Autoantibody production is enhanced after mild SARS-CoV-2 infection despite vaccination in individuals with and without long COVID

Abstract:

Long COVID patients who experienced severe acute SARS-CoV-2 infection can present with humoral autoimmunity. However, whether mild SARS-CoV-2 infection increases autoantibody responses and whether vaccination can decrease autoimmunity in long COVID patients is unknown.

Here, we demonstrate that mild SARS-CoV-2 infection increases autoantibodies associated with systemic lupus erythematosus (SLE) and inflammatory myopathies in long COVID patients with persistent neurologic symptoms to a greater extent than COVID convalescent controls at 8 months post-infection. Furthermore, high titers of SLE-associated autoantibodies in long COVID patients are associated with impaired cognitive performance and greater symptom severity, and subsequent vaccination/booster does not decrease autoantibody titers.

In summary, we found that mild SARS-CoV-2 infection can induce persistent humoral autoimmunity in both long COVID patients and healthy COVID convalescents, suggesting that a reappraisal of vaccination and mitigation strategies is warranted.

Source: Visvabharathy L, Zhu C, Orban ZS, Yarnoff K, Palacio N, Jimenez M, Lim PH, Penaloza-MacMaster P, Koralnik IJ. Autoantibody production is enhanced after mild SARS-CoV-2 infection despite vaccination in individuals with and without long COVID. medRxiv [Preprint]. 2023 Apr 12:2023.04.07.23288243. doi: 10.1101/2023.04.07.23288243. PMID: 37090595; PMCID: PMC10120795. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120795/ (Full text)

Risks of digestive diseases in long COVID: Evidence from a large-scale cohort study

Abstract:

Objectives This study aims to evaluate the effect of coronavirus disease 2019 (COVID-19) on the long-term risk of digestive diseases in the general population.

Design Large-scale population-based cohort study based on a prospective cohort.

Setting UK Biobank cohort linked to multiple nationwide electronic health records databases.

Participants The cohort consisted of 112,311 individuals who survived the initial 30 days following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as well as two control groups: a contemporary group (n = 359,671) without any history of COVID-19, and a historical control group (n = 370,979) that predated the COVID-19 outbreak.

Main outcome measures Main outcomes were predefined digestive diseases. Hazard ratios and corresponding 95% confidence intervals (CI) were computed utilizing the Cox regression models after inverse probability weighting.

Results Compared with the contemporary control group, patients with previous COVID-19 infection had higher risks of digestive diseases, including functional gastrointestinal disorders (hazard ratios [HR] 1.95 (95% CI 1.62 to 2.35)); peptic ulcer disease (HR 1.27 (1.04 to 1.56)); gastroesophageal reflux disease (GERD) (HR 1.46 (1.34 to 1.58)); inflammatory bowel diseases (HR 1.40 (1.02 to 1.90)); gallbladder disease (HR 1.28 (1.13 to 1.46)); severe liver disease (HR 1.46 (1.12 to 1.90)); non-alcoholic liver disease (HR 1.33 (1.15 to 1.55)); and pancreatic disease (HR 1.43 (1.17 to 1.74)). The risks of GERD were stepwise increased with severity of the acute phase of COVID-19 infection. The results were consistent when using the historical cohort as the control group.

Conclusions Our study provides important insights into the association between COVID-19 and the long-term risk of digestive system disorders. COVID-19 patients are at a higher risk of developing gastrointestinal disorders, with stepwise increased risk with the severity and persisting even after one year follow-up.

