The Gut Microbiome in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)

Abstract:

Myalgic encephalomyelitis (ME) or Chronic Fatigue Syndrome (CFS) is a neglected, debilitating multi-systemic disease without diagnostic marker or therapy. Despite evidence for neurological, immunological, infectious, muscular and endocrine pathophysiological abnormalities, the etiology and a clear pathophysiology remains unclear. The gut microbiome gained much attention in the last decade with manifold implications in health and disease. Here we review the current state of knowledge on the interplay between ME/CFS and the microbiome, to identify potential diagnostic or interventional approaches, and propose areas where further research is needed.

We iteratively selected and elaborated on key theories about a correlation between microbiome state and ME/CFS pathology, developing further hypotheses. Based on the literature we hypothesize that antibiotic use throughout life favours an intestinal microbiota composition which might be a risk factor for ME/CFS. Main proposed pathomechanisms include gut dysbiosis, altered gut-brain axis activity, increased gut permeability with concomitant bacterial translocation and reduced levels of short-chain-fatty acids, D-lactic acidosis, an abnormal tryptophan metabolism and low activity of the kynurenine pathway. We review options for microbiome manipulation in ME/CFS patients including probiotic and dietary interventions as well as fecal microbiota transplantations. Beyond increasing gut permeability and bacterial translocation, specific dysbiosis may modify fermentation products, affecting peripheral mitochondria. Considering the gut-brain axis we strongly suspect that the microbiome may contribute to neurocognitive impairments of ME/CFS patients.

Further larger studies are needed, above all to clarify whether D-lactic acidosis and early-life antibiotic use may be part of ME/CFS etiology and what role changes in the tryptophan metabolism might play. An association between the gut microbiome and the disease ME/CFS is plausible. As causality remains unclear, we recommend longitudinal studies. Activity levels, bedridden hours and disease progression should be compared to antibiotic exposure, drug intakes and alterations in the composition of the microbiota. The therapeutic potential of fecal microbiota transfer and of targeted dietary interventions should be systematically evaluated.

Source: König RS, Albrich WC, Kahlert CR, Bahr LS, Löber U, Vernazza P, Scheibenbogen C, Forslund SK. The Gut Microbiome in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Front Immunol. 2022 Jan 3;12:628741. doi: 10.3389/fimmu.2021.628741. PMID: 35046929; PMCID: PMC8761622. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761622/ (Full text)

 

Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. A syndrome clinically similar to ME/CFS has been reported following well-documented infections with the coronaviruses SARS-CoV and MERS-CoV. At least 10% of COVID-19 survivors develop post acute sequelae of SARS-CoV-2 infection (PASC). Although many individuals with PASC have evidence of structural organ damage, a subset have symptoms consistent with ME/CFS including fatigue, post exertional malaise, cognitive dysfunction, gastrointestinal disturbances, and postural orthostatic intolerance. These common features in ME/CFS and PASC suggest that insights into the pathogenesis of either may enrich our understanding of both syndromes, and could expedite the development of strategies for identifying those at risk and interventions that prevent or mitigate disease.

Methods: Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls.

Results: In ME/CFS cases, regression, Bayesian and enrichment analyses revealed evidence of peroxisomal dysfunction with decreased levels of plasmalogens. Other findings included decreased levels of several membrane lipids, including phosphatidylcholines and sphingomyelins, that may indicate dysregulation of the cytidine-5’-diphosphocholine pathway. Enrichment analyses revealed decreased levels of choline, ceramides and carnitines, and increased levels of long chain triglycerides (TG) and hydroxy-eicosapentaenoic acid. Elevated levels of dicarboxylic acids were consistent with abnormalities in the tricarboxylic acid cycle. Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873).

Conclusion: Our findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight new abnormalities that may provide insights into the pathogenesis of ME/CFS.

One sentence summary: Plasma levels of plasmalogens are decreased in patients with myalgic encephalomyelitis/chronic fatigue syndrome suggesting peroxisome dysfunction.

