Serum from Myalgic encephalomyelitis/chronic fatigue syndrome patients causes loss of coherence in cellular circadian rhythms

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling disorder characterized by disrupted daily patterns of activity, sleep, and physiology. Past studies in ME/CFS patients have examined circadian rhythms, suggested that desynchronization between central and peripheral rhythms may be an important pathological feature, and identified associated changes in post-inflammatory cytokines such as transforming growth factor beta (TGFB). However, no previous studies have examined circadian rhythms in ME/CFS using cellular models or studied the role of cytokines on circadian rhythms.

In this study, we used serum samples previously collected from ME/CFS patients (n = 20) selected for the presence of insomnia symptoms and matched controls (n = 20) to determine the effects of serum factors and TGFB on circadian rhythms in NIH3T3 mouse immortalized fibroblasts stably transfected with the Per2-luc bioluminescent circadian reporter.

Compared to control serum, ME/CFS serum caused a significant loss of rhythm robustness (decreased goodness of fit) and nominally increased the rate of damping of cellular rhythms. Damping rate was associated with insomnia severity in ME/CFS patients using the Pittsburgh Sleep Quality Index (PSQI). Recombinant TGFB1 peptide applied to cells reduced rhythm amplitude, caused phase delay and decreased robustness of rhythms.

However, there was no difference in TGFB1 levels between ME/CFS and control serum indicating the effects of serum on cellular rhythms cannot be explained by levels of this cytokine. Future studies will be required to identify additional serum factors in ME/CFS patients that alter circadian rhythms in cells.

Source: Heather Wei, Zoe Adelsheim, Rita Fischer, Michael J. McCarthy. Serum from Myalgic encephalomyelitis/chronic fatigue syndrome patients causes loss of coherence in cellular circadian rhythms. Journal of Neuroimmunology. Available online 24 June 2023, 578142. https://doi.org/10.1016/j.jneuroim.2023.578142 https://www.sciencedirect.com/science/article/abs/pii/S0165572823001285

Circulating miRNAs Expression in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multifactorial disease that causes increasing morbidity worldwide, and many individuals with ME/CFS symptoms remain undiagnosed due to the lack of diagnostic biomarkers. Its etiology is still unknown, but increasing evidence supports a role of herpesviruses (including HHV-6A and HHV-6B) as potential triggers.
Interestingly, the infection by these viruses has been reported to impact the expression of microRNAs (miRNAs), short non-coding RNA sequences which have been suggested to be epigenetic factors modulating ME/CFS pathogenic mechanisms. Notably, the presence of circulating miRNAs in plasma has raised the possibility to use them as valuable biomarkers for distinguishing ME/CFS patients from healthy controls.
Thus, this study aimed at determining the role of eight miRNAs, which were selected for their previous association with ME/CFS, as potential circulating biomarkers of the disease. Their presence was quantitatively evaluated in plasma from 40 ME/CFS patients and 20 healthy controls by specific Taqman assays, and the results showed that six out of the eight of the selected miRNAs were differently expressed in patients compared to controls; more specifically, five miRNAs were significantly upregulated (miR-127-3p, miR-142-5p, miR-143-3p, miR-150-5p, and miR-448), and one was downmodulated (miR-140-5p). MiRNA levels directly correlated with disease severity, whereas no significant correlations were observed with the plasma levels of seven pro-inflammatory cytokines or with the presence/load of HHV-6A/6B genome, as judged by specific PCR amplification.
The results may open the way for further validation of miRNAs as new potential biomarkers in ME/CFS and increase the knowledge of the complex pathways involved in the ME/CFS development.
Source: Soffritti I, Gravelsina S, D’Accolti M, Bini F, Mazziga E, Vilmane A, Rasa-Dzelzkaleja S, Nora-Krukle Z, Krumina A, Murovska M, et al. Circulating miRNAs Expression in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. International Journal of Molecular Sciences. 2023; 24(13):10582. https://doi.org/10.3390/ijms241310582 https://www.mdpi.com/1422-0067/24/13/10582 (Full text)

Impact of Covid-19 disease on thyroid function: longitudinal study

Abstract:

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic disease (Covid-19) affects thyroid function with different mechanisms: non-thyroidal illness syndrome (NTIS), direct infection of thyroid gland and cytokine storm. We provided the first description of painless atypical thyroiditis coexisting with NTIS in patients hospitalised for moderate-to-severe Covid-19 disease. We aimed to: 1) correlate thyroid dysfunction with Covid-19 disease severity; 2) follow the evolution of thyroid function over time.

