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)

Increased red blood cell deformation in children and adolescents after SARS-CoV-2 infection

Abstract:

Severe coronavirus disease 2019 (COVID-19) is associated with hyperinflammation, hypercoagulability and hypoxia. Red blood cells (RBCs) play a key role in microcirculation and hypoxemia and are therefore of special interest in COVID-19 pathophysiology. While this novel disease has claimed the lives of many older patients, it often goes unnoticed or with mild symptoms in children.

This study aimed to investigate morphological and mechanical characteristics of RBCs after SARS-CoV-2 infection in children and adolescents by real-time deformability-cytometry (RT-DC), to investigate the relationship between alterations of RBCs and clinical course of COVID-19. Full blood of 121 students from secondary schools in Saxony, Germany, was analyzed. SARS-CoV-2-serostatus was acquired at the same time.

Median RBC deformation was significantly increased in SARS-CoV-2-seropositive compared to seronegative children and adolescents, but no difference could be detected when the infection dated back more than 6 months. Median RBC area was the same in seropositive and seronegative adolescents. ‘

Our findings of increased median RBC deformation in SARS-CoV-2 seropositive children and adolescents until 6 months post COVID-19 could potentially serve as a progression parameter in the clinical course of the disease with an increased RBC deformation pointing towards a mild course of COVID-19.

Source: Eder J, Schumm L, Armann JP, Puhan MA, Beuschlein F, Kirschbaum C, Berner R, Toepfner N. Increased red blood cell deformation in children and adolescents after SARS-CoV-2 infection. Sci Rep. 2023 Jun 17;13(1):9823. doi: 10.1038/s41598-023-35692-6. PMID: 37330522. https://www.nature.com/articles/s41598-023-35692-6 (Full text)

“We’re drowning and we’re alone”: a qualitative study of the lived experience of people experiencing persistent post-COVID-19 symptoms

Abstract:

Background: The “long tail” of the COVID-19 pandemic will be reflected in disabling symptoms that persist, fluctuate or recur for extended periods for an estimated 20%-30% of those who had a SARS-CoV-2 infection; development of effective interventions to address these symptoms must account for the realities faced by these patients. We sought to describe the lived experience of patients living with persistent post-COVID-19 symptoms.

Methods: We conducted a qualitative study, using interpretive description, of the lived experiences of adults experiencing persistent post-COVID-19 symptoms. We collected data from in-depth, semistructured virtual focus groups in February and March 2022. We used thematic analysis to analyze the data and met with several participants twice for respondent validation.

Results: The study included 41 participants (28 females) from across Canada with a mean age of 47.9 years and mean time since initial SARS-CoV-2 infection of 15.8 months. Four overarching themes were identified: the unique burdens of living with persistent post-COVID-19 symptoms; the complex nature of patient work in managing symptoms and seeking treatment during recovery; erosion of trust in the health care system; and the process of adaptation, which included taking charge and transformed self-identity.

Interpretation: Living with persistent post-COVID-19 symptoms within a health care system ill-equipped to provide needed resources profoundly challenges the ability of survivors to restore their well-being. Whereas policy and practice increasingly emphasize the importance of self-management within the context of post-COVID-19 symptoms, new investments that enhance services and support patient capacity are required to promote better outcomes for patients, the health care system and society.

Source: Goodridge D, Lowe TN, Cai S, Herriot FN, Silverberg RV, Heynen M, Hall KC, Peters J, Butcher S, Oyedokun T. “We’re drowning and we’re alone”: a qualitative study of the lived experience of people experiencing persistent post-COVID-19 symptoms. CMAJ Open. 2023 Jun 13;11(3):E504-E515. doi: 10.9778/cmajo.20220205. PMID: 37311595; PMCID: PMC10270655. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10270655/ (Full text)

Sex-Dependent Transcriptional Changes in Response to Stress in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Project

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multi-symptom illness characterized by debilitating fatigue and post-exertional malaise (PEM). Numerous studies have reported sex differences at the epidemiological, cellular, and molecular levels between male and female ME/CFS patients. To gain further insight into these sex-dependent changes, we evaluated differential gene expression by RNA-sequencing (RNA-Seq) in 33 ME/CFS patients (20 female, 13 male) and 34 matched healthy controls (20 female and 14 male) before, during, and after an exercise challenge intended to provoke PEM.
Our findings revealed that pathways related to immune-cell signaling (including IL-12) and natural killer cell cytotoxicity were activated as a result of exertion in the male ME/CFS cohort, while female ME/CFS patients did not show significant enough changes in gene expression to meet the criteria for the differential expression. Functional analysis during recovery from an exercise challenge showed that male ME/CFS patients had distinct changes in the regulation of specific cytokine signals (including IL-1β). Meanwhile, female ME/CFS patients had significant alterations in gene networks related to cell stress, response to herpes viruses, and NF-κβ signaling. The functional pathways and differentially expressed genes highlighted in this pilot project provide insight into the sex-specific pathophysiology of ME/CFS.
Source: Gamer J, Van Booven DJ, Zarnowski O, Arango S, Elias M, Kurian A, Joseph A, Perez M, Collado F, Klimas N, et al. Sex-Dependent Transcriptional Changes in Response to Stress in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Project. International Journal of Molecular Sciences. 2023; 24(12):10255. https://doi.org/10.3390/ijms241210255 https://www.mdpi.com/1422-0067/24/12/10255 (Full text)