Tag: long Covid

The importance of patient-partnered research in addressing long COVID: Takeaways for biomedical research study design from the RECOVER Initiative’s Mechanistic Pathways taskforce

Abstract:

The NIH-funded RECOVER study is collecting clinical data on patients who experience a SARS-CoV-2 infection. As patient representatives of the RECOVER Initiative’s Mechanistic Pathways task force, we offer our perspectives on patient motivations for partnering with researchers to obtain results from mechanistic studies. We emphasize the challenges of balancing urgency with scientific rigor. We recognize the importance of such partnerships in addressing post-acute sequelae of SARS-CoV-2 infection (PASC), which includes ‘long COVID,’ through contrasting objective and subjective narratives.

Long COVID’s prevalence served as a call to action for patients like us to become actively involved in efforts to understand our condition. Patient-centered and patient-partnered research informs the balance between urgency and robust mechanistic research. Results from collaborating on protocol design, diverse patient inclusion, and awareness of community concerns establish a new precedent in biomedical research study design. With a public health matter as pressing as the long-term complications that can emerge after SARS-CoV-2 infection, considerate and equitable stakeholder involvement is essential to guiding seminal research. Discussions in the RECOVER Mechanistic Pathways task force gave rise to this commentary as well as other review articles on the current scientific understanding of PASC mechanisms.

Source: Kim C, Chen B, Mohandas S, Rehman J, Sherif ZA, Coombs K; RECOVER Mechanistic Pathways Task Force; RECOVER Initiative. The importance of patient-partnered research in addressing long COVID: Takeaways for biomedical research study design from the RECOVER Initiative’s Mechanistic Pathways taskforce. Elife. 2023 Sep 22;12:e86043. doi: 10.7554/eLife.86043. PMID: 37737716; PMCID: PMC10516599. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10516599/ (Full text)

Effects of six-month creatine supplementation on patient- and clinician-reported outcomes, and tissue creatine levels in patients with post-COVID-19 fatigue syndrome

Abstract:

Dietary creatine has been recently put forward as a possible intervention strategy to reduce post-COVID-19 fatigue syndrome yet no clinical study so far evaluated its efficacy and safety for this perplexing condition. In this parallel-group, randomized placebo-controlled double-blind trial, we analyzed the effects of 6-month creatine supplementation (4 g of creatine monohydrate per day) on various patient- and clinician-reported outcomes, and tissue creatine levels in 12 patients with post-COVID-19 fatigue syndrome.

Creatine intake induced a significant increase in tissue creatine levels in vastus medialis muscle and right parietal white matter compared to the baseline values at both 3-month and 6-month follow-ups (p < .05). Two-way analysis of variance with repeated measures revealed a significant difference (treatment vs. time interaction) between interventions in tissue creatine levels (p < .05), with the creatine group was superior to placebo to augment creatine levels at vastus medialis muscle, left frontal white matter, and right parietal white matter.

Creatine supplementation induced a significant reduction in general fatigue after 3 months of intake compared to baseline values (p = .04), and significantly improved scores for several post-COVID-19 fatigue syndrome-related symptoms (e.g., ageusia, breathing difficulties, body aches, headache, and difficulties concentrating) at 6-month follow-up (p < .05). Taking creatine for 6 months appears to improve tissue bioenergetics and attenuate clinical features of post-COVID-19 fatigue syndrome; additional studies are warranted to confirm our findings in various post-COVID-19 cohorts.

Source: Slankamenac, J., Ranisavljev, M., Todorovic, N., Ostojic, J., Stajer, V., & Ostojic, S. M. (2023). Effects of six-month creatine supplementation on patient- and clinician-reported outcomes, and tissue creatine levels in patients with post-COVID-19 fatigue syndrome. Food Science & Nutrition, 00, 1–7. https://doi.org/10.1002/fsn3.3597 (Full text)

Clinical Rationale for Dietary Lutein Supplementation in Post COVID-19 and mRNA Vaccine Injury Syndromes

Abstract:

Lutein, a plant-derived xanthophyl-carotenoid, is an exceptional antioxidant and anti-inflammatory constituent found in food. Elevated concentrations of lutein found in human blood and plasma, due to high dietary intake, are beneficial against eye disease and improve cardiometabolic health.

Lutein plays an important protective role against the development of neurological disorders, including Alzheimer’s disease (AD), multiple sclerosis (MS) and Parkinson’s disease (PD). It has also been shown to be beneficial for liver, kidney and respiratory health. Lutein, acting as a very strong antioxidant, can alleviate oxidative stress and downgrade reactive oxygen species (ROS). Oxidative stress is one of the key pathogenic mechanisms in post-COVID and mRNA vaccine injury syndromes.