Source: Che X, Brydges CR, Yu Y, Price A, Joshi S, Roy A, Lee B, Barupal DK, Cheng A, Palmer DM, Levine S, Peterson DL, Vernon SD, Bateman L, Hornig M, Montoya JG, Komaroff AL, Fiehn O, Lipkin WI. Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. medRxiv [Preprint]. 2022 Jan 11:2021.06.14.21258895. doi: 10.1101/2021.06.14.21258895. PMID: 35043127; PMCID: PMC8764736. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764736/ (Full text)

Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM)

Abstract:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS and Gulf War Illness (GWI) share features of post-exertional malaise (PEM), exertional exhaustion, or postexertional symptom exacerbation. In a two-day model of PEM, submaximal exercise induced significant changes in activation of the dorsal midbrain during a high cognitive load working memory task (Washington 2020) (Baraniuk this issue). Controls had no net change. However, ME/CFS had increased activity after exercise, while GWI had significantly reduced activity indicating differential responses to exercise and pathological mechanisms.
These data plus findings of the midbrain and brainstem atrophy in GWI inspired a review of the anatomy and physiology of the dorsal midbrain and isthmus nuclei in order to infer dysfunctional mechanisms that may contribute to disease pathogenesis and postexertional malaise. The nuclei of the ascending arousal network were addressed. Midbrain and isthmus nuclei participate in threat assessment, awareness, attention, mood, cognition, pain, tenderness, sleep, thermoregulation, light and sound sensitivity, orthostatic symptoms, and autonomic dysfunction and are likely to contribute to the symptoms of postexertional malaise in ME/CFS and GWI.
Source: James N. Baraniuk. Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM) Brain Sci. 2022, 12(2), 132; https://doi.org/10.3390/brainsci12020132 (registering DOI) https://www.mdpi.com/2076-3425/12/2/132/htm (Full text)

Prevalence, characteristics, and predictors of Long COVID among diagnosed cases of COVID-19

Abstract:

Background: Long COVID or long-term complication after COVID-19 has the ability to affect health and quality of life. Knowledge about the burden and predictors could aid in their prevention and management. Most of the studies are from high-income countries and focus on severe cases. We did this study to estimate the prevalence and identify the characteristics and predictors of Long COVID among our patients.

Methodology: We recruited adult (≥18 years) patients who were diagnosed as Reverse Transcription Polymerase Chain Reaction (RTPCR) confirmed SARS-COV-2 infection and were either hospitalized or tested on outpatient basis. Eligible participants were followed up telephonically after four weeks of diagnosis of SARS-COV-2 infection to collect data on sociodemographic, clinical history, vaccination history, Cycle threshold (Ct) values during diagnosis and other variables. Characteristics of Long COVID were elicited, and multivariable logistic regression was done to find the predictors of Long COVID.

Results: We have analyzed 487 individual data with a median follow-up of 44 days (Inter quartile range (IQR): 39,47). Overall, Long COVID was reported by 29.2% (95% Confidence interval (CI): 25.3%,33.4%) participants. Prevalence of Long COVID among patients with mild/moderate disease (n = 415) was 23.4% (95% CI: 19.5%,27.7%) as compared to 62.5% (95% CI: 50.7%,73%) in severe/critical cases(n=72). The most common Long COVID symptom was fatigue (64.8%) followed by cough (32.4%). Statistically significant predictors of Long COVID were – Pre-existing medical conditions (Adjusted Odds ratio (aOR)=2.00, 95% CI: 1.16,3.44), having a more significant number of symptoms during acute phase of COVID-19 disease (aOR=11.24, 95% CI: 4.00,31.51), two doses of COVID-19 vaccination (aOR=2.32, 95% CI: 1.17,4.58), the severity of illness (aOR=5.71, 95% CI: 3.00,10.89) and being admitted to hospital (Odds ratio (OR)=3.89, 95% CI: 2.49,6.08).

Conclusion: A considerable proportion of COVID-19 cases reported Long COVID symptoms. More research is needed in Long COVID to objectively assess the symptoms and find the biological and radiological markers.

Source: M. C. Arjun, Arvind Kumar Singh, Debkumar Pal, Kajal Das, Alekhya Gajjala, Mahalingam Venkateshan, Baijayantimala Mishra, Binod Kumar Patro, Prasanta Raghab Mohapatra, Sonu Hangma Subba. Prevalence, characteristics, and predictors of Long COVID among diagnosed cases of COVID-19. medRxiv 2022.01.04.21268536; doi: https://doi.org/10.1101/2022.01.04.21268536 https://www.medrxiv.org/content/10.1101/2022.01.04.21268536v1.full-text (Full text)

Symptoms Experienced at the Acute Phase of SARS-CoV-2 Infection as Risk Factor of Long-term Post-COVID Symptoms: The LONG-COVID-EXP-CM Multicenter Study

Abstract:

Objective: This multicenter study investigated clinical risk factors associated with the number of long-term post-COVID symptoms.