Methods: Baseline (at hospital admittance) and longitudinal study of patients hospitalised for moderate-to-severe Covid-19 disease, without known history of thyroid disfunction, assessing serum thyroid function and autoantibodies, inflammatory markers and thyroid ultrasound scan (US). Patients showing at US focal hypoechoic areas suggestive for thyroiditis (thyroiditis-areas) also underwent thyroid 99mTc or I123 uptake scan.

Results: 183 Covid-19 patients were studied baseline, of whom 63 (34%) were already on steroid treatment before hospital admission, thus were not considered for TSH analysis. Decreased serum TSH positively correlated with albumin (P=0.02) and lymphocyte count (P<0.01) but not with C-reactive-protein (P=0.12) and interleukin-6 (P=0.10); TSH also progressively and inversely correlated to the need of oxygen support (P=0.02). Serum FT3 correlated positively with albumin (P<0.01) and inversely with D-dimer (P=0.02). Baseline thyroid US scan showed thyroiditis-areas in 18/65 (28%) patients, associated with reduced thyroid uptake at 99mTc/I123 scintigraphy in 14/17 (82%) cases. Thyroiditis-areas were more frequent among patients with baseline low TSH (6/10, 60%) compared with those with normal TSH (10/40, 25%, P=0.034). The patients with thyroiditis-areas also had higher baseline FT4 (P=0.018) and IL-6 (P=0.016) compared with those with normal thyroid US. Follow-up analysis was conducted in 75/183 (41%) patients; thyroid function and inflammatory markers normalized at all time-points in nearly all cases and no increase of thyroid autoantibodies positivity was observed. The thyroiditis-areas, even if often reduced in size, were still present after 6 and 12 months in 13/15 (87%) and 6/12 (50%) patients, respectively. After 9 months the thyroid uptake at 99mTc/I123 scintigraphy was still reduced in 4/6 (67%) patients, even if partially recovered (mean +28%) compared with baseline.

Conclusions: Thyroid dysfunction during moderate-to-severe Covid-19 disease is mild and transient, and thyroid hormones correlate with disease severity. Thyroiditis-areas at US occur frequently and may persist after one year, even if reduced in size; long-term consequences are unknown. The association of thyroiditis-areas with low TSH and high FT4 and IL-6 serum concentrations support the hypothesis of direct thyroid gland involvement in SARS-CoV-2 infection.

Source: Ilaria Muller, Matteo Varallo, Anita Daturi, Tiziana E Re, Davide Dazzi, Virgilio Longari, Andrea Gori, Giovanna Mantovani , Maura Arosio & Mario Salvi. Impact of Covid-19 disease on thyroid function: longitudinal study. Endocrine Abstracts (2022) 81 RC11.1 | DOI: 10.1530/endoabs.81.RC11.1 https://www.endocrine-abstracts.org/ea/0081/ea0081rc11.1

Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in long COVID

Abstract:

Critical COVID-19 disease is accompanied by depletion of plasma tryptophan (TRY) and increases in indoleamine-dioxygenase (IDO)-stimulated production of neuroactive tryptophan catabolites (TRYCATs), including kynurenine (KYN). The TRYCAT pathway has not been studied extensively in association with the physiosomatic and affective symptoms of Long COVID.

In the present study, we measured serum TRY, TRYCATs, insulin resistance (using the Homeostatic Model Assessment Index 2-insulin resistance, HOMA2-IR), C-reactive protein (CRP), physiosomatic, depression, and anxiety symptoms in 90 Long COVID patients, 3–10 months after remission of acute infection.

We were able to construct an endophenotypic class of severe Long COVID (22% of the patients) with very low TRY and oxygen saturation (SpO2, during acute infection), increased kynurenine, KYN/TRY ratio, CRP, and very high ratings on all symptom domains. One factor could be extracted from physiosomatic symptoms (including chronic fatigue-fibromyalgia), depression, and anxiety symptoms, indicating that all domains are manifestations of the common physio-affective phenome.

Three Long COVID biomarkers (CRP, KYN/TRY, and IR) explained around 40% of the variance in the physio-affective phenome. The latter and the KYN/TRY ratio were significantly predicted by peak body temperature (PBT) and lowered SpO2 during acute infection. One validated latent vector could be extracted from the three symptom domains and a composite based on CRP, KYN/TRY, and IR (Long COVID), and PBT and SpO2 (acute COVID-19).

