Autoimmune gene expression profiling of fingerstick whole blood in Chronic Fatigue Syndrome

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating condition that can lead to severe impairment of physical, psychological, cognitive, social, and occupational functions. The cause of ME/CFS remains incompletely understood. There is no clinical diagnostic test for ME/CFS. Although many therapies have been used off-label to manage symptoms of ME/CFS, there are limited, if any, specific therapies or cure for ME/CFS. In this study, we investigated the expression of genes specific to key immune functions, and viral infection status in ME/CFS patients with an aim of identifying biomarkers for characterization and/or treatment of the disease.

Methods: In 2021, one-hundred and sixty-six (166) patients diagnosed with ME/CFS and 83 healthy controls in the US participated in this study via a social media-based application (app). The patients and heathy volunteers consented to the study and provided self-collected finger-stick blood and first morning void urine samples from home. RNA from the fingerstick blood was tested using DxTerity’s 51-gene autoimmune RNA expression panel (AIP). In addition, DNA from the same fingerstick blood sample was extracted to detect viral load of 4 known ME/CFS associated viruses (HHV6, HHV7, CMV and EBV) using a real-time PCR method.

Results: Among the 166 ME/CFS participants in the study, approximately half (49%) of the ME/CFS patients reported being house-bound or bedridden due to severe symptoms of the disease. From the AIP testing, ME/CFS patients with severe, bedridden conditions displayed significant increases in gene expression of IKZF2, IKZF3, HSPA8, BACH2, ABCE1 and CD3D, as compared to patients with mild to moderate disease conditions. These six aforementioned genes were further upregulated in the 22 bedridden participants who suffer not only from ME/CFS but also from other autoimmune diseases. These genes are involved in T cell, B cell and autoimmunity functions. Furthermore, IKZF3 (Aiolos) and IKZF2 (Helios), and BACH2 have been implicated in other autoimmune diseases such as systemic lupus erythematosus (SLE) and Rheumatoid Arthritis (RA). Among the 240 participants tested with the viral assays, 9 samples showed positive results (including 1 EBV positive and 8 HHV6 positives).

Conclusions: Our study indicates that gene expression biomarkers may be used in identifying or differentiating subsets of ME/CFS patients having different levels of disease severity. These gene targets may also represent opportunities for new therapeutic modalities for the treatment of ME/CFS. The use of social media engaged patient recruitment and at-home sample collection represents a novel approach for conducting clinical research which saves cost, time and eliminates travel for office visits.

Source: Wang Z, Waldman MF, Basavanhally TJ, Jacobs AR, Lopez G, Perichon RY, Ma JJ, Mackenzie EM, Healy JB, Wang Y, Hersey SA. Autoimmune gene expression profiling of fingerstick whole blood in Chronic Fatigue Syndrome. J Transl Med. 2022 Oct 25;20(1):486. doi: 10.1186/s12967-022-03682-3. PMID: 36284352; PMCID: PMC9592873.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9592873/ (Full study)

The SARS-CoV-2 S1 Spike Protein Promotes MAPK and NF-kB Activation in Human Lung Cells and Inflammatory Cytokine Production in Human Lung and Intestinal Epithelial Cells

Abstract:

