These may occur due to comorbidities such as Crohn’s disease or irritable bowel syndrome (IBS), or as a symptom of ME/CFS itself due to an interruption of the complex interplay between the gut microbiota (GM) and the host GI tract. An altered composition and overall decrease in diversity of GM has been observed in ME/CFS cases compared to controls. In this review, we reflect on genetics, infections, and other influences that may factor into the alterations seen in the GM of ME/CFS individuals, we discuss consequences arising from these changes, and we contemplate the therapeutic potential of treating the gut to alleviate ME/CFS symptoms holistically.

Source: Varesi A, Deumer US, Ananth S, Ricevuti G. The Emerging Role of Gut Microbiota in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Current Evidence and Potential Therapeutic Applications. J Clin Med. 2021 Oct 29;10(21):5077. doi: 10.3390/jcm10215077. PMID: 34768601. https://pubmed.ncbi.nlm.nih.gov/34768601/

mapMECFS: a portal to enhance data discovery across biological disciplines and collaborative sites

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease which involves multiple body systems (e.g., immune, nervous, digestive, circulatory) and research domains (e.g., immunology, metabolomics, the gut microbiome, genomics, neurology). Despite several decades of research, there are no established ME/CFS biomarkers available to diagnose and treat ME/CFS. Sharing data and integrating findings across these domains is essential to advance understanding of this complex disease by revealing diagnostic biomarkers and facilitating discovery of novel effective therapies.

Methods: The National Institutes of Health funded the development of a data sharing portal to support collaborative efforts among an initial group of three funded research centers. This was subsequently expanded to include the global ME/CFS research community. Using the open-source comprehensive knowledge archive network (CKAN) framework as the base, the ME/CFS Data Management and Coordinating Center developed an online portal with metadata collection, smart search capabilities, and domain-agnostic data integration to support data findability and reusability while reducing the barriers to sustainable data sharing.

Results: We designed the mapMECFS data portal to facilitate data sharing and integration by allowing ME/CFS researchers to browse, share, compare, and download molecular datasets from within one data repository. At the time of publication, mapMECFS contains data curated from public data repositories, peer-reviewed publications, and current ME/CFS Research Network members.

Conclusions: mapMECFS is a disease-specific data portal to improve data sharing and collaboration among ME/CFS researchers around the world. mapMECFS is accessible to the broader research community with registration. Further development is ongoing to include novel systems biology and data integration methods.

Source: Mathur R, Carnes MU, Harding A, Moore A, Thomas I, Giarrocco A, Long M, Underwood M, Townsend C, Ruiz-Esparza R, Barnette Q, Brown LM, Schu M. mapMECFS: a portal to enhance data discovery across biological disciplines and collaborative sites. J Transl Med. 2021 Nov 8;19(1):461. doi: 10.1186/s12967-021-03127-3. PMID: 34749736. https://pubmed.ncbi.nlm.nih.gov/34749736/

The impact of COVID-19 stress on pain and fatigue in people with and without a central sensitivity syndrome

Abstract:

Objectives: Stress may augment somatic symptoms in central sensitivity syndromes (CSS) such as fibromyalgia, chronic fatigue syndrome, and irritable bowel syndrome. To test this hypothesis, we examined whether the association between COVID-19 stress and somatic symptom severity would be stronger in people with than without CSS and whether psychological flexibility would buffer the impact of this stress on symptom severity.

Methods: In a 2-sample, repeated cross-sectional design, we analysed questionnaire data from Dutch people with and without CSS, collected in two independent surveys: before the COVID-19 pandemic (2018; CSS: n = 194, non-CSS: n = 337) and at the peak of the pandemic (2020; CSS: n = 428, non-CSS: n = 1101). Somatic symptom severity, worry and stress due to the pandemic, and psychological flexibility were examined in regression analyses. Two stress operationalisations were analysed: stress levels during the peak of the pandemic, and a comparison of measurements in 2020 and 2018 (assuming higher stress levels in 2020).