Methods: Clinical features, symptoms at hospital admission, hospitalization data, and the number of post-COVID symptoms was systematically assessed from patients recovered from COVID-19 at four hospitals in Madrid (Spain) from February 20 to May 31, 2020.

Results: Overall, 1,969 patients (46.5% women, age: 61, SD: 16 years) were randomly assessed at 8.4 months (SD 1.5) after hospital discharge. Female gender (OR1.82, 95%CI 1.57-2.10), number of morbidities (OR1.182, 95%CI 1.08-1.29), number of symptoms at hospital admission (OR1.309, 95%CI 1.15-1.49) and days at the hospital (OR1.01, 95%CI 1.007-1.017) were associated (all, P<0.001) with more long-term post-COVID symptoms. Further, vomiting (OR1.78, 95%CI 1.26-2.52), throat pain (OR1.36, 95%CI 1.02-1.81), diarrhoea (OR1.51, 95%CI 1.25-1.82), dyspnea (OR1.20, 95%CI 1.01-1.41), or headache (OR1.50, 95%CI 1.28-1.75) as symptoms at hospital admission were also associated (all, P<0.01) with a higher number of post-COVID symptoms.

Conclusion: This multicenter study found that a higher number of symptoms at hospital admission was the most relevant risk factor for developing more post-COVID symptoms, supporting the assumption that a higher symptom load at the acute phase is associated with a greater likelihood of long-term post-COVID symptoms.

Source: Fernández-de-Las-Peñas C, Pellicer-Valero OJ, Navarro-Pardo E, Palacios-Ceña D, Florencio LL, Guijarro C, Martín-Guerrero JD. Symptoms Experienced at the Acute Phase of SARS-CoV-2 Infection as Risk Factor of Long-term Post-COVID Symptoms: The LONG-COVID-EXP-CM Multicenter Study. Int J Infect Dis. 2022 Jan 8:S1201-9712(22)00007-8. doi: 10.1016/j.ijid.2022.01.007. Epub ahead of print. PMID: 35017102; PMCID: PMC8743274. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743274/ (Full text)

Premorbid vulnerability and disease severity impact on Long-COVID cognitive impairment

Abstract:

Background: Cognitive deficits have been increasingly reported as possible long-term manifestations after SARS-CoV-2 infection.

Aims: In this study we aimed at evaluating the factors associated with cognitive deficits 6 months after hospitalization for Coronavirus Disease 2019 (COVID-19).

Methods: One hundred and six patients, discharged from a pneumology COVID-19 unit between March 1 and May 30 2020, accepted to be evaluated at 6 months according to an extensive neurological protocol, including the Montreal Cognitive Assessment (MoCA).

Results: Abnormal MoCA scores at 6 months follow-up were associated with higher pre-hospitalization National Health System (NHS) score (Duca et al. in Emerg Med Pract 22:1-2, 2020) (OR 1.27; 95% CI 1.05-1.6; p = 0.029) and more severe pulmonary disease expressed by the Brescia-COVID Respiratory Severity Scale (Duca et al. in Emerg Med Pract 22:1-2, 2020) (BCRSS > 1OR 4.73; 95% CI 1.53-14.63; p = 0.003) during the acute phase of the disease.

Discussion: This longitudinal study showed that the severity of COVID-19, indicated by BCRSS, and a complex score given by age and premorbid medical conditions, expressed by NHS, play a major role in modulating the long-term cognitive consequences of COVID-19 disease.

Conclusions: These findings indicate that the association of age and premorbid factors might identify people at risk for long-term neurological consequences of COVID-19 disease, thus deserving longer and proper follow-up.

Source: Cristillo V, Pilotto A, Cotti Piccinelli S, Bonzi G, Canale A, Gipponi S, Bezzi M, Leonardi M, Padovani A; Neuro Covid Next Study group. Premorbid vulnerability and disease severity impact on Long-COVID cognitive impairment. Aging Clin Exp Res. 2022 Jan 11:1–4. doi: 10.1007/s40520-021-02042-3. Epub ahead of print. PMID: 35014002; PMCID: PMC8747881. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8747881/ (Full text)

Evaluation of 3-month follow-up of patients with post-acute COVID-19 syndrome

Abstract:

Background: In addition to the highly variable clinical presentation of acute COVID-19 infection, it can also cause various post-acute signs and symptoms. This study aimed to evaluate patients with post-acute COVID-19 over 12 weeks of follow-up.