Source: Yuying Ma, Lijun Zhang, Rui Wei, Weiyu Dai, Ruijie Zeng, Dongling Luo, Rui Jiang, Huihuan Wu, Zewei Zhuo, Qi Yang, Jingwei Li, Felix W Leung, Chongyang Duan, Weihong Sha, Hao Chen. Risks of digestive diseases in long COVID: Evidence from a large-scale cohort study. medRxiv 2023.04.25.23289080; doi: https://doi.org/10.1101/2023.04.25.23289080 https://www.medrxiv.org/content/10.1101/2023.04.25.23289080v1.full-text (Full text)

Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC)

Abstract:

With a global tally of more than 500 million cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections to date, there are growing concerns about the post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Recent studies suggest that exaggerated immune responses are key determinants of the severity and outcomes of the initial SARS-CoV-2 infection as well as subsequent PASC. The complexity of the innate and adaptive immune responses in the acute and post-acute period requires in-depth mechanistic analyses to identify specific molecular signals as well as specific immune cell populations which promote PASC pathogenesis.

In this review, we examine the current literature on mechanisms of immune dysregulation in severe COVID-19 and the limited emerging data on the immunopathology of PASC. While the acute and post-acute phases may share some parallel mechanisms of immunopathology, it is likely that PASC immunopathology is quite distinct and heterogeneous, thus requiring large-scale longitudinal analyses in patients with and without PASC after an acute SARS-CoV-2 infection. By outlining the knowledge gaps in the immunopathology of PASC, we hope to provide avenues for novel research directions that will ultimately lead to precision therapies which restore healthy immune function in PASC patients.

Source: Sindhu MohandasPrasanna JagannathanTimothy J HenrichZaki A SherifChristian BimeErin QuinlanMichael A PortmanMarila GennaroJalees RehmanRECOVER Mechanistic Pathways Task Force (2023) Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC) eLife 12:e86014. https://elifesciences.org/articles/86014 (Full text)

Rheumatology and Long COVID: lessons from the study of fibromyalgia

Abstract:

Rheumatology, such as other subspecialties, has both a unique perspective to offer as well as an evolving role to play in the global COVID-19 pandemic. Our field has already contributed meaningfully to the development and repurposing of many of the immune-based therapeutics which are now standard treatments for severe forms of the disease as well as to the understanding of the epidemiology, risk factors and natural history of COVID-19 in immune-mediated inflammatory diseases. Still in evolution is our potential to contribute to burgeoning research efforts in the next phase of the pandemic: the syndrome of postacute sequelae of COVID-19 or Long COVID. While our field brings many assets to the study of Long COVID including our expertise in the investigation of chronic inflammation and autoimmunity, our Viewpoint focuses on the strong similarities between fibromyalgia (FM) and Long COVID. While one can speculate on how embracing and confident practising rheumatologists already are regarding these interrelationships, we assert that in the emerging field of Long COVID the potential lessons from the field of fibromyalgia care and research have been underappreciated and marginalised and most importantly now deserve a critical appraisal.

Source: Clauw DJ, Calabrese L. Rheumatology and Long COVID: lessons from the study of fibromyalgia. Ann Rheum Dis. 2023 May 25:ard-2023-224250. doi: 10.1136/ard-2023-224250. Epub ahead of print. PMID: 37230736. https://ard.bmj.com/content/early/2023/05/24/ard-2023-224250 (Full text)

Autonomic Nervous System Affection Due to Post Covid Syndrome

Identification of the Effects of Post Covid Syndrome on the Autonomic Nervous System With Heart Rate Variability

Post-Covid syndrome is defined as symptoms that develop in addition to respiratory symptoms in individuals who have had Covid-19 infection for more than 12 weeks. Symptoms such as fatigue, headache, cognitive impairment, dyspnea, heart palpitations, heat intolerance, digestive system disorders, sleep disorders, dermal problems, orthostatic intolerance come to the fore in individuals with post-Covid syndrome. It has been tried to be revealed in some studies that Covid-19 infection affects the autonomic nervous system (ANS) and the relationship between Post-Covid 19 syndrome and ANS dysfunction.
Heart rate variability (HRV) measurement method can be used to evaluate ANS activity. HRV is a non-invasive method and is a measure of the change in heart rate over a period of time. HRV is a scalar quantity that shows the time between two beats of the heart and defines the oscillations between the R-R intervals. In HRV measurements, time-dependent and frequency-dependent measurement results are obtained and from these measurements, time-dependent RMSSD (square root of the square of the difference of the R-R intervals) and frequency-dependent high-frequency (HF) and low frequency (LF) measurement components are used in relation to the sympathetic nervous system (CNS) and parasympathetic nervous system (PSS). HRV can be measured in short-term (5 minutes) in terms of measurement time.
The aim of this study is to clearly reveal the relationship between Post-Covid 19 syndrome and ANS dysfunction and to provide standardization related to HRV measurement method and sub-parameters.
Source: Ali Veysel Özden, M.D. Bahçeşehir University. Istanbul, Beşiktaş, Turkey, 34000. ICH GCP US Clinical Trials Registry, Clinical Trial NCT05502094 https://ichgcp.net/clinical-trials-registry/NCT05502094

Changes in the proteomics of exhaled breath condensate under the influence of inhaled hydrogen in patients with post-COVID syndrome.

Abstract:

Purpose. To study the effect of inhalation therapy with an active form of hydrogen (APH) on the protein composition of exhaled air condensate (EAC) in patients with post-COVID syndrome (PCS).

Material and methods. A randomized controlled parallel prospective study included 60 patients who had a novel coronavirus infection (COVID-19, COronaVIrus Disease 2019) with PCD during the recovery period, had clinical manifestations of chronic fatigue syndrome and received standard therapy according to the protocol for managing patients with chronic fatigue syndrome. The patients were divided into 2 groups: group 1 (main) – 30 people who received standard therapy and APV inhalations (device “SUISONIA”, Japan) for 10 days, and group 2 (control) – 30 medical workers who received only standard therapy. Patients in both groups were comparable in terms of gender and mean age. All participants in the study on the 1st and 10th days. samples were taken from the CVV.

Results. A total of 478 proteins and 1350 peptides were identified using high resolution mass spectrometry. The number of proteins in samples after APV therapy, on average, is 12% more than before treatment. An analysis of the distribution of proteins in different groups of patients showed that only half of these proteins (112) are common for all groups of samples and are detected in EVC before, after, and regardless of hydrogen therapy. In addition to the qualitative difference in the protein compositions of CEA in different groups, quantitative changes in the concentration of 36 proteins (mainly structural and protective) were also detected, which together made it possible to reliably distinguish between subgroups before and after treatment. It is important to note that among these proteins there are participants in the processes of blood coagulation (a-1-antitrypsin), mediated by chemokines and cytokines of inflammation,

Conclusion. The use of hydrogen therapy can contribute to the switching of a number of physiological processes, which may affect the success of restorative treatment in PKD. In particular, the obtained results indicate the activation of aerobic synthesis of adenosine triphosphate in mitochondria by hydrogen therapy, which correlates well with the decrease in blood lactate levels detected by laboratory studies in the studied patients. At the same time, it is important that this therapy can inhibit pro-inflammatory activity, negatively affecting the coagulation processes and signaling pathways of integrins and apoptosis, and, in addition, activate protective pathways, the tricarboxylic acid cycle, FAS signaling, and purine metabolism, which can be significant. for effective recovery after suffering COVID-19.

Source: Ryabokon, A. M.; Zakharova, N. V.; Indeikina, M. I.; Kononikhin, A. S.; Shogenova, L. V.; Medvedev, O. S.; Kostinov, M. P.; Svitich, O. A.; Ibaraki, K.; Maehara, H.; Nikolaev, E. N.; Varfolomeev, S. D.; Chuchalin, A. G. Changes in the proteomics of exhaled breath condensate under the influence of inhaled hydrogen in patients with post-COVID syndrome. Cardiovascular Therapy and Prevention (Russian Federation) ; 22(3):50-59, 2023. https://www.researchgate.net/publication/369954717_Changes_in_the_proteomics_of_exhaled_breath_condensate_under_the_influence_of_inhaled_hydrogen_in_patients_with_post-COVID_syndrome

Effects of whole-body cryotherapy and static stretching are maintained 4 weeks after treatment in most patients with chronic fatigue syndrome

Abstract

In the previous study, whole-body cryotherapy (WBC)+static stretching (SS) has been shown to reduce the severity of some symptoms in Chronic Fatigue Syndrome (CFS) noted just after the therapy. Here we consider the effects of treatment and explore the sustainability of symptom improvements at four weeks (one-month) follow-up.

Twenty-two CFS patients were assessed one month after WBC + SS programme. Parameters related to fatigue (Chalder Fatigue Questionnaire (CFQ), Fatigue Impact Scale (FIS), Fatigue Severity Scale (FSS)), cognitive function (Trial Making test part A and B (TMT A and TMT B and its difference (TMT B-A)), Coding) hemodynamic, aortic stiffness (aortic systolic blood pressure (sBP aortic)) and autonomic nervous system functioning were measured. TMT A, TMT B, TMT B-A and Coding improved at one month after the WBC + SS programme.

WBC + SS had a significant effect on the increase in sympathetic nervous system activity in rest. WBC + SS had a significant, positive chronotropic effect on the cardiac muscle. Peripheral and aortic systolic blood pressure decreased one month after WBC + SS in comparison to before.

Effects of WBC + SS on reduction of fatigue, indicators of aortic stiffness and symptoms severity related to autonomic nervous system disturbance and improvement in cognitive function were maintained at one month.

However, improvement in all three fatigue scales (CFQ, FIS and FSS) was noted in 17 of 22 patients. In addition, ten patients were treated initially but they were not assessed at 4 weeks, and are thus not included in the 22 patients who were examined on follow-up. The overall effects of WBC + SS noted at one month post-treatment should be interpreted with caution.

Source: Kujawski S, Zalewski P, Godlewska BR, Cudnoch-Jędrzejewska A, Murovska M, Newton JL, Sokołowski Ł, Słomko J. Effects of whole-body cryotherapy and static stretching are maintained 4 weeks after treatment in most patients with chronic fatigue syndrome. Cryobiology. 2023 May 23:S0011-2240(23)00035-4. doi: 10.1016/j.cryobiol.2023.05.003. Epub ahead of print. PMID: 37230457. https://www.sciencedirect.com/science/article/pii/S0011224023000354?via%3Dihub (Full text)

Fighting Post-COVID and ME/CFS – development of curative therapies

Abstract:

The sequela of COVID-19 include a broad spectrum of symptoms that fall under the umbrella term post-COVID-19 condition or syndrome (PCS). Immune dysregulation, autoimmunity, endothelial dysfunction, viral persistence, and viral reactivation have been identified as potential mechanisms.

However, there is heterogeneity in expression of biomarkers, and it is unknown yet whether these distinguish different clinical subgroups of PCS. There is an overlap of symptoms and pathomechanisms of PCS with postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

No curative therapies are available for neither ME/CFS nor PCS. The mechanisms identified so far provide targets for therapeutic interventions.

To accelerate the development of therapies, we propose evaluating drugs targeting different mechanisms in clinical trial networks using harmonized diagnostic and outcome criteria and subgrouping patients based on a thorough clinical profiling including a comprehensive diagnostic and biomarker phenotyping.

Source: Carmen Scheibenbogen, Judith T. Bellmann-Strobl, Cornelia Heindrich, Kirsten Wittke, Elisa Stein, Christiana Franke, Harald Prüss, Hannah Preßler, Marie-Luise Machule, Heinrich Audebert, Carsten Finke, Hanna G. Zimmerman,  Birgit Sawitzki, Christian Meisel, Markus Tölle, Anne Krüger, Anna C. Aschenbrenner, Joachim L. Schultz, Marc D. Beyer, Markus Ralser, Michael Mülleder, Leif E. Sander, Frank Konietschke, Friedemann Paul, Silvia Stojanov, Lisa Bruckert, Dennis M. Hedderich, Franziska Knolle, Gabriela Riemekasten, Maria J. Vehreschild, Oliver A. Cornely, Uta Behrends and Susen Burock.  Fighting Post-COVID and ME/CFS – development of curative therapies. Frontiers in Medicine, Sec. Infectious Diseases: Pathogenesis and Therapy: Volume 10 – 2023. https://www.frontiersin.org/articles/10.3389/fmed.2023.1194754/abstract

 

Identifying Demographic Trends in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients Presenting with Fibromyalgia as a Comorbidity in the Nationwide Inpatient Sample Database

Abstract

This retrospective observational study investigates the demographic differences between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients with and without Fibromyalgia as a comorbidity using the Nationwide Inpatient Sample database.

Results reveal significant differences in demographics, including a higher proportion of females and a younger mean age in the Fibromyalgia group. Additionally, the Fibromyalgia group had lower in-hospital mortality, higher proportion of patients discharged home or to short-term hospitals, shorter lengths of stay, and lower hospital charges.

Despite having lower Elixhauser comorbidity scores, ME/CFS patients with Fibromyalgia had higher prevalence of certain conditions.

Limitations include missing data, and further research is warranted to refine ME/CFS definitions and develop personalized treatment plans. The study highlights the need for better understanding of ME/CFS mechanisms, correlations with comorbidities like Fibromyalgia, and potential predictors to improve diagnosis and treatment.

Source: Arvind Vishnu Murali. Identifying Demographic Trends in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients Presenting with Fibromyalgia as a Comorbidity in the Nationwide Inpatient Sample Database. Icahn School of Medicine at Mount Sinai ProQuest Dissertations Publishing,  2023. 30494377. https://www.proquest.com/openview/12cb80c96056a220f9e1d8bd7ea5fecc/1?pq-origsite=gscholar&cbl=18750&diss=y

Investigating antibody reactivity to the intestinal microbiome in severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystemic disease of unknown aetiology that is characterised by disabling chronic fatigue and involves both the immune and gastrointestinal (GI) systems. Patients display alterations in GI microbiome with a significant proportion experiencing GI discomfort and pain and elevated blood biomarkers for altered intestinal permeability compared with healthy individuals.

To investigate a possible GI origin of ME/CFS we designed a feasibility study to test the hypothesis that ME/CFS pathogenesis is a consequence of increased intestinal permeability that results in microbial translocation and a breakdown in immune tolerance leading to generation of antibodies reactive to indigenous intestinal microbes. Secretory IgA and serum IgG levels and reactivity to intestinal microbes were assessed in five pairs of severe ME/CFS patients and matched same-household healthy controls. For profiling serum IgG we developed IgG-Seq which combines flow-cytometry based bacterial cell sorting and metagenomics to detect mucosal IgG reactivity to the microbiome.

We uncovered evidence for immune dysfunction in severe ME/CFS patients that was characterised by reduced capacity and reactivity of serum IgG to stool microbes, irrespective of their source. This study provides the rationale for additional studies in larger cohorts of ME/CFS patients to further explore immune-microbiome interactions.

Source: Katharine A. Seton, Marianne Defernez, Andrea Telatin, Sumeet K. Tiwari, George M. Savva, Antonietta Hayhoe, Alistair Noble, Ana Carvalho, Steve James, Amolak Bansal, Thomas Wileman, Simon R. Carding. Investigating antibody reactivity to the intestinal microbiome in severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). medRxiv 2023.05.21.23290299; doi: https://doi.org/10.1101/2023.05.21.23290299 https://www.medrxiv.org/content/10.1101/2023.05.21.23290299v1.full-text (Full text)