The coronavirus disease 2019 (COVID-19) pandemic began in January 2020 in Wuhan, China, with a new coronavirus designated SARS-CoV-2. The principal cause of death from COVID-19 disease quickly emerged as acute respiratory distress syndrome (ARDS). A key ARDS pathogenic mechanism is the “Cytokine Storm”, which is a dramatic increase in inflammatory cytokines in the blood.
In the last two years of the pandemic, a new pathology has emerged in some COVID-19 survivors, in which a variety of long-term symptoms occur, a condition called post-acute sequelae of COVID-19 (PASC) or “Long COVID”. Therefore, there is an urgent need to better understand the mechanisms of the virus.
The spike protein on the surface of the virus is composed of joined S1–S2 subunits. Upon S1 binding to the ACE2 receptor on human cells, the S1 subunit is cleaved and the S2 subunit mediates the entry of the virus. The S1 protein is then released into the blood, which might be one of the pivotal triggers for the initiation and/or perpetuation of the cytokine storm.
In this study, we tested the hypothesis that the S1 spike protein is sufficient to activate inflammatory signaling and cytokine production, independent of the virus. Our data support a possible role for the S1 spike protein in the activation of inflammatory signaling and cytokine production in human lung and intestinal epithelial cells in culture. These data support a potential role for the SARS-CoV-2 S1 spike protein in COVID-19 pathogenesis and PASC.
Source: Forsyth CB, Zhang L, Bhushan A, Swanson B, Zhang L, Mamede JI, Voigt RM, Shaikh M, Engen PA, Keshavarzian A. The SARS-CoV-2 S1 Spike Protein Promotes MAPK and NF-kB Activation in Human Lung Cells and Inflammatory Cytokine Production in Human Lung and Intestinal Epithelial Cells. Microorganisms. 2022; 10(10):1996. https://doi.org/10.3390/microorganisms10101996 https://www.mdpi.com/2076-2607/10/10/1996/htm (Full text)

Genetic and epigenetic regulation of Catechol-O-methyltransferase in relation to inflammation in chronic fatigue syndrome and Fibromyalgia

Abstract:

Background: Catechol-O-methyltransferase (COMT) has been shown to influence clinical pain, descending modulation, and exercise-induced symptom worsening. COMT regulates nociceptive processing and inflammation, key pathophysiological features of Chronic Fatigue Syndrome and Fibromyalgia (CFS/FM). We aimed to determine the interactions between genetic and epigenetic mechanisms regulating COMT and its influence on inflammatory markers and symptoms in patients with CFS/FM.

Methods: A case-control study with repeated-measures design was used to reduce the chance of false positive and increase the power of our findings. Fifty-four participants (28 patients with CFS/FM and 26 controls) were assessed twice within 4 days. The assessment included clinical questionnaires, neurophysiological assessment (pain thresholds, temporal summation, and conditioned pain modulation), and blood withdrawal in order to assess rs4818, rs4633, and rs4680 COMT polymorphisms and perform haplotype estimation, DNA methylation in the COMT gene (both MB-COMT and S-COMT promoters), and cytokine expression (TNF-α, IFN-γ, IL-6, and TGF-β).

Results: COMT haplotypes were associated with DNA methylation in the S-COMT promoter, TGF-β expression, and symptoms. However, this was not specific for one condition. Significant between-group differences were found for increased DNA methylation in the MB-COMT promoter and decreased IFN-γ expression in patients.

Discussion: Our results are consistent with basic and clinical research, providing interesting insights into genetic-epigenetic regulatory mechanisms. MB-COMT DNA methylation might be an independent factor contributing to the pathophysiology of CFS/FM. Further research on DNA methylation in complex conditions such as CFS/FM is warranted. We recommend future research to employ a repeated-measure design to control for biomarkers variability and within-subject changes.

Source: Polli A, Hendrix J, Ickmans K, Bakusic J, Ghosh M, Monteyne D, Velkeniers B, Bekaert B, Nijs J, Godderis L. Genetic and epigenetic regulation of Catechol-O-methyltransferase in relation to inflammation in chronic fatigue syndrome and Fibromyalgia. J Transl Med. 2022 Oct 25;20(1):487. doi: 10.1186/s12967-022-03662-7. PMID: 36284330; PMCID: PMC9598022. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9598022/ (Full text)

Combination of whole-body cryotherapy with static stretching exercises reduces fatigue and improves functioning of the autonomic nervous system in Chronic Fatigue Syndrome

Abstract:

Background: The aim of this study was to explore the tolerability and effect of static stretching (SS) and whole body cryotherapy (WBC) upon fatigue, daytime sleepiness, cognitive functioning and objective and subjective autonomic nervous system functioning in those with Chronic Fatigue Syndrome (CFS) compared to a control population.

