Cerebrospinal Fluid Analysis Post-COVID-19 Is Not Suggestive of Persistent Central Nervous System Infection

Abstract:

This study was undertaken to assess whether SARS-CoV-2 causes a persistent central nervous system infection. SARS-CoV-2-specific antibody index and SARS-CoV-2 RNA were studied in cerebrospinal fluid following COVID-19. Cerebrospinal fluid was assessed between days 1 and 30 (n = 12), between days 31 and 90 (n = 8), or later than 90 days (post-COVID-19, n = 20) after COVID-19 diagnosis. SARS-CoV-2 RNA was absent in all patients, and in none of the 20 patients with post-COVID-19 syndrome were intrathecally produced anti-SARS-CoV-2 antibodies detected. The absence of evidence of SARS-CoV-2 in cerebrospinal fluid argues against a persistent central nervous system infection as a cause of neurological or neuropsychiatric post-COVID-19 syndrome.

Source: Schweitzer F, Goereci Y, Franke C, Silling S, Bösl F, Maier F, Heger E, Deiman B, Prüss H, Onur OA, Klein F, Fink GR, Di Cristanziano V, Warnke C. Cerebrospinal Fluid Analysis Post-COVID-19 Is Not Suggestive of Persistent Central Nervous System Infection. Ann Neurol. 2022 Jan;91(1):150-157. doi: 10.1002/ana.26262. Epub 2021 Nov 22. PMID: 34724243; PMCID: PMC8653324. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8653324/ (Full text)

PD-1 blockade counteracts post-COVID-19 immune abnormalities and stimulates the anti-SARS-CoV-2 immune response

Abstract:

A substantial proportion of patients who have recovered from coronavirus disease-2019 (COVID-19) experience COVID-19-related symptoms even months after hospital discharge. We extensively immunologically characterized patients who recovered from COVID-19. In these patients, T cells were exhausted, with increased PD-1+ T cells, as compared with healthy controls. Plasma levels of IL-1β, IL-1RA, and IL-8, among others, were also increased in patients who recovered from COVID-19.

This altered immunophenotype was mirrored by a reduced ex vivo T cell response to both nonspecific and specific stimulation, revealing a dysfunctional status of T cells, including a poor response to SARS-CoV-2 antigens. Altered levels of plasma soluble PD-L1, as well as of PD1 promoter methylation and PD1-targeting miR-15-5p, in CD8+ T cells were also observed, suggesting abnormal function of the PD-1/PD-L1 immune checkpoint axis. Notably, ex vivo blockade of PD-1 nearly normalized the aforementioned immunophenotype and restored T cell function, reverting the observed post-COVID-19 immune abnormalities; indeed, we also noted an increased T cell-mediated response to SARS-CoV-2 peptides. Finally, in a neutralization assay, PD-1 blockade did not alter the ability of T cells to neutralize SARS-CoV-2 spike pseudotyped lentivirus infection. Immune checkpoint blockade ameliorates post-COVID-19 immune abnormalities and stimulates an anti-SARS-CoV-2 immune response.

Source: Loretelli C, Abdelsalam A, D’Addio F, Ben Nasr M, Assi E, Usuelli V, Maestroni A, Seelam AJ, Ippolito E, Di Maggio S, Loreggian L, Radovanovic D, Vanetti C, Yang J, El Essawy B, Rossi A, Pastore I, Montefusco L, Lunati ME, Bolla AM, Biasin M, Antinori S, Santus P, Riva A, Zuccotti GV, Galli M, Rusconi S, Fiorina P. PD-1 blockade counteracts post-COVID-19 immune abnormalities and stimulates the anti-SARS-CoV-2 immune response. JCI Insight. 2021 Dec 22;6(24):e146701. doi: 10.1172/jci.insight.146701. PMID: 34784300. https://insight.jci.org/articles/view/146701 (Full text)

The Long-COVID Syndrome: smoking and enhanced suicide risk

Extract:

The QJM has been at the forefront in highlighting the mental health problems associated with COVID-19 infection in society.1–6 In a Commentary piece in this issue of the Journal, Leo Sher, Professor of Psychiatry from the Mount Sinai School of Medicine, highlights the role of smoking being associated with a worse prognosis in acute infections and enhancing the risk of suicide in patients suffering persistent disabling symptoms associated with the Long-COVID Syndrome.