In conclusion, the physio-affective phenome of Long COVID is a manifestation of inflammatory responses during acute and Long COVID, and lowered plasma tryptophan and increased kynurenine may contribute to these effects.

Source: Al-Hakeim HK, Khairi Abed A, Rouf Moustafa S, Almulla AF, Maes M. Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in long COVID. Front Mol Neurosci. 2023 Jun 2;16:1194769. doi: 10.3389/fnmol.2023.1194769. PMID: 37333619; PMCID: PMC10272345. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10272345/ (Full text)

Comparison of serum acylcarnitine levels in patients with myalgic encephalomyelitis/chronic fatigue syndrome and healthy controls: a systematic review and meta-analysis

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease (ME/CFS/SEID) is a condition diagnosed primarily based on clinical symptoms, including prolonged fatigue and post-exertional malaise; however, there is no specific test for the disease. Additionally, diagnosis can be challenging since healthcare professionals may lack sufficient knowledge about the disease. Prior studies have shown that patients with ME/CFS/SEID have low serum acylcarnitine levels, which may serve as a surrogate test for patients suspected of having this disease. This systematic review and meta-analysis aimed to investigate the differences in serum acylcarnitine levels between patients with ME/CFS/SEID and healthy controls.

Methods: This systematic review was conducted using PubMed and Ichushi-Web databases. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, we included all studies from the databases’ inception until February 17, 2023, that evaluated blood tests in both patients with ME/CFS/SEID and healthy control groups. The primary endpoint was the difference in serum acylcarnitine levels between the two groups.

Results: The electronic search identified 276 studies. Among them, seven met the eligibility criteria. The serum acylcarnitine levels were analyzed in 403 patients with ME/CFS/SEID. The patient group had significantly lower serum acylcarnitine levels when compared with the control group, and the statistical heterogeneity was high.

Conclusion: The patient group had significantly lower serum acylcarnitine levels when compared with the control group. In the future, the measurement of serum acylcarnitine levels, in addition to clinical symptoms, may prove to be a valuable diagnostic tool for this condition.

Source: Jinushi R, Masuda S, Tanisaka Y, Nishiguchi S, Shionoya K, Sato R, Sugimoto K, Shin T, Shiomi R, Fujita A, Mizuide M, Ryozawa S. Comparison of serum acylcarnitine levels in patients with myalgic encephalomyelitis/chronic fatigue syndrome and healthy controls: a systematic review and meta-analysis. J Transl Med. 2023 Jun 19;21(1):398. doi: 10.1186/s12967-023-04226-z. PMID: 37337273; PMCID: PMC10280864. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10280864/ (Full text)

Causal Effects between Gut Microbiome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Two-Sample Mendelian Randomization Study

Abstract:

Background: Evidence from previous studies have implicated an important association between gut microbiota (GM) and Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS), but whether there is a definite causal relationship between GM and ME/CFS has not been elucidated.

Method: This study obtained instrumental variables of 211 GM taxa from the Genome Wide Association Study (GWAS), and mendelian randomization (MR) study was carried out to assess the effect of gut microbiota on ME/CFS risk from UK Biobank GWAS (2076 ME/CFS cases and 460857 controls). Inverse variance weighted (IVW) was the primary method to analyze causality in this study, and a series of sensitivity analyses was performed to validate the robustness of the results.

The inverse variance weighted (IVW) method indicated that genus Paraprevotella (OR:1.001, 95%CI:1.000-1.003, p-value<0.05) and Ruminococca-ceae_UCG_014(OR 1.003, 95% CI 1.000 to 1.005, p-value < 0.05) were positively associated with ME/CFS risk. Results from the weighted median method supported genus Paraprevotella (OR 1.003, 95% CI 1.000 to 1.005, p-value < 0.05) as a risk factor for ME/CFS.

Conclusions: This study reveals a causal relationship between genus.paraprevotella, genus.Ruminococcaceae_UCG_014 and ME/CFS, and our findings provide novel insights for further elucidating the developmental mechanisms mediated by the gut microbiota of ME/CFS.

