Tag: viral reactivation

The immunology of long COVID

Abstract:

Long COVID is the patient-coined term for the disease entity whereby persistent symptoms ensue in a significant proportion of those who have had COVID-19, whether asymptomatic, mild or severe. Estimated numbers vary but the assumption is that, of all those who had COVID-19 globally, at least 10% have long COVID. The disease burden spans from mild symptoms to profound disability, the scale making this a huge, new health-care challenge.

Long COVID will likely be stratified into several more or less discrete entities with potentially distinct pathogenic pathways. The evolving symptom list is extensive, multi-organ, multisystem and relapsing–remitting, including fatigue, breathlessness, neurocognitive effects and dysautonomia. A range of radiological abnormalities in the olfactory bulb, brain, heart, lung and other sites have been observed in individuals with long COVID. Some body sites indicate the presence of microclots; these and other blood markers of hypercoagulation implicate a likely role of endothelial activation and clotting abnormalities.

Diverse auto-antibody (AAB) specificities have been found, as yet without a clear consensus or correlation with symptom clusters. There is support for a role of persistent SARS-CoV-2 reservoirs and/or an effect of Epstein–Barr virus reactivation, and evidence from immune subset changes for broad immune perturbation. Thus, the current picture is one of convergence towards a map of an immunopathogenic aetiology of long COVID, though as yet with insufficient data for a mechanistic synthesis or to fully inform therapeutic pathways.

Source: Altmann, D.M., Whettlock, E.M., Liu, S. et al. The immunology of long COVID. Nat Rev Immunol (2023). https://doi.org/10.1038/s41577-023-00904-7 https://www.nature.com/articles/s41577-023-00904-7 (Full text)

Acute and post-acute sequelae of SARS-CoV-2 infection: a review of risk factors and social determinants

Abstract:

SARS-CoV-2 infection leading to Coronavirus Disease 2019 (COVID-19) has caused more than 762 million infections worldwide, with 10-30% of patients suffering from post-acute sequelae of SARS-CoV-2 infections (PASC). Initially thought to primarily affect the respiratory system, it is now known that SARS-CoV-2 infection and PASC can cause dysfunction in multiple organs, both during the acute and chronic stages of infection.

There are also multiple risk factors that may predispose patients to worse outcomes from acute SARS-CoV-2 infection and contribute to PASC, including genetics, sex differences, age, reactivation of chronic viruses such as Epstein Barr Virus (EBV), gut microbiome dysbiosis, and behavioral and lifestyle factors, including patients’ diet, alcohol use, smoking, exercise, and sleep patterns.

In addition, there are important social determinants of health, such as race and ethnicity, barriers to health equity, differential cultural perspectives and biases that influence patients’ access to health services and disease outcomes from acute COVID-19 and PASC.

Here, we review risk factors in acute SARS-CoV-2 infection and PASC and highlight social determinants of health and their impact on patients affected with acute and chronic sequelae of COVID-19.

Source: Wang C, Ramasamy A, Verduzco-Gutierrez M, Brode WM, Melamed E. Acute and post-acute sequelae of SARS-CoV-2 infection: a review of risk factors and social determinants. Virol J. 2023 Jun 16;20(1):124. doi: 10.1186/s12985-023-02061-8. PMID: 37328773; PMCID: PMC10276420. https://virologyj.biomedcentral.com/articles/10.1186/s12985-023-02061-8 (Full text)

Increased circulating fibronectin, depletion of natural IgM and heightened EBV, HSV-1 reactivation in ME/CFS and long COVID

Abstract:

Myalgic Encephalomyelitis/ Chronic Fatigue syndrome (ME/CFS) is a complex, debilitating, long-term illness without a diagnostic biomarker. ME/CFS patients share overlapping symptoms with long COVID patients, an observation which has strengthened the infectious origin hypothesis of ME/CFS. However, the exact sequence of events leading to disease development is largely unknown for both clinical conditions.

Here we show antibody response to herpesvirus dUTPases, particularly to that of Epstein-Barr virus (EBV) and HSV-1, increased circulating fibronectin (FN1) levels in serum and depletion of natural IgM against fibronectin ((n)IgM-FN1) are common factors for both severe ME/CFS and long COVID. We provide evidence for herpesvirus dUTPases-mediated alterations in host cell cytoskeleton, mitochondrial dysfunction and OXPHOS.