Results: Higher worry and stress during the pandemic (standardized β = 0.14), the presence of a CSS (β = 0.40), and lower psychological flexibility (β = -0.33) were all (p < .0001) associated with more severe somatic symptoms, but the associations of each stress operationalisation with somatic symptoms was not particularly strong in people with CSS (β = -0.026, p = .27; β = -0.037, p = .22), and psychological flexibility (β = -0.025, p = .18; β = 0.076, p = .35) did not buffer this association.

Conclusions: Findings do not support the hypotheses that COVID-19 stress augments somatic symptoms, particularly in CSS, or that psychological flexibility buffers this impact. Rather, COVID-19-related stress appears to have an uncertain impact on somatic symptoms.

Source: Koppert TY, Jacobs JWG, Lumley MA, Geenen R. The impact of COVID-19 stress on pain and fatigue in people with and without a central sensitivity syndrome. J Psychosom Res. 2021 Oct 29;151:110655. doi: 10.1016/j.jpsychores.2021.110655. Epub ahead of print. PMID: 34739944. https://pubmed.ncbi.nlm.nih.gov/34739944/

Sign for MECFS!

In Germany, there is virtually no medical care for ME/CFS patients and to date there is no government funding for biomedical scientific research into this devastating disease. With 50,000 signatories before the end of the deadline, we will even be granted a public hearing in the German Bundestag. This would be our best chance to finally draw attention to the issue of ME/CFS in German federal politics. Sign the petition! It will only take a few minutes and can be done online. Anyone can sign, worldwide! Read more here>>

Deficient butyrate-producing capacity in the gut microbiome of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients is associated with fatigue symptoms

Abstract:

Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, debilitating disease of unknown cause for which there is no specific therapy. Patients suffering from ME/CFS commonly experience persistent fatigue, post-exertional malaise, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever and irritable bowel syndrome (IBS). Recent evidence implicates gut microbiome dysbiosis in ME/CFS. However, most prior studies are limited by small sample size, differences in clinical criteria used to define cases, limited geographic sampling, reliance on bacterial culture or 16S rRNA gene sequencing, or insufficient consideration of confounding factors that may influence microbiome composition. In the present study, we evaluated the fecal microbiome in the largest prospective, case-control study to date (n=106 cases, n=91 healthy controls), involving subjects from geographically diverse communities across the United States.

Results Using shotgun metagenomics and qPCR and rigorous statistical analyses that controlled for important covariates, we identified decreased relative abundance and quantity of Faecalibacterium, Roseburia, and Eubacterium species and increased bacterial load in feces of subjects with ME/CFS. These bacterial taxa play an important role in the production of butyrate, a multifunctional bacterial metabolite that promotes human health by regulating energy metabolism, inflammation, and intestinal barrier function. Functional metagenomic and qPCR analyses were consistent with a deficient microbial capacity to produce butyrate along the acetyl-CoA pathway in ME/CFS. Metabolomic analyses of short-chain fatty acids (SCFAs) confirmed that fecal butyrate concentration was significantly reduced in ME/CFS. Further, we found that the degree of deficiency in butyrate-producing bacteria correlated with fatigue symptom severity among ME/CFS subjects. Finally, we provide evidence that IBS comorbidity is an important covariate to consider in studies investigating the microbiome of ME/CFS subjects, as differences in microbiota alpha diversity, some bacterial taxa, and propionate were uniquely associated with self-reported IBS diagnosis.

Conclusions Our findings indicate that there is a core deficit in the butyrate-producing capacity of the gut microbiome in ME/CFS subjects compared to healthy controls. The relationships we observed among symptom severity and these gut microbiome disturbances may be suggestive of a pathomechanistic linkage, however, additional research is warranted to establish any causal relationship. These findings provide support for clinical trials that explore the utility of dietary, probiotic and prebiotic interventions to boost colonic butyrate production in ME/CFS.

Source: Cheng Guo, Xiaoyu Che, Thomas Briese, Orchid Allicock, Rachel A. Yates, Aaron Cheng, Amit Ranjan, Dana March, Mady Hornig, Anthony L. Komaroff, Susan Levine, Lucinda Bateman, Suzanne D. Vernon, Nancy G. Klimas, Jose G. Montoya, Daniel L. Peterson, W. Ian Lipkin, Brent L. Williams. Deficient butyrate-producing capacity in the gut microbiome of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients is associated with fatigue symptoms. medRxiv 2021.10.27.21265575; doi: https://doi.org/10.1101/2021.10.27.21265575 https://www.medrxiv.org/content/10.1101/2021.10.27.21265575v1?fbclid=IwAR16pb6by73xZx5lZM3j-5dOc_YT2JapILaRS-DcUZj5EHZxnoSa2fAAIuE (Full text available to download)

ME/CFS: Exercise goals should be set by patients and not driven by treatment plan, says NICE

Letter:

Rapid Response:

Patient reports of harm from GET cannot be ignored

Dear Editor

Professor Trudie Chalder from King’s College Hospital states that:

“The NICE guidelines for CFS/ME are at odds with the research evidence. Researchers from different institutions in different countries have found graded exercise therapy and cognitive behaviour therapy to be effective for some patients with CFS.

Evidence has shown they reduce fatigue and improve functioning without harm, if delivered by trained therapists in specialist clinics. Being a clinician and researcher in this field, I can’t help but think clinicians will be confused by this message from a respected organisation.”

Having carefully reviewed all the very extensive evidence on efficacy and safety for graded exercise therapy (GET) from relevant clinical trials, medical experts and from people with ME/CFS, the NICE guideline committee concluded that in addition to there being no sound evidence for efficacy for GET there was also consistent patient evidence of harm, sometimes serious and persisting, occurring.

Read the rest of this letter HERE. 

Source: Charles Shepherd. BMJ 2021; 375 doi: https://doi.org/10.1136/bmj.n2643 (Published 29 October 2021) BMJ 2021;375:n2643

Estimating total morbidity burden of COVID-19: relative importance of death and disability

Abstract:

Objective: Calculations of disease burden of COVID-19, used to allocate scarce resources, have historically considered only mortality. However, survivors often develop postinfectious ‘long-COVID’ similar to chronic fatigue syndrome; physical sequelae such as heart damage, or both. This paper quantifies relative contributions of acute case fatality, delayed case fatality, and disability to total morbidity per COVID-19 case.

Study design and setting: Healthy life years lost per COVID-19 case were computed as the sum of (incidence*disability weight*duration) for death and long-COVID by sex and 10-year age category in three plausible scenarios.

Results: In all models, acute mortality was only a small share of total morbidity. For lifelong moderate symptoms, healthy years lost per COVID-19 case ranged from 0.92 (male in his 30s) to 5.71 (girl under 10) and were 3.5 and 3.6 for the oldest females and males. At higher symptom severities, young people and females bore larger shares of morbidity; if survivors’ later mortality increased, morbidity increased most in young people of both sexes.

Conclusions: Under most conditions most COVID-19 morbidity was in survivors. Future research should investigate incidence, risk factors, and clinical course of long-COVID to elucidate total disease burden, and decisionmakers should allocate scarce resources to minimize total morbidity. WHAT IS NEW; KEY FINDINGS: : Under most plausible model scenarios, most COVID-19 morbidity (death + disability) is likely to be due to disability (‘long-COVID’) or delayed death due to organ damage, rather than immediate death. Only if long-COVID resolves (atypical of postinfectious syndromes) is morbidity higher in old than young WHAT THIS ADDS TO WHAT IS KNOWN: : While COVID-19 deaths are numerous, they likely cause less morbidity overall than does disability or organ damage in survivors. Morbidity is highest in females, especially those infected young.

What should change now: Scarce resources such as vaccines should be allocated to minimize morbidity rather than focusing solely on mortality. Data on long-COVID, especially its sex bias, should be collected and publicized.

Source: Smith MP. Estimating total morbidity burden of COVID-19: relative importance of death and disability. J Clin Epidemiol. 2021 Oct 26:S0895-4356(21)00339-5. doi: 10.1016/j.jclinepi.2021.10.018. Epub ahead of print. PMID: 34715312. https://pubmed.ncbi.nlm.nih.gov/34715312/