Methods: Thirty-two CFS and eighteen healthy controls (HC) participated in 2 weeks of a SS + WBC programme. This programme was composed of five sessions per week, 10 sessions in total.

Results: A significant decrease in fatigue was noted in the CFS group in response to SS + WBC. Some domains of cognitive functioning (speed of processing visual information and set-shifting) also improved in response to SS + WBC in both CFS and HC groups. Our study has confirmed that WBC is well tolerated by those with CFS and leads to symptomatic improvements associated with changes in cardiovascular and autonomic function.

Conclusions: Given the preliminary data showing the beneficial effect of cryotherapy, its relative ease of application, good tolerability, and proven safety, therapy with cold exposure appears to be an approach worth attention. Further studies of cryotherapy as a potential treatment in CFS is important in the light of the lack of effective therapeutic options for these common and often disabling symptoms.

Source: Kujawski S, Słomko J, Godlewska BR, Cudnoch-Jędrzejewska A, Murovska M, Newton JL, Sokołowski Ł, Zalewski P. Combination of whole body cryotherapy with static stretching exercises reduces fatigue and improves functioning of the autonomic nervous system in Chronic Fatigue Syndrome. J Transl Med. 2022 Jun 17;20(1):273. doi: 10.1186/s12967-022-03460-1. PMID: 35715857; PMCID: PMC9204866.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204866/ (Full text)

Long-haul COVID: heed the lessons from other infection-triggered illnesses

According to the Johns Hopkins Coronavirus Resource Center, more than 115 million people worldwide have been infected with SARS-CoV-2 during the COVID-19 pandemic, with extensive implications for morbidity and mortality. Description of long-term effects of COVID-19 are apparing in the medical literature; the first large cohort study with 6-months’ follow-up has been published, and more data are sure to follow. A small number of studies point not only to persistent imaging and testing abnormalities across several organ systems in the postacute period, but to a high frequency of patient-reported symptoms such as fatigue, insomnia, anxiety and depression, autonomic disturbances, cognitive difficulties, pain, and others. The presence of patient support groups, and the rapid expansion of clinics to manage or treat these symptoms, validate further their existence and impact.
Although the frequency, severity, and potentially the etiology of persistent symptoms can vary, sequelae after COVID-19 appears poised to join the range of other postinfectious syndromes described in the field of infectious diseases.

These often share a common symptom phenotype, which might also meet case definitions for myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia, or post-treatment Lyme disease. We hope that researchers and clinicians will draw on these other conditions as they continue to advance scientific understanding of so-called long-haul or persistent COVID-19. We would also argue that there are important lessons to learn and pitfalls to avoid; our specific area of clinical care and research (post-treatment Lyme disease) has remained a fiercely contentious condition for more than 30 years.

Read the rest of this article HERE.
Source: John N Aucott, Alison W Rebman. Long-haul COVID: heed the lessons from other infection-triggered illnesses. The Lancet, CORRESPONDENCE| VOLUME 397, ISSUE 10278, P967-968, MARCH 13, 2021 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00446-3/fulltext (Full text) 

Beyond COVID-19 and SARS-CoV-2, cardiovascular outcomes of “long covid” from a pathological perspective – a look back and road ahead

Abstract:

With the decrease in severity of COVID-19 there is a sense of relief in the general population. However, there has been an increased incidence of cardiovascular and other organ complications post-infection, which have raised concerns about long COVID. The term “long COVID” was first used by Perego on social media to denote the persistence of symptoms weeks or months after initial SARS-CoV-2 infection and the term ‘long haulers’ was first described by Watson and by Yong to identify post-COVID conditions.

There has been an increased incidence of sudden cardiac death and MI post-COVID-19 in healthy individuals, sports persons and prominent movie stars. Potential mechanisms contributing to the pathophysiology of post-acute COVID-19 may include 1) Damage to tissues and cells that are important for blood flow, so clotting of blood is increased. 2) Persistence of fragments of virus or its sub-particles/ protein material in a wide range of body sites and, 3) an immune system gone haywire.