Recent in silico studies suggest that lutein and other naturally derived antioxidants, by docking at the site where the SARS-CoV-2 spike protein (SP) binds to the angiotensin enzyme type 2 (ACE2) receptor, may neutralize the SP-ACE2 interactions. Lutein can be added to a detoxification regimen to aid in clearing Spike protein and relieving symptoms.

In agreement with Hippocrates’ dictum to “Let food be thy medicine,” this review establishes dietary lutein as a valuable therapy in the treatment of post-COVID syndrome, mRNA vaccine injury syndromes, and a wide range of other chronic illnesses.

Source: Kyriakopoulos, A.M.; Nigh, G.; McCullough, P.A.; Seneff, S. Clinical Rationale for Dietary Lutein Supplementation in Post COVID-19 and mRNA Vaccine Injury Syndromes. Preprints 2023, 2023091385. https://doi.org/10.20944/preprints202309.1385.v1 https://www.preprints.org/manuscript/202309.1385/v1 https://www.preprints.org/manuscript/202309.1385/v1 (Full text available as PDF file)

Immune Adsorption for the Treatment of Fatigue-Dominant Long-/Post-COVID Syndrome

Introduction:

Following an infection with SARS-CoV-2, a relevant proportion of patients suffer from fatigue-dominant long-/post-COVID syndrome. In 57% of patients with long-/post-COVID syndrome, who were treated in a university hospital, increased levels of autoantibodies (AABs) to G-protein-coupled neurotransmitter receptors (including ß-adrenergic and muscarinic) were detected ().

Reduction of ß-adrenergic AABs by immunoadsorption therapy was associated with clinical improvement in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) (). Increasingly, reports of individual cases of successful treatment of long/post-COVID syndrome with the help of apheresis techniques have been widely disseminated via social media. By contrast, cases or studies with negative outcomes are much less likely to receive proper attention. Given the overall lack of data to date, medical societies are calling for a broader scientific basis, to which we would like to contribute with this case series.

Source: Ruhe J, Giszas B, Schlosser M, Reuken PA, Wolf G, Stallmach A. Immune Adsorption for the Treatment of Fatigue-Dominant Long-/Post-COVID Syndrome: A Series of Cases With Standardized Individual Experimental Therapy. Dtsch Arztebl Int. 2023 Jul;120(29-30):499–500. doi: 10.3238/arztebl.m2023.0073. Epub 2023 Jul 24. PMCID: PMC10511006. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10511006/ (Full text)

Incidence of immune-mediated inflammatory diseases following COVID-19: a matched cohort study in UK primary care

Abstract:

Background: Some patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) go on to experience post-COVID-19 condition or long COVID. Preliminary findings have given rise to the theory that long COVID may be due in part to a deranged immune response. In this study, we assess whether there is an association between SARS-CoV-2 infection and the incidence of immune-mediated inflammatory diseases (IMIDs).

Methods: Matched cohort study using primary care electronic health record data from the Clinical Practice Research Datalink Aurum database. The exposed cohort included 458,147 adults aged 18 years and older with a confirmed SARS-CoV-2 infection and no prior diagnosis of IMIDs. They were matched on age, sex, and general practice to 1,818,929 adults with no diagnosis of confirmed or suspected SARS-CoV-2 infection. The primary outcome was a composite of any of the following IMIDs: autoimmune thyroiditis, coeliac disease, inflammatory bowel disease (IBD), myasthenia gravis, pernicious anaemia, psoriasis, rheumatoid arthritis (RA), Sjogren’s syndrome, systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1DM), and vitiligo. The secondary outcomes were each of these conditions separately. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for the primary and secondary outcomes, adjusting for age, sex, ethnic group, smoking status, body mass index, relevant infections, and medications.

Results: Six hundred and nighty six (0.15%) and 2230 (0.12%) patients in the exposed and unexposed cohort developed an IMID during the follow-up period over 0.29 person-years, giving a crude incidence rate of 4.59 and 3.65 per 1000 person-years, respectively. Patients in the exposed cohort had a 22% increased risk of developing an IMID, compared to the unexposed cohort (aHR 1.22, 95% CI 1.12 to 1.33). The incidence of three IMIDs was significantly associated with SARS-CoV-2 infection. These were T1DM (aHR 1.56, 1.09 to 2.23), IBD (aHR 1.36, 1.18 to 1.56), and psoriasis (1.23, 1.05 to 1.42).

Conclusions: SARS-CoV-2 was associated with an increased incidence of IMIDs including T1DM, IBD and psoriasis. However, these findings could be potentially due to ascertainment bias. Further research is needed to replicate these findings in other populations and to measure autoantibody profiles in cohorts of individuals with COVID-19.