Source: Gang He, Yu Cao, Wangzi Xu and Houzhao Wang. Causal Effects between Gut Microbiome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Two-Sample Mendelian Randomization Study. Front. Microbiol. Volume 14 – 2023 | doi: 10.3389/fmicb.2023.1190894 https://www.frontiersin.org/articles/10.3389/fmicb.2023.1190894/abstract

Posttreatment Lyme disease syndrome and myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review and comparison of pathogenesis

Abstract:

Lyme disease is the most common vector-borne illness in the United States and has been causing significant morbidity since its discovery in 1977. It is well-documented that about 10% of patients properly treated with antibiotics never fully recover, but instead go on to develop a chronic illness dubbed, posttreatment Lyme disease syndrome (PTLDS) characterized by severe fatigue, cognitive slowing, chronic pain, and sleep difficulties. This review includes 18 studies that detail the symptoms of patients with PTLDS and uses qualitative analysis to compare them to myalgic encephalitis/chronic fatigue syndrome (ME/CFS), a strikingly similar syndrome.

In the majority of the PTLDS studies, at least four of the six major symptoms of ME/CFS were also noted, including substantial impairment in activity level and fatigue for more than 6 months, post-exertional malaise, and unrefreshing sleep. In one of the included PTLDS articles, 26 of the 29 ME/CFS symptoms were noted. This study adds to the expanding literature on the post-active phase of infection syndromes, which suggests that chronic illnesses such as PTLDS and ME/CFS have similar pathogenesis despite different infectious origins.

Key points

  • This systematic review uses qualitative analysis to compare posttreatment Lyme disease syndrome to myalgic encephalitis/chronic fatigue syndrome, both of which are post-active phases of infection syndromes.
  • The result of this review suggests that chronic illnesses such as PTLDS and ME/CFS have similar pathogenesis despite different infectious origins.

Source: Bai, NA, Richardson, CS. Posttreatment Lyme disease syndrome and myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review and comparison of pathogenesis. Chronic Dis Transl Med. 2023; 1– 8. doi:10.1002/cdt3.74 https://onlinelibrary.wiley.com/doi/full/10.1002/cdt3.74 (Full text)

Post-COVID sequalae effect in chronic fatigue syndrome: SARS-CoV-2 triggers latent adenovirus in the oral mucosa

Abstract:

The post-viral fatigue syndromes long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have multiple, potentially overlapping, pathological processes. These include persisting reservoirs of virus e.g. SARS-CoV-2 in long COVID patient’s tissues, immune dysregulation with or without reactivation of underlying pathogens, such as Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV6), as we recently described in ME/CFS, and possibly yet unidentified viruses.

In the present study we tested saliva samples from two cohorts for IgG against human adenovirus (HAdV): patients with ME/CFS (n=84) and healthy controls (n=94), with either mild/asymptomatic SARS-CoV-2 infection or no infection. A significantly elevated anti-HAdV IgG response after SARS-CoV-2 infection was detected exclusively in the patient cohort. Longitudinal/time analysis, before and after COVID-19, in the very same individuals confirmed HAdV IgG elevation after. In plasma there was no HAdV IgG elevation.

We conclude that COVID-19 triggered reactivation of dormant HAdV in the oral mucosa of chronic fatigue patients indicating an exhausted dysfunctional antiviral immune response in ME/CFS, allowing reactivation of adenovirus upon stress encounter such as COVID-19.

Source: Ulf Hannestad, Eirini Apostolou, Per Sjogren, Björn Bragée, Olli Polo, Bo C. Bertilson and Anders Rosén. Post-COVID sequalae effect in chronic fatigue syndrome: SARS-CoV-2 triggers latent adenovirus in the oral mucosa. Front. Med. Sec. Infectious Diseases: Pathogenesis and Therapy, Volume 10 – 2023 | doi: 10.3389/fmed.2023.1208181 https://www.frontiersin.org/articles/10.3389/fmed.2023.1208181/abstract

Vagus Nerve Dysfunction in the Post-COVID-19 Condition

Abstract:

Background: The post-COVID-19 condition (PCC) is a disabling syndrome affecting 5-15% of subjects who survive COVID-19. SARS-CoV-2 mediated vagus nerve dysfunction could explain some of the PCC symptoms, including persistent dysphonia, dysphagia, dyspnea, dizziness, tachycardia, orthostatic hypotension, gastrointestinal disturbances or neurocognitive complaints.

Methods: We performed a cross-sectional pilot study in subjects with PCC with symptoms suggesting vagus nerve dysfunction (n=30) and compared them to subjects fully recovered from acute COVID-19 (n=14) and individuals never infected with SARS-CoV-2 (n=16), matched by age and sex. We evaluated the structure and function of the vagus nerve, including dysphonia, dysphagia, and dysautonomia tests, and evaluated the structure and function of respiratory muscles with vagus nerve innervation.

Findings: Participants were mostly (80%) women with median 44 years of age. Their most prevalent symptoms were cognitive dysfunction (83%), dyspnea (80%) and tachycardia (80%). Compared with COVID-19-recovered and uninfected controls, respectively, subjects with PCC were more likely to show thickening and hyperechogenic vagus nerve in neck ultrasounds (mean ± SD left vagus nerve cross-sectional area: 2.4 ± 0.97mm2 vs. 2 ± 0.52mm2 vs. 1.9 ± 0.73 mm2, p=0.080), flattened diaphragmatic curve (47% vs 6% vs 14%, p=0.007), reduced esophageal peristalsis (34% vs 0% vs 21%, p=0.020), gastroesophageal reflux (34% vs 19% vs 7%, p=0.130), hiatal hernia (25% vs 0% vs 7%, p=0.050) and reduced maximal inspiratory pressure in functional respiratory tests (62% vs. 6% vs. 17%, p ≤0.001).

Interpretation: Vagus nerve dysfunction has a central pathogenic role in the pathophysiology of the post-COVID condition.

Source: Lladós, Gemma and Massanella, Marta and Coll-Fernández, Roser and Rodríguez, Raúl and Hernández, Electra and Lucente, Giuseppe and López, Cristina and Loste, Cora and Santos, José Ramón and España-Cueto, Sergio and Nevot, Maria and Muñoz-López, Francisco and Arrieta, Sandra Silva and Brander, Christian and Durà, Maria José and Cuadras, Patricia and Bechini, Jordi and Tenesa, Montserrat and Martinez-Piñeiro, Alicia and Herrero, Cristina and Chamorro, Anna and Garcia, Anna and Grau, Eulalia and Clotet, Bonaventura and Paredes, Roger and Mateu, Lourdes and Unit, Germans Trias Long-COVID, Vagus Nerve Dysfunction in the Post-COVID-19 Condition. Available at SSRN: https://ssrn.com/abstract=4479598 or http://dx.doi.org/10.2139/ssrn.4479598

What lies beneath: White matter microstructure in pediatric myalgic encephalomyelitis/chronic fatigue syndrome using diffusion MRI

Abstract:

Recent studies in adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suggest that changes in brain white matter microstructural organization may correlate with core ME/CFS symptoms, and represent a potential biomarker of disease. However, this has yet to be investigated in the pediatric ME/CFS population. We examined group differences in macrostructural and microstructural white matter properties, and their relationship with clinical measures, between adolescents recently diagnosed with ME/CFS and healthy controls.

Forty-eight adolescents (25 ME/CFS, 23 controls, mean age 16 years) underwent brain diffusion MRI, and a robust multi-analytic approach was used to evaluate white and gray matter volume, regional brain volume, cortical thickness, fractional anisotropy, mean/axial/radial diffusivity, neurite dispersion and density, fiber density, and fiber cross section.

From a clinical perspective, adolescents with ME/CFS showed greater fatigue and pain, poorer sleep quality, and poorer performance on cognitive measures of processing speed and sustained attention compared with controls. However, no significant group differences in white matter properties were observed, with the exception of greater white matter fiber cross section of the left inferior longitudinal fasciculus in the ME/CFS group compared with controls, which did not survive correction for intracranial volume.

Overall, our findings suggest that white matter abnormalities may not be predominant in pediatric ME/CFS in the early stages following diagnosis. The discrepancy between our null findings and white matter abnormalities identified in the adult ME/CFS literature could suggest that older age and/or longer illness duration influence changes in brain structure and brain-behavior relationships that are not yet established in adolescence.

Source: Josev EK, Chen J, Seal M, Scheinberg A, Cole RC, Rowe K, Lubitz L, Knight SJ. What lies beneath: White matter microstructure in pediatric myalgic encephalomyelitis/chronic fatigue syndrome using diffusion MRI. J Neurosci Res. 2023 Jun 18. doi: 10.1002/jnr.25223. Epub ahead of print. PMID: 37331007. https://onlinelibrary.wiley.com/doi/10.1002/jnr.25223 (Full text)