Methods: The study included 151 patients who were diagnosed with COVID-19 by real-time PCR of a nasopharyngeal swab 1 month earlier, had radiologic findings consistent with COVID-19 pneumonia, and presented to the post-COVID-19 outpatient clinic between May and August 2021. The patients were divided into three groups based on COVID-19 severity: non-severe pneumonia (group 1), severe pneumonia (group 2), and severe pneumonia requiring intensive care (group 3).

Results: Evaluation of laboratory parameters at 4 and 12 weeks showed that group 3 had higher lactose dehydrogenase (LDH) level and lower mean platelet volume than the other groups at both time points (p=0.001 for all). Group 3 also had lower FVC%, FEV1%, and DLCO/VA% compared to groups 1 and 2 at week 4 (p=0.001, 0.004, 0.001, respectively) and compared to group 1 at 12 weeks (p=0.002, 0.03, 0.001, respectively). Patients with persistent dyspnea at 12 weeks had significantly lower FEV1%, FVC%, DLCO/VA%, and saturation levels in room air and significantly higher LDH, pro-BNP, D-dimer, and heart rate compared to those without dyspnea (p=0.001 for all).

Conclusion: Although the lungs are most commonly affected after COVID-19 infection, vascular and endothelial damage also causes multisystem involvement. Our study indicates that laboratory values, radiological signs, and pulmonary functional capacity improved in most patients after 12 weeks of follow-up. This article is protected by copyright. All rights reserved.

Source: Kerget B, Çelik E, Kerget F, Aksakal A, Uçar EY, Araz Ö, Akgün M. Evaluation of 3-month follow-up of patients with post-acute COVID-19 syndrome. J Med Virol. 2022 Jan 9. doi: 10.1002/jmv.27579. Epub ahead of print. PMID: 35001367. https://pubmed.ncbi.nlm.nih.gov/35001367/

Successful application of pulsed electromagnetic fields in a patient with post-COVID-19 fatigue: a case report

Abstract:

in English, German

Background: Post-COVID-19 fatigue is a frequent symptom in COVID-19 survivors, which substantially limits patients to achieve full recovery and potentially restrains return to work. The previous literature has not yet reported the use of pulsed electromagnetic fields in this indication.

Methods: Over the course of 5 weeks, 10 sessions of pulsed electromagnetic field treatment with a high magnetic flux density were applied to a patient suffering from post-COVID-19 fatigue syndrome. Fatigue, work ability, quality of life as well as anxiety, depression, stress level, and resilience were evaluated using validated patient-reported outcome measures.

Results: Fatigue, work ability, quality of life, and psychological well-being improved clearly over the course of the treatment and showed stable results 6 weeks later.

Conclusion: The use of pulsed electromagnetic field therapy with a device that allows sufficient penetration of the body tissue might be a promising physical modality to manage post-COVID-19 fatigue syndrome, which could reduce clinical and economic health consequences. Clinical sham-controlled studies are needed to evaluate the effect of pulsed electromagnetic fields in this indication.

Source: Wagner B, Steiner M, Markovic L, Crevenna R. Successful application of pulsed electromagnetic fields in a patient with post-COVID-19 fatigue: a case report. Wien Med Wochenschr. 2022 Jan 10:1–6. doi: 10.1007/s10354-021-00901-2. Epub ahead of print. PMID: 35006516; PMCID: PMC8743351. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743351/ (Full text)

Role of Nutritents for COVID-19 recovery: an integrative approach

Introduction: Many patients (“long-haulers”) suffer lingering illness following COVID-19. The aim of this presentation is to evaluate the evidence of nutrient deficiencies affecting immune function and chronic symptoms from covid19 infection in a subgroup of patients. We will discuss the potential benefit of supplementing with multi-nutrients as an integrative approach to reducing long-hauler symptoms.

Methods: A narrative review followed a search of Medline/Pubmed, CINAHL, Google Scholar for studies published between January 2000 and March 2021, using key terms “coronavirus”, “COVID-19”, “immune system”, “inflammation”, “microbiome”, “oxidative stress”, “mitochondrial function”, “micronutrients”, “vitamin”, “minerals”, and “antioxidants”. Six reviews were selected which examined on the role of nutrients in immune and neurological function, including inflammatory processes, microbiome homeostasis, and mitochondrial function.

Results: Symptoms of long-haulers may be similar to myalgic encephalomyelitis/chronic fatigue syndrome associated with mitochondria dysfunction due to oxidative stress. Similar findings of chronic inflammation and microbiome dysbiosis associated with mood disorders also suggest the association between nutrient deficiencies and immuno-neurological functions. Nutrients required for optimal immune function included: antioxidants such as CoQ10 is required for mitochondrial function and is depleted quickly during acute immune response. Vitamins C and E and selenium also have antioxidant properties that can decrease proinflammatory cytokines and increase leukocyte and NK cell function. The B vitamins are involved in decrease pro-inflammatory cytokines and increase NK cell activities. Similarly, these nutrients are required for optimal neurological functioning in the CNS.

Conclusion: Initial evidence suggests chronic inflammatory processes in the CNS may contribute to the symptoms of covid-19 long-haulers. Given the complementary roles of different nutrient in immune response and CNS pathways, integrating multiple nutrients as treatment for long-haulers warrants further study.

Source: Leung B. Role of Nutritents for COVID-19 recovery: an integrative approach European Journal of Integrative Medicine. 2021 Dec;48:101978-101978. PMCID: PMC8696099. https://europepmc.org/article/pmc/pmc8696099#free-full-text (Full text)

Long COVID symptoms and duration in SARS-CoV-2 positive children – a nationwide cohort study

Abstract:

Most children have a mild course of acute COVID-19. Only few mainly non-controlled studies with small sample size have evaluated long-term recovery from SARS-CoV-2 infection in children. The aim of this study was to evaluate symptoms and duration of ‘long COVID’ in children. A nationwide cohort study of 37,522 children aged 0-17 years with RT-PCR verified SARS-CoV-2 infection (response rate 44.9%) and a control group of 78,037 children (response rate 21.3%).

An electronic questionnaire was sent to all children from March 24th until May 9th, 2021. Symptoms lasting > 4 weeks were common among both SARS-CoV-2 children and controls. However, SARS-CoV-2 children aged 6-17 years reported symptoms more frequently than the control group (percent difference 0.8%). The most reported symptoms among pre-school children were fatigue Risk Difference (RD) 0.05 (CI 0.04-0.06), loss of smell RD 0.01 (CI 0.01-0.01), loss of taste RD 0.01 (CI 0.01-0.02) and muscle weakness RD 0.01 (CI 0.00-0.01). Among school children the most significant symptoms were loss of smell RD 0.12 (CI 0.12-0.13), loss of taste RD 0.10 (CI 0.09-0.10), fatigue RD 0.05 (CI 0.05-0.06), respiratory problems RD 0.03 (CI 0.03-0.04), dizziness RD 0.02 (CI 0.02-0.03), muscle weakness RD 0.02 (CI 0.01-0.02) and chest pain RD 0.01 (CI 0.01-0.01). Children in the control group experienced significantly more concentration difficulties, headache, muscle and joint pain, cough, nausea, diarrhea and fever than SARS-CoV-2 infected. In most children ‘long COVID’ symptoms resolved within 1-5 months.

Conclusions: Long COVID in children is rare and mainly of short duration.

What is Known:

• There are increasing reports on ‘long COVID’ in adults.

• Only few studies have evaluated the long-term recovery from COVID-19 in children, and common for all studies is a small sample size (median number of children included 330), and most lack a control group.

What is New:

• 0.8% of SARS-CoV-2 positive children reported symptoms lasting >4 weeks (‘long COVID’), when compared to a control group.

• The most common ‘long COVID’ symptoms were fatigue, loss of smell and loss of taste, dizziness, muscle weakness, chest pain and respiratory problems.

• These ‘long COVID’ symptoms cannot be assigned to psychological sequelae of social restrictions.

• Symptoms such as concentration difficulties, headache, muscle- and joint pain as well as nausea are not ‘long COVID’ symptoms.

• In most cases ‘long COVID’ symptoms resolve within 1-5 months.

Source: Borch L, Holm M, Knudsen M, Ellermann-Eriksen S, Hagstroem S. Long COVID symptoms and duration in SARS-CoV-2 positive children – a nationwide cohort study. Eur J Pediatr. 2022 Jan 9:1–11. doi: 10.1007/s00431-021-04345-z. Epub ahead of print. PMID: 35000003; PMCID: PMC8742700. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742700/ (Full text)