As the majority of countries across the globe are easing coronavirus precautionary measures, there is an urgent need by health care organizations and policymakers worldwide to generate awareness by educating the public at large, about the ill effects of long-COVID and varied types of post-acute sequelae of COVID-19.

Source: Aden D, Zaheer S, Kumar R, Raj S, Khan T, Varshney S. Beyond COVID-19 and SARS-CoV-2, cardiovascular outcomes of “long covid” from a pathological perspective – a look back and road ahead. Pathol Res Pract. 2022 Sep 29;239:154144. doi: 10.1016/j.prp.2022.154144. Epub ahead of print. PMID: 36242969; PMCID: PMC9519512.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9519512/ (Full text)

Long-COVID in people with intellectual disabilities: A call for research of a neglected area

Abstract:

Background: Long-COVID (also known as post-coronavirus-19 syndrome) is a term used to describe symptoms that people experience following their recovery from the COVID-19 virus. The severity of long-COVID is well recognised, with healthcare providers commissioning services to diagnose and treat those affected, as well as funded research into the condition.

Methods: We performed a systematic search for relevant articles but were unable to find any research on long-COVID in people with intellectual disabilities. Due to the lack of data, we have only been able to make extrapolations from what is known about the condition within the general population.

Findings: We provide an overview of long-COVID and its potential relevance to people with an intellectual disability. We have focused specifically on symptoms or signs, prevalence, risk factors and treatments of the condition in this group, highlighting areas for clinical practice and future research from a psychosocial perspective. We raise serious questions about our current understanding and the availability of the evidence-based to inform treatments tailored towards this population.

Conclusion: This is the first report that we are aware of on the topic of long-COVID in people with an intellectual disability. The lack of research is preventing us from gaining a greater understanding of how the condition impacts people with an intellectual disability.

Source: Rawlings GH, Beail N. Long-COVID in people with intellectual disabilities: A call for research of a neglected area. Br J Learn Disabil. 2022 Aug 29:10.1111/bld.12499. doi: 10.1111/bld.12499. Epub ahead of print. PMID: 36247098; PMCID: PMC9538317. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9538317/  (Full text)

Negative correlation between ACE2 gene expression levels and loss of taste in a cohort of COVID-19 hospitalized patients: New clues to long-term cognitive disorders

Abstract:

In early 2020, one of the most prevalent symptoms of SARS-CoV-2 infection was the loss of smell (anosmia), found in 60-70% of all cases. Anosmia used to occur early, concomitantly with other symptoms, and often persisted after recovery for an extended period, sometimes for months. In addition to smell disturbance, COVID-19 has also been associated with loss of taste (ageusia). The latest research suggests that SARS-CoV-2 could spread from the respiratory system to the brain through receptors in sustentacular cells localized to the olfactory epithelium. The virus invades human cells via the obligatory receptor, angiotensin-converting enzyme II (ACE2), and a priming protease, TMPRSS2, facilitating viral penetration. There is an abundant expression of both ACE2 and TMPRSS2 in sustentacular cells.

In this study, we evaluated 102 COVID-19 hospitalized patients, of which 17.60% presented anosmia and 9.80% ageusia. ACE1, ACE2, and TMPRSS2 gene expression levels in nasopharyngeal tissue were obtained by RT-qPCR and measured using ΔCT analysis. ACE1 Alu287bp association was also evaluated. Logistic regression models were generated to estimate the effects of variables on ageusia and anosmia.

Association of ACE2 expression levels with ageusia. was observed (OR: 1.35; 95% CI: 1.098-1.775); however, no association was observed between TMPRSS2 and ACE1 expression levels and ageusia. No association was observed among the three genes and anosmia, and the Alu287bp polymorphism was not associated with any of the outcomes.

Lastly, we discuss whetherthere is a bridge linking these initial symptoms, including molecular factors, to long-term COVID-19 health consequences such as cognitive dysfunctions.