Source: Syed U, Subramanian A, Wraith DC, Lord JM, McGee K, Ghokale K, Nirantharakumar K, Haroon S. Incidence of immune-mediated inflammatory diseases following COVID-19: a matched cohort study in UK primary care. BMC Med. 2023 Sep 21;21(1):363. doi: 10.1186/s12916-023-03049-5. PMID: 37735654; PMCID: PMC10512476. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10512476/ (Full text)

Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19

Abstract:

The long-term health effects of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are quickly evolving into a major public health concern, but the underlying cellular and molecular etiology remain poorly defined. There is growing evidence that PASC is linked to abnormal immune responses and/or poor organ recovery post-infection. However, the exact processes linking non-resolving inflammation, impaired tissue repair, and PASC are still unclear.

In this report, we utilized a cohort of respiratory PASC patients with viral infection-mediated pulmonary fibrosis and a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. Using a combination of imaging and spatial transcriptomics, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, and the development of fibrotic sequelae after acute viral pneumonia.

Mechanistically, CD8+ T cell derived IFN-γ and TNF stimulated lung macrophages to chronically release IL-1β, resulting in the abnormal accumulation of dysplastic epithelial progenitors in fibrotic areas. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1β after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function.

Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC and identify potential therapeutic targets to dampen chronic pulmonary sequelae post respiratory viral infections including SARS-CoV-2.

Source: Narasimhan H, Cheon IS, Qian W, Hu S, Parimon T, Li C, Goplen N, Wu Y, Wei X, Son YM, Fink E, Santos G, Tang J, Yao C, Muehling L, Canderan G, Kadl A, Cannon A, Pramoonjago P, Shim YM, Woodfolk J, Zang C, Chen P, Sun J. Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19. bioRxiv [Preprint]. 2023 Sep 14:2023.09.13.557622. doi: 10.1101/2023.09.13.557622. PMID: 37745354; PMCID: PMC10515929. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10515929/ (Full text)

Characterization of long COVID temporal sub-phenotypes by distributed representation learning from electronic health record data: a cohort study

Abstract:

Background: Characterizing Post-Acute Sequelae of COVID (SARS-CoV-2 Infection), or PASC has been challenging due to the multitude of sub-phenotypes, temporal attributes, and definitions. Scalable characterization of PASC sub-phenotypes can enhance screening capacities, disease management, and treatment planning.

Methods: We conducted a retrospective multi-centre observational cohort study, leveraging longitudinal electronic health record (EHR) data of 30,422 patients from three healthcare systems in the Consortium for the Clinical Characterization of COVID-19 by EHR (4CE). From the total cohort, we applied a deductive approach on 12,424 individuals with follow-up data and developed a distributed representation learning process for providing augmented definitions for PASC sub-phenotypes.

Findings: Our framework characterized seven PASC sub-phenotypes. We estimated that on average 15.7% of the hospitalized COVID-19 patients were likely to suffer from at least one PASC symptom and almost 5.98%, on average, had multiple symptoms. Joint pain and dyspnea had the highest prevalence, with an average prevalence of 5.45% and 4.53%, respectively.

Interpretation: We provided a scalable framework to every participating healthcare system for estimating PASC sub-phenotypes prevalence and temporal attributes, thus developing a unified model that characterizes augmented sub-phenotypes across the different systems.

Source: Dagliati A, Strasser ZH, Hossein Abad ZS, Klann JG, Wagholikar KB, Mesa R, Visweswaran S, Morris M, Luo Y, Henderson DW, Samayamuthu MJ, Tan BWQ, Verdy G, Omenn GS, Xia Z, Bellazzi R; Consortium for Clinical Characterization of COVID-19 by EHR (4CE),; Murphy SN, Holmes JH, Estiri H; Consortium for Clinical Characterization of COVID-19 by EHR (4CE). Characterization of long COVID temporal sub-phenotypes by distributed representation learning from electronic health record data: a cohort study. EClinicalMedicine. 2023 Sep 14;64:102210. doi: 10.1016/j.eclinm.2023.102210. PMID: 37745021; PMCID: PMC10511779. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10511779/ (Full text)

Immune cell proteomes of Long COVID patients have functional changes similar to those in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Of those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ~ 10% develop the chronic post-viral debilitating condition, Long COVID (LC). Although LC is a heterogeneous condition, about half of cases have a typical post-viral fatigue condition with onset and symptoms that are very similar to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A key question is whether these conditions are closely related.

ME/CFS is a post-stressor fatigue condition that arises from multiple triggers. To investigate the pathophysiology of LC, a pilot study of patients and healthy controls has used quantitative proteomics to discover changes in peripheral blood mononuclear cell (PBMC) proteins. A principal component analysis separated all Long COVID patients from healthy controls.

Analysis of 3131 proteins identified 162 proteins differentially regulated, of which 37 were related to immune functions, and 21 to mitochondrial functions. Markov cluster analysis identified clusