A Machine-Generated View of the Role of Blood Glucose Levels in the Severity of COVID-19

Abstract:

SARS-CoV-2 started spreading toward the end of 2019 causing COVID-19, a disease that reached pandemic proportions among the human population within months. The reasons for the spectrum of differences in the severity of the disease across the population, and in particular why the disease affects more severely the aging population and those with specific preconditions are unclear. We developed machine learning models to mine 240,000 scientific articles openly accessible in the CORD-19 database, and constructed knowledge graphs to synthesize the extracted information and navigate the collective knowledge in an attempt to search for a potential common underlying reason for disease severity. The machine-driven framework we developed repeatedly pointed to elevated blood glucose as a key facilitator in the progression of COVID-19. Indeed, when we systematically retraced the steps of the SARS-CoV-2 infection, we found evidence linking elevated glucose to each major step of the life-cycle of the virus, progression of the disease, and presentation of symptoms.

Specifically, elevations of glucose provide ideal conditions for the virus to evade and weaken the first level of the immune defense system in the lungs, gain access to deep alveolar cells, bind to the ACE2 receptor and enter the pulmonary cells, accelerate replication of the virus within cells increasing cell death and inducing an pulmonary inflammatory response, which overwhelms an already weakened innate immune system to trigger an avalanche of systemic infections, inflammation and cell damage, a cytokine storm and thrombotic events. We tested the feasibility of the hypothesis by manually reviewing the literature referenced by the machine-generated synthesis, reconstructing atomistically the virus at the surface of the pulmonary airways, and performing quantitative computational modeling of the effects of glucose levels on the infection process.

We conclude that elevation in glucose levels can facilitate the progression of the disease through multiple mechanisms and can explain much of the differences in disease severity seen across the population. The study provides diagnostic considerations, new areas of research and potential treatments, and cautions on treatment strategies and critical care conditions that induce elevations in blood glucose levels.

Source: Logette E, Lorin C, Favreau C, et al. A Machine-Generated View of the Role of Blood Glucose Levels in the Severity of COVID-19. Front Public Health. 2021;9:695139. Published 2021 Jul 28. doi:10.3389/fpubh.2021.695139 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356061/ (Full text)

Epstein-Barr virus may be leading cause of multiple sclerosis

Press Release:

January 13, 2022: Multiple sclerosis (MS), a progressive disease that affects 2.8 million people worldwide and for which there is no definitive cure, is likely caused by infection with the Epstein-Barr virus (EBV), according to a study led by Harvard T.H. Chan School of Public Health researchers.

Their findings will be published online in Science on January 13, 2022.

“The hypothesis that EBV causes MS has been investigated by our group and others for several years, but this is the first study providing compelling evidence of causality,” said Alberto Ascherio, professor of epidemiology and nutrition at Harvard Chan School and senior author of the study. “This is a big step because it suggests that most MS cases could be prevented by stopping EBV infection, and that targeting EBV could lead to the discovery of a cure for MS.”

MS is a chronic inflammatory disease of the central nervous system that attacks the myelin sheaths protecting neurons in the brain and spinal cord. Its cause is not known, yet one of the top suspects is EBV, a herpes virus that can cause infectious mononucleosis and establishes a latent, lifelong infection of the host. Establishing a causal relationship between the virus and the disease has been difficult because EBV infects approximately 95% of adults, MS is a relatively rare disease, and the onset of MS symptoms begins about ten years after EBV infection. To determine the connection between EBV and MS, the researchers conducted a study among more than 10 million young adults on active duty in the U.S. military and identified 955 who were diagnosed with MS during their period of service.

The team analyzed serum samples taken biennially by the military and determined the soldiers’ EBV status at time of first sample and the relationship between EBV infection and MS onset during the period of active duty. In this cohort, the risk of MS increased 32-fold after infection with EBV but was unchanged after infection with other viruses. Serum levels of neurofilament light chain, a biomarker of the nerve degeneration typical in MS, increased only after EBV infection. The findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.

Ascherio says that the delay between EBV infection and the onset of MS may be partially due the disease’s symptoms being undetected during the earliest stages and partially due to the evolving relationship between EBV and the host’s immune system, which is repeatedly stimulated whenever latent virus reactivates.

“Currently there is no way to effectively prevent or treat EBV infection, but an EBV vaccine or targeting the virus with EBV-specific antiviral drugs could ultimately prevent or cure MS,” said Ascherio.

Other Harvard Chan School researchers who contributed to this study include Kjetil Bjornevik, Marianna Cortese, Michael Mina, and Kassandra Munger.

Funding for this study came the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NS046635, NS042194, and NS103891), the National Multiple Sclerosis Society (PP-1912-35234), the German Research Foundation (CO 2129/ 1-1), the National Institutes of Health (DP5- OD028145), and the Howard Hughes Medical Institute.

Source: Materials provided by Harvard T.H. Chan School of Public Health.

Increased CD8+ T cell response to Epstein-Barr virus lytic antigens in the active phase of multiple sclerosis

Abstract:

It has long been known that multiple sclerosis (MS) is associated with an increased Epstein-Barr virus (EBV) seroprevalence and high immune reactivity to EBV and that infectious mononucleosis increases MS risk. This evidence led to postulate that EBV infection plays a role in MS etiopathogenesis, although the mechanisms are debated. This study was designed to assess the prevalence and magnitude of CD8+ T-cell responses to EBV latent (EBNA-3A, LMP-2A) and lytic (BZLF-1, BMLF-1) antigens in relapsing-remitting MS patients (n = 113) and healthy donors (HD) (n = 43) and to investigate whether the EBV-specific CD8+ T cell response correlates with disease activity, as defined by clinical evaluation and gadolinium-enhanced magnetic resonance imaging.

Using HLA class I pentamers, lytic antigen-specific CD8+ T cell responses were detected in fewer untreated inactive MS patients than in active MS patients and HD while the frequency of CD8+ T cells specific for EBV lytic and latent antigens was higher in active and inactive MS patients, respectively. In contrast, the CD8+ T cell response to cytomegalovirus did not differ between HD and MS patients, irrespective of the disease phase. Marked differences in the prevalence of EBV-specific CD8+ T cell responses were observed in patients treated with interferon-β and natalizumab, two licensed drugs for relapsing-remitting MS.

Longitudinal studies revealed expansion of CD8+ T cells specific for EBV lytic antigens during active disease in untreated MS patients but not in relapse-free, natalizumab-treated patients. Analysis of post-mortem MS brain samples showed expression of the EBV lytic protein BZLF-1 and interactions between cytotoxic CD8+ T cells and EBV lytically infected plasma cells in inflammatory white matter lesions and meninges. We therefore propose that inability to control EBV infection during inactive MS could set the stage for intracerebral viral reactivation and disease relapse.

Source: Angelini DF, Serafini B, Piras E, Severa M, Coccia EM, Rosicarelli B, Ruggieri S, Gasperini C, Buttari F, Centonze D, Mechelli R, Salvetti M, Borsellino G, Aloisi F, Battistini L. Increased CD8+ T cell response to Epstein-Barr virus lytic antigens in the active phase of multiple sclerosis. PLoS Pathog. 2013;9(4):e1003220. doi: 10.1371/journal.ppat.1003220. Epub 2013 Apr 11. PMID: 23592979; PMCID: PMC3623710. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623710/ (Full text)

Stigma perceived by patients with functional somatic syndromes and its effect on health outcomes – A systematic review

Abstract:

Background: Patients with functional somatic syndromes (FSS) experience stigma which arguably affects their health.

Aim: To determine the presence of perceived stigma and its effects on physical and mental health in patients with FSS compared to patients with comparable explained conditions.

Methods: A comprehensive search of PubMed, Embase, PsycINFO, CINAHL and Cochrane Library was performed to select studies focusing on stigma perceived by patients with irritable bowel syndrome (IBS), fibromyalgia (FM) or chronic fatigue syndrome (CFS), comparing these patients to patients with comparable but explained conditions.

Results: We identified 1931 studies after duplicate removal. After screening we included eight studies: one study about all three FSS, one about IBS, five about FM and one about CFS. We found that patients with IBS did not consistently experience higher levels of stigma than those with a comparable explained condition. Patients with CFS and FM experienced higher levels of stigma compared to patients with comparable explained conditions. All studies showed a correlation between stigma and negative health outcomes.

Discussion: Patients with FSS experience stigma and negative health outcomes. However, experiencing stigma is not restricted to patients with FSS, as many patients with explained health conditions also experience stigma. Whether stigma has more negative health consequences in patients with FSS compared to patients with explained health conditions remains unclear and should be assessed in future research.

Source: Ko C, Lucassen P, van der Linden B, Ballering A, Olde Hartman T. Stigma perceived by patients with functional somatic syndromes and its effect on health outcomes – A systematic review. J Psychosom Res. 2022 Jan 6;154:110715. doi: 10.1016/j.jpsychores.2021.110715. Epub ahead of print. PMID: 35016138. https://pubmed.ncbi.nlm.nih.gov/35016138/

 

2021: That Was The Year That Was

Original public domain image from Wikimedia Commons

Last year was, by all accounts, a doozy. The nation endured a spate of tornadoes, fires, floods and, of course, the pandemic. The fact that we made it to 2022 seems like a minor miracle.

Despite the many challenges of 2021, AMMES continued to grow. We welcomed two new board members: Mark Zinn and Tamara Staples. Mark is well known in the research community for his groundbreaking work on brain connectivity in ME/CFS patients. Currently, Mark is a director and investigator at the NeuroCognitive Research Institute in Chicago, IL, where he conducts studies which model brain connectivity in patients using 3-D neuroimaging EEG techniques.

Tamara Staples is our new Coordinator for Support and Outreach. As a long-term ME/CFS patient, she ran one of the largest Fibro-ME/CFS support groups in the country. Before the group closed, it was providing its approximately 900 members with monthly newsletter, webinar, an in-person group focused on education, as well as a very active Facebook group. For several years, Tamara has been in a remission that has allowed hiking, camping and backpacking to become a passion. (Stay tuned for her remission story!)

AMMES also added two new resource pages to the website. Our informational page about COVID-19 and ME/CFS includes physicians’ recommendations regarding the COVID vaccine for people with ME/CFS, patient surveys on how the vaccine has affected them, research articles on long-Covid and ME/CFS, related news items, and tips from doctors on how to treat patients with ME/CFS who contract COVID-19. You can find the page here:  https://ammes.org/covid-19/

Last year, we launched a page devoted to interviews with ME/CFS doctors and researchers. Interviews are a great way to keep track of what researchers in the field are doing, and to get the details on how specialists are currently treating the disease. We will be expanding this section over 2022, adding more interviews as we go along. https://ammes.org/interviews-with-doctors-and-researchers/

The AMMES financial crisis fund has been going strong. In 2021 we distributed $41,143.86 in badly needed assistance to severely ill ME/CFS patients. We helped with rent (which was the most frequent request for financial aid), food, medical costs (including consults, ambulance fees, wheelchairs, and prescriptions), household expenses, utilities, and other basic needs. Read about the fund here: https://ammes.org/ammes-financial-crisis-fund/

Continue reading “2021: That Was The Year That Was” →

Male vs. Female Differences in Responding to Oxygen-Ozone Autohemotherapy (O 2-O 3-AHT) in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a syndrome that has fatigue as its major symptom. Evidence suggests that ozone is able to relieve ME/CFS-related fatigue in affected patients.

Objective: To evaluate whether differences exist between males and females in ozone therapy outputs in ME/CFS. (3) Methods: In total, 200 patients previously diagnosed with ME/CFS (mean age 33 ± 13 SD years) underwent treatment with oxygen-ozone autohemotherapy (O2-O3-AHT). Fatigue was investigated via an FSS 7-scoring questionnaire before and following 1 month after treatment.

Results: The Mann-Whitney test (MW test) assessed the significance of this difference (H = 13.8041, p = 0.0002), and female patients showed better outcomes than males. This difference was particularly striking in the youngest age cohort (14-29 years), and a KW test resulted in H = 7.1609, p = 0.007 for the Δ = 28.3% (males = 3.8, females = 5.3).

Conclusions: When treated with O2-O3-AHT, females respond better than males.

Source: Chirumbolo S, Valdenassi L, Franzini M, Pandolfi S, Ricevuti G, Tirelli U. Male vs. Female Differences in Responding to Oxygen-Ozone Autohemotherapy (O2-O3-AHT) in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). J Clin Med. 2021 Dec 29;11(1):173. doi: 10.3390/jcm11010173. PMID: 35011914. https://pubmed.ncbi.nlm.nih.gov/35011914/

Relationship Between Myocardial Injury During Index Hospitalization for SARS-CoV-2 Infection and Longer-Term Outcomes

Abstract:

Background: Myocardial injury in patients with COVID-19 is associated with increased mortality during index hospitalization; however, the relationship to long-term sequelae of SARS-CoV-2 is unknown. This study assessed the relationship between myocardial injury (high-sensitivity cardiac troponin T level) during index hospitalization for COVID-19 and longer-term outcomes.

Methods and Results: This is a prospective cohort of patients who were hospitalized at a single center between March and May 2020 with SARS-CoV-2. Cardiac biomarkers were systematically collected. Outcomes were adjudicated and stratified on the basis of myocardial injury. The study cohort includes 483 patients who had high-sensitivity cardiac troponin T data during their index hospitalization. During index hospitalization, 91 (18.8%) died, 70 (14.4%) had thrombotic complications, and 126 (25.6%) had cardiovascular complications. By 12 months, 107 (22.2%) died. During index hospitalization, 301 (62.3%) had cardiac injury (high-sensitivity cardiac troponin T≧14 ng/L); these patients had 28.6%, 32.2%, and 33.2% mortality during index hospitalization, at 6 months, and at 12 months, respectively, compared with 4.1%, 4.9%, and 4.9% mortality for those with low-level positive troponin and 0%, 0%, and 0% for those with undetectable troponin. Of 392 (81.2%) patients who survived the index hospitalization, 94 (24%) had at least 1 readmission within 12 months, of whom 61 (65%) had myocardial injury during the index hospitalization. Of 377 (96%) patients who were alive and had follow-up after the index hospitalization, 211 (56%) patients had a documented, detailed clinical assessment at 6 months. A total of 78 of 211 (37.0%) had ongoing COVID-19-related symptoms; 34 of 211 (16.1%) had neurocognitive decline, 8 of 211 (3.8%) had increased supplemental oxygen requirements, and 42 of 211 (19.9%) had worsening functional status.

Conclusions: Myocardial injury during index hospitalization for COVID-19 was associated with increased mortality and may predict who are more likely to have postacute sequelae of COVID-19. Among patients who survived their index hospitalization, the incremental mortality through 12 months was low, even among troponin-positive patients.

Source: Weber B, Siddiqi H, Zhou G, Vieira J, Kim A, Rutherford H, Mitre X, Feeley M, Oganezova K, Varshney AS, Bhatt AS, Nauffal V, Atri DS, Blankstein R, Karlson EW, Di Carli M, Baden LR, Bhatt DL, Woolley AE. Relationship Between Myocardial Injury During Index Hospitalization for SARS-CoV-2 Infection and Longer-Term Outcomes. J Am Heart Assoc. 2022 Jan 4;11(1):e022010. doi: 10.1161/JAHA.121.022010. Epub 2021 Dec 31. PMID: 34970914. https://www.ahajournals.org/doi/10.1161/JAHA.121.022010 (Full text)

Combined triple treatment of fibrin amyloid microclots and platelet pathology in individuals with Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) can resolve their persistent symptoms

Abstract:

We recognise that fibrin(ogen) amyloid microclots and platelet hyperactivation, that we have previously observed in COVID-19 and Long COVID/Post-Acute Sequelae of COVID-19 (PASC) patients, might form a suitable set of foci for the clinical treatment of the symptoms of long COVID/PASC. We first report on the comorbidities and symptoms found in a cohort of 845 South African Long COVID/PASC patients who filled in the South African Long COVID/PASC registry, of which hypertension and high cholesterol levels (dyslipidaemia) were the most important comorbidities. The gender balance (70% female) and the most commonly reported Long COVID/PASC symptoms (fatigue, brain fog, loss of concentration and forgetfulness, shortness of breath, as well as joint and muscle pains) were comparable to those reported elsewhere. This suggests that our sample was not at all atypical. Using a previously published scoring system for fibrin amyloid microclots and platelet pathology, we analysed blood samples from 70 patients, and report the presence of significant fibrin amyloid microclots and platelet pathology in all cases; these were associated with Long COVID/PASC symptoms that persisted after the recovery from acute COVID-19.

A subset of 24 patients was treated with one month of dual antiplatelet therapy (DAPT) (Clopidogrel 75mg/Aspirin 75mg) once a day, as well as a direct oral anticoagulant (DOAC) (Apixiban) 5 mg twice a day. A proton pump inhibitor (PPI) pantoprazole 40 mg/day was also prescribed for gastric protection. Such a regime must only be followed under strict and qualified medical guidance to obviate any dangers, especially haemorrhagic bleeding, and of the therapy as a whole. Thromboelastography (TEG®) was used to assist in determining their clotting status.

Each of the 24 treated cases reported that their main symptoms were resolved and fatigue as the main symptom was relieved, and this was also reflected in a decrease of both the fibrin amyloid microclots and platelet pathology scores. Nine patients were genotyped for genetic variation in homocysteine metabolism implicated in hypertension, a common COVID-19 co-morbidity reported in both patients found to be homozygous for the risk-associated MTHFR 677 T-allele. Fibrin amyloid microclots that block capillaries and inhibit the transport of O2 to tissues, accompanied by platelet hyperactivation, provide a ready explanation for the symptoms of Long COVID/PASC. The removal and reversal of these underlying endotheliopathies provide an important treatment option that seems to be highly efficacious, and warrants controlled clinical studies.

Source: Pretorius, Etheresia & Venter, Chantelle & Laubscher, Gert & Kotze, Maritha & Moremi, Kelebogile & Oladejo, Sunday & Watson, Liam & Rajaratnam, Kanshu & Watson, Bruce & Kell, Douglas. Combined triple treatment of fibrin amyloid microclots and platelet pathology in individuals with Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) can resolve their persistent symptoms. Preprint from Research Square, 28 Dec 2021 https://assets.researchsquare.com/files/rs-1205453/v1_covered.pdf?c=1640805028 (Full text)

Fatigue and Cognitive Impairment in Post-COVID-19 Syndrome: A Systematic Review and Meta-Analysis

Abstract:

Importance: COVID-19 is associated with clinically significant symptoms despite resolution of the acute infection (i.e., post-COVID-19 syndrome). Fatigue and cognitive impairment are amongst the most common and debilitating symptoms of post-COVID-19 syndrome.

Objective: To quantify the proportion of individuals experiencing fatigue and cognitive impairment 12 or more weeks following COVID-19 diagnosis, and to characterize the inflammatory correlates and functional consequences of post-COVID-19 syndrome.

Data sources: Systematic searches were conducted without language restrictions from database inception to June 8, 2021 on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, and select reference lists.

Study selection: Primary research articles which evaluated individuals at least 12 weeks after confirmed COVID-19 diagnosis and specifically reported on fatigue, cognitive impairment, inflammatory parameters, and/or functional outcomes were selected.

Data extraction & synthesis: Two reviewers independently extracted published summary data and assessed methodological quality and risk of bias. A meta-analysis of proportions was conducted to pool Freeman-Turkey double arcsine transformed proportions using the random-effects restricted maximum-likelihood model.

Main outcomes & measures: The co-primary outcomes were the proportions of individuals reporting fatigue and cognitive impairment, respectively, 12 or more weeks after COVID-19 infection. The secondary outcomes were inflammatory correlates and functional consequences of post-COVID-19 syndrome.