Our data show altered active immune complexes, immunoglobulin-mediated mitochondrial fragmentation as well as adaptive IgM production in ME/CFS patients. Our findings provide mechanistic insight into both ME/CFS and long COVID development. Finding of increased circulating FN1 and depletion of (n)IgM-FN1 as a biomarker for the severity of both ME/CFS and long COVID has an immediate implication in diagnostics and development of treatment modalities.

Source: Zheng Liu, Claudia Hollmann, Sharada Kalanidhi, Arnhild Grothey, Samuel Keating, Irene Mena-Palomo, Stephanie Lamer, Andreas Schlosser, Agnes Kaiping, Carsten Scheller, Franziska Sotzny, Anna Horn, Carolin Nuernberger, Vladimir Cejka, Boshra Afshar, Thomas Bahmer, Stefan Schreiber, Joerg Janne Vehreschild, Olga Milljukov, Christian Schaefer, Luzie Kretzler, Thomas Keil, Jens-Peter Reese, Felizitas A Eichner, Lena Schmidbauer, Peter U Heuschmann, Stefan Stoerk, Caroline Morbach, Gabriela Riemekasten, Niklas Beyersdorf, Carmen Scheibenbogen, Robert K Naviaux, Marshall Williams, Maria E Ariza, Bhupesh Kumar Prusty. Increased circulating fibronectin, depletion of natural IgM and heightened EBV, HSV-1 reactivation in ME/CFS and long COVID. medRxiv 2023.06.23.23291827; doi: https://doi.org/10.1101/2023.06.23.23291827 https://www.medrxiv.org/content/10.1101/2023.06.23.23291827v1 (Full text available as PDF file)

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

Laboratory Findings and Biomarkers in Long COVID: What Do We Know So Far? Insights Into Epidemiology, Pathogenesis, Therapeutic Perspectives and Challenges

Abstract:

Long COVID (LC) encompasses a constellation of long-term symptoms experienced by at least 10% of people after the initial SARS-CoV-2 infection, and so far has affected about 65 million people. The etiology of LC remains unclear; however, many pathophysiological pathways may be involved, including viral persistence; chronic, low grade inflammatory response; immune dysregulation and defective immune response; reactivation of latent viruses; autoimmunity; persistent endothelial dysfunction and coagulopathy; gut dysbiosis; hormonal dysregulation, mitochondrial dysfunction; and autonomic nervous system dysfunction.

There are no specific tests for the diagnosis of LC, and clinical features including laboratory findings and biomarkers may not specifically relate to LC. Therefore, it is of paramount importance to develop and validate biomarkers that can be employed for the prediction, diagnosis and prognosis of LC and its therapeutic response. Promising candidate biomarkers that are found in some patients are markers of systemic inflammation including acute phase proteins, cytokines and chemokines; biomarkers reflecting SARS-CoV-2 persistence, reactivation of herpesviruses and immune dysregulation; biomarkers of endotheliopathy, coagulation and fibrinolysis; microbiota alterations; diverse proteins and metabolites; hormonal and metabolic biomarkers; as well as cerebrospinal fluid biomarkers. At present, there are only two reviews summarizing relevant biomarkers; however, they do not cover the entire umbrella of current biomarkers or their link to etiopathogenetic mechanisms, and the diagnostic work-up in a comprehensive manner.

Herein, we aim to appraise and synopsize the available evidence on the typical laboratory manifestations and candidate biomarkers of LC, their classification based on main LC symptomatology in the frame of the epidemiological and pathogenetic aspects of the syndrome, and furthermore assess limitations and challenges as well as potential implications in candidate therapeutic interventions.