Source: Braga-Paz I, Ferreira de Araújo JL, Alves HJ, de Ávila RE, Resende GG, Teixeira MM, de Aguiar RS, de Souza RP, Bahia D. Negative correlation between ACE2 gene expression levels and loss of taste in a cohort of COVID-19 hospitalized patients: New clues to long-term cognitive disorders. Front Cell Infect Microbiol. 2022 Sep 29;12:905757. doi: 10.3389/fcimb.2022.905757. PMID: 36250059; PMCID: PMC9556632. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9556632/ (Full text)

Long COVID: An inevitable sequela of SARS-CoV-2 infection

Abstract:

At present, there are more than 560 million confirmed cases of the coronavirus disease 2019 (COVID-19) worldwide. Although more than 98% of patients with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection can survive acute COVID, a significant portion of survivors can develop residual health problems, which is termed as long COVID. Although severe COVID-19 is generally associated with a high risk of long COVID, patients with asymptomatic or mild disease can also show long COVID.

The definition of long COVID is inconsistent and its clinical manifestations are protean. In addition to general symptoms, such as fatigue, long COVID can affect many organ systems, including the respiratory, neurological, psychosocial, cardiovascular, gastrointestinal, and metabolic systems. Moreover, patients with long COVID may experience exercise intolerance and impaired daily function and quality of life. Long COVID may be caused by SARS-CoV-2 direct injury or its associated immune/inflammatory response.

Assessment of patients with long COVID requires comprehensive evaluation, including history taking, physical examination, laboratory tests, radiography, and functional tests. However, there is no known effective treatment for long COVID. Based on the limited evidence, vaccines may help to prevent the development of long COVID. As long COVID is a new clinical entity that is constantly evolving, there are still many unknowns, and further investigation is warranted to enhance our understanding of this disease.

Source: Chih-Cheng Lai, Chi-Kuei Hsu, Muh-Yong Yen, Ping-Ing Lee, Wen-Chien Ko, Po-Ren Hsueh. Long COVID: An inevitable sequela of SARS CoV-2 infection. Journal of Microbiology, Immunology and Infection, 2022, ISSN 1684-1182,
https://doi.org/10.1016/j.jmii.2022.10.003 (Full text)

Headaches and Dizziness as Disabling, Persistent Symptoms in Patients with Long COVID-A National Multicentre Study

Abstract:

Background: Currently, about 15% of coronavirus disease-19 (COVID-19) patients are affected by Long COVID worldwide; however, this condition has not yet been sufficiently studied. The aim of this study was to identify the impact of symptom persistence as well as clinical and socio-demographic variables in a cohort of people with Long COVID.

Methods: We conducted a descriptive cross-sectional study of a sample of adult patients from different Spanish regions presenting with Long COVID. Data collection was conducted between April and July 2021. Functional status and dependency were assessed.

Results: A multivariate linear regression was performed, and the model was statistically significant (F (7; 114) = 8.79; p < 0.001), according to the overall ALDQ score. The variables with a statistically significant effect on the degree of dependence were age (p = 0.014), time since diagnosis (p = 0.02), headaches (p = 0.031), and dizziness (p = 0.039). Functional status post-COVID showed a positive and significant relationship with the percentage of dependence (p < 0.001).

Conclusions: People affected by Long COVID showed moderate dependency status and limitations in functionality. Those with neurological symptoms, such as dizziness and headaches, as well as older age, showed a higher degree of dependency. Improvements in dependency status occurred with increasing time since diagnosis.

Source: Rodríguez-Pérez MP, Sánchez-Herrera-Baeza P, Rodríguez-Ledo P, Serrada-Tejeda S, García-Bravo C, Pérez-de-Heredia-Torres M. Headaches and Dizziness as Disabling, Persistent Symptoms in Patients with Long COVID-A National Multicentre Study. J Clin Med. 2022 Oct 6;11(19):5904. doi: 10.3390/jcm11195904. PMID: 36233769; PMCID: PMC9572453. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9572453/ (Full text)