Results: The literature search yielded 10,979 studies, and 81 studies were selected for inclusion. The fatigue meta-analysis comprised 68 studies, the cognitive impairment meta-analysis comprised 43 studies, and 48 studies were included in the narrative synthesis. Meta-analysis revealed that the proportion of individuals experiencing fatigue 12 or more weeks following COVID-19 diagnosis was 0.32 (95% CI, 0.27, 0.37; p < 0.001; n = 25,268; I2=99.1%). The proportion of individuals exhibiting cognitive impairment was 0.22 (95% CI, 0.17, 0.28; p < 0.001; n = 13,232; I2=98.0). Moreover, narrative synthesis revealed elevations in proinflammatory markers and considerable functional impairment in a subset of individuals.

Conclusions & relevance: A significant proportion of individuals experience persistent fatigue and/or cognitive impairment following resolution of acute COVID-19. The frequency and debilitating nature of the foregoing symptoms provides the impetus to characterize the underlying neurobiological substrates and how to best treat these phenomena.

Study Registration PROSPERO (CRD42021256965).

Source: Ceban F, Ling S, Lui LMW, Lee Y, Gill H, Teopiz KM, Rodrigues NB, Subramaniapillai M, Di Vincenzo JD, Cao B, Lin K, Mansur RB, Ho RC, Rosenblat JD, Miskowiak KW, Vinberg M, Maletic V, McIntyre RS. Fatigue and Cognitive Impairment in Post-COVID-19 Syndrome: A Systematic Review and Meta-Analysis. Brain Behav Immun. 2021 Dec 29;101:93–135. doi: 10.1016/j.bbi.2021.12.020. Epub ahead of print. PMID: 34973396; PMCID: PMC8715665. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8715665/ (Full text)

Sulodexide in the treatment of patients with long COVID 19 symptoms and endothelial dysfunction: The results of TUN-EndCOV study

Abstract:

Background: Endothelial dysfunction is probably one of the mechanisms of long COVID-19 symptoms. Sulodexide has pleiotropic properties within the vascular endothelium that can prove beneficial in the long COVID-19 symptoms.

Purpose: We aimed to evaluate the effect of sulodexide when used in patients with endothelial dysfunction and long COVID-19 symptoms.

Methods: We conducted a prospective multicenter longitudinal case-control study. Endothelial function was evaluated with DTM “E4-Diagnose” Polymath based on the Endothelium Quality Index (EQI). A group of patients with endothelial dysfunction (EQI < 2.0) received sulodexide. All the patients were followed-up 21 days after inclusion. Primary outcomes were defined as endothelial function amelioration (delta EQI) and long COVID-19 symptoms evolution during the follow-up.

Results: A total of 410 patients were included in this study. Patients were included at an average time of 1.89 ± 1.2 month after COVID-19 infection. At inclusion, 210 (51.2%) patients had an EQI < 2. The median age was 49 ± 13.8 (18–80) years. Among the patients with endothelial dysfunction, only 79 patients received sulodexide. Patients in sulodexide group had lower EQI than the non-medical intervention group (0.94 ± 0.6 vs. 1.52 ± 0.4; P < 10−3). They were more diabetic, hypertensive, had more coronary artery disease and received more long-term medications (aspirin, Bblockers and statins) than the others (P = 0.01, 0.002, 0.01, 0.009, 0.001 and 0.01, respectively). At the 21-days follow-up, patients in sulodexide group presented lower long COVID symptoms especially chest pain, palpitations, fatigue and neuro-cognitive difficulties associated to a significant amelioration of endothelial function (delta EQI 1.26 ± 1.07 vs. 0.22 ± 0.7; P < 10−3).

Conclusion: Sulodexide in patients with long COVID-19 may be a good intervention to ameliorate chest pain, palpitations, fatigue and neuro-cognitive difficulties associated to endothelial dysfunction.

Source: S. Charfeddine, H. Ibn Hadjamor, S. Torjmen, S. Kraiem, R. Hammami, A. Bahloul, N. Kallel, N. Moussa, I. Touil, J. Jdidi, S. Abdesselem, L. Abid. Sulodexide in the treatment of patients with long COVID 19 symptoms and endothelial dysfunction: The results of TUN-EndCOV study,
Archives of Cardiovascular Diseases Supplements. Volume 14, Issue 1, 2022, Page 127, ISSN 1878-6480,
https://doi.org/10.1016/j.acvdsp.2021.10.007. (https://www.sciencedirect.com/science/article/pii/S1878648021006455)