Source: Tsilingiris, D.; Vallianou, N.G.; Karampela, I.; Christodoulatos, G.S.; Papavasileiou, G.; Petropoulou, D.; Magkos, F.; Dalamaga, M. Laboratory Findings and Biomarkers in Long COVID: What Do We Know So Far? Insights Into Epidemiology, Pathogenesis, Therapeutic Perspectives and Challenges. Preprints.org 2023, 2023051487. https://doi.org/10.20944/preprints202305.1487.v1 (Full text available as PDF file)

Viral persistence, reactivation, and mechanisms of long COVID

Abstract:

The COVID-19 global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has infected hundreds of millions of individuals. Following COVID-19 infection, a subset can develop a wide range of chronic symptoms affecting diverse organ systems referred to as post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. A National Institutes of Health-sponsored initiative, RECOVER: Researching COVID to Enhance Recovery, has sought to understand the basis of long COVID in a large cohort. Given the range of symptoms that occur in long COVID, the mechanisms that may underlie these diverse symptoms may also be diverse.

In this review, we focus on the emerging literature supporting the role(s) that viral persistence or reactivation of viruses may play in PASC. Persistence of SARS-CoV-2 RNA or antigens is reported in some organs, yet the mechanism by which they do so and how they may be associated with pathogenic immune responses is unclear. Understanding the mechanisms of persistence of RNA, antigen or other reactivated viruses and how they may relate to specific inflammatory responses that drive symptoms of PASC may provide a rationale for treatment.

Source: Chen B, Julg B, Mohandas S, Bradfute SB; RECOVER Mechanistic Pathways Task Force. Viral persistence, reactivation, and mechanisms of long COVID. Elife. 2023 May 4;12:e86015. doi: 10.7554/eLife.86015. PMID: 37140960; PMCID: PMC10159620. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10159620/ (Full text)

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)

Abstract:

COVID-19, with persistent and new onset of symptoms such as fatigue, post-exertional malaise, and cognitive dysfunction that last for months and impact everyday functioning, is referred to as Long COVID under the general category of post-acute sequelae of SARS-CoV-2 infection (PASC). PASC is highly heterogenous and may be associated with multisystem tissue damage/dysfunction including acute encephalitis, cardiopulmonary syndromes, fibrosis, hepatobiliary damages, gastrointestinal dysregulation, myocardial infarction, neuromuscular syndromes, neuropsychiatric disorders, pulmonary damage, renal failure, stroke, and vascular endothelial dysregulation. A better understanding of the pathophysiologic mechanisms underlying PASC is essential to guide prevention and treatment.

This review addresses potential mechanisms and hypotheses that connect SARS-CoV-2 infection to long-term health consequences. Comparisons between PASC and other virus-initiated chronic syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome will be addressed. Aligning symptoms with other chronic syndromes and identifying potentially regulated common underlining pathways may be necessary for understanding the true nature of PASC.

The discussed contributors to PASC symptoms include sequelae from acute SARS-CoV-2 injury to one or more organs, persistent reservoirs of the replicating virus or its remnants in several tissues, re-activation of latent pathogens such as Epstein-Barr and herpes viruses in COVID-19 immune-dysregulated tissue environment, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation dysregulation, dysfunctional brainstem/vagus nerve signaling, dysautonomia or autonomic dysfunction, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage specific patients.

Source: Sherif ZA, Gomez CR, Connors TJ, Henrich TJ, Reeves WB; RECOVER Mechanistic Pathway Task Force. Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC). Elife. 2023 Mar 22;12:e86002. doi: 10.7554/eLife.86002. PMID: 36947108; PMCID: PMC10032659. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10032659/ (Full text)

Systematic review with meta-analysis of active herpesvirus infections in patients with COVID-19: Old players on the new field

Abstract:

Objectives: Herpesviruses are ubiquitous and after primary infection they establish lifelong latency. The impairment of maintaining latency with short-term or long-term consequences could be triggered by other infection. Therefore, reactivation of herpesviruses in COVID-19 patients represents an emerging issue.

Design and methods: This study provided the first systematic review with meta-analysis of studies that evaluated active human herpesvirus (HHV) infection (defined as the presence of IgM antibodies or HHV-DNA) in COVID-19 patients and included 36 publications collected by searching through PubMed, SCOPUS, and Web of science until November 2022.

Results: The prevalence of active EBV, HHV6, HSV, CMV, HSV1, and VZV infection in COVID-19 population was 41% (95% CI =27%-57%),3% (95% CI=17%-54%),28% (95% CI=1%-85%),25% (95% CI=1%-63%),22% (95% CI=10%-35%),and 18% (95% CI=4%-34%),respectively. There was a 6 times higher chance for active EBV infection in patients with severe COVID-19 than in non-COVID-19 controls (OR=6.45, 95% CI=1.09-38.13, p=0.040), although there was no difference in the prevalence of all evaluated active herpesvirus infections between COVID-19 patients and non-COVID-19 controls.

Conclusions: Future research of herpesvirus and SARS-CoV-2 coinfections must be prioritized to define: who, when and how to be tested, as well as how to effectively treat HHVs reactivations in acute and long COVID-19 patients.

Source: Banko A, Miljanovic D, Cirkovic A. Systematic review with meta-analysis of active herpesvirus infections in patients with COVID-19: Old players on the new field. Int J Infect Dis. 2023 Jan 31:S1201-9712(23)00037-1. doi: 10.1016/j.ijid.2023.01.036. Epub ahead of print. PMID: 36736577; PMCID: PMC9889115. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9889115/ (Full text)

Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID

Abstract:

A novel syndrome called long-haul COVID or long COVID is increasingly recognized in a significant percentage of individuals within a few months after infection with SARS-CoV-2. This disorder is characterized by a wide range of persisting, returning or even new but related symptoms that involve different tissues and organs, including respiratory, cardiac, vascular, gastrointestinal, musculo-skeletal, neurological, endocrine and systemic.
Some overlapping symptomatologies exist between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Very much like with long ME/CFS, infections with herpes family viruses, immune dysregulation, and the persistence of inflammation have been reported as the most common pattern for the development of long COVID.
This review describes several factors and determinants of long COVID that have been proposed, elaborating mainly on viral persistence, reactivation of latent viruses such as Epstein–Barr virus and human herpesvirus 6 which are also associated with the pathology of ME/CFS, viral superantigen activation of the immune system, disturbance in the gut microbiome, and multiple tissue damage and autoimmunity.
Based on these factors, we propose diagnostic strategies such as the measurement of IgG and IgM antibodies against SARS-CoV-2, EBV, HHV-6, viral superantigens, gut microbiota, and biomarkers of autoimmunity to better understand and manage this multi-factorial disorder that continues to affect millions of people in the world.
Source: Vojdani A, Vojdani E, Saidara E, Maes M. Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID. Viruses. 2023; 15(2):400. https://doi.org/10.3390/v15020400 https://www.mdpi.com/1999-4915/15/2/400 (Full text)

Chronic viral coinfections differentially affect the likelihood of developing long COVID

Abstract:

BACKGROUND. The presence and reactivation of chronic viral infections, such as EBV, CMV, and HIV, have been proposed as potential contributors to long COVID (LC), but studies in well-characterized postacute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited.

METHODS. In a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status) and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms.

RESULTS. We observed that LC symptoms, such as fatigue and neurocognitive dysfunction, at a median of 4 months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen–diffuse IgG positivity) or high nuclear antigen (EBNA) IgG levels but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (early antigen–diffuse IgG positivity) was most strongly associated with fatigue (OR = 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR = 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR = 0.52).

CONCLUSION. Overall, these findings suggest differential effects of chronic viral coinfections on the likelihood of developing LC and association with distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.

Source: Peluso MJ, Deveau TM, Munter SE, Ryder D, Buck A, Beck-Engeser G, Chan F, Lu S, Goldberg SA, Hoh R, Tai V, Torres L, Iyer NS, Deswal M, Ngo LH, Buitrago M, Rodriguez A, Chen JY, Yee BC, Chenna A, Winslow JW, Petropoulos CJ, Deitchman AN, Hellmuth J, Spinelli MA, Durstenfeld MS, Hsue PY, Kelly JD, Martin JN, Deeks SG, Hunt PW, Henrich TJ. Chronic viral coinfections differentially affect the likelihood of developing long COVID. J Clin Invest. 2023 Feb 1;133(3):e163669. doi: 10.1172/JCI163669. PMID: 36454631. https://www.jci.org/articles/view/163669 (Full text)