It is well recognized that smoking is associated with suicidal ideation, suicide attempts, suicide death and a contributing factor in the pathophysiology of suicide. The author highlights the evidence that suggests that the COVID-19 pandemic has led to increased tobacco consumption as smokers use more tobacco to cope with pandemic-related stress, anxiety, depression and loneliness. Smoking will have significant psychobiological effects resulting in enhanced impulsivity and aggression which will be compounded by in particular the brain-related symptoms…

Source: Seamas C Donnelly, The Long-COVID Syndrome: smoking and enhanced suicide risk, QJM: An International Journal of Medicine, Volume 114, Issue 11, November 2021, Page 765, https://doi.org/10.1093/qjmed/hcab300

Global surveillance, research, and collaboration needed to improve understanding and management of long COVID

The scale of chronic ill health and disability after COVID-19 has been described as the next big global health challenge. Prevalence estimates of a post-COVID-19 condition, long COVID, or post-acute sequelae of SARS-CoV-2 vary according to definition, methodology, and population. A recent systematic review reported persistent symptoms at 3–6 months in a median of 57% (range 13–92) of hospitalised patients (six studies) and 26% (2–62) of non-hospitalised patients (ten studies). This study and other reviews identified few studies from low-income settings, but with more than 245 million SARS-CoV-2 infections reported globally, millions of people are likely to already be experiencing long-term illness. While COVID-19 vaccines have reduced the risk of severe COVID-19 and death, continued high rates of SARS-CoV-2 infection will lead to further disability, having a huge impact on individuals, their families, health services, and society.

Read the rest of this article HERE.

Source: Ward H, Flower B, Garcia PJ, Ong SWX, Altmann DM, Delaney B, Smith N, Elliott P, Cooke G. Global surveillance, research, and collaboration needed to improve understanding and management of long COVID. Lancet. 2021 Dec 4;398(10316):2057-2059. doi: 10.1016/S0140-6736(21)02444-2. Epub 2021 Nov 10. PMID: 34774190; PMCID: PMC8580495. (Full text)

Physiological predictors of long-term effects of covid-19 in patients with sars-cov-2: focus on lymphocyte proliferation-improving micronutrients

Abstract

Patients with long-term effects of coronavirus disease, the so-called “long-term COVID-19 syndrome” (long-COVID-19) after SARS-CoV-2 infection, have a postponed recovery lasting from 4 weeks and up to six months, spread worldwide.

Physiological predictors based on human blood biomarkers and host-virus responses to SARS-CoV-2 are still unknown. There is growing evidence about the impact of micronutrients on improving lymphocyte proliferation and their essential roles for a functioning human immune system and regulating metabolic health. This paper aims to review information about micronutrients in patients with SARS-CoV-2 infection that determines long-COVID-19 outcomes and highlight the importance of diagnostics in predictors of long-COVID-19.

We reviewed articles returned from searches on PubMed/SCOPUS/Web of Science/ EMBASE databases using a combination of terms “long COVID-19”, “long-term effects of COVID-19”, “post-COVID-19 symptoms”, “COVID-19 associated stress”, “micronutrients”. Evidence indicates the relationship between lymphocyte proliferation improving micronutrient level and long-COVID-19 induction. Zinc, selenium, iron, manganese have an immunomodulatory function in innate and adaptive immune responses to viral infection. Anti-inflammatory functions of Vits A and B groups include the regulation of lymphocyte proliferation and metabolic health. Further research using sampling and artificial intelligence-assisted algorithms could assist in the recognition of the correlation of micronutrients and long-COVID-19 clinical outcomes.

Source: Karkhut S-M, Muzyka I, Savytska M, Dzhyoieva K, Pohoretska Y, Ivanchenko N, Zayachkivska O, Schloss JV, Szabo S. PHYSIOLOGICAL PREDICTORS OF LONG-TERM EFFECTS OF COVID-19 IN PATIENTS WITH SARS-COV-2: FOCUS ON LYMPHOCYTE PROLIFERATION-IMPROVING MICRONUTRIENTS. Proc Shevchenko Sci Soc Med Sci [Internet]. 2021Dec.12 [cited 2022Jan.18];65(2). Available from: https://mspsss.org.ua/index.php/journal/article/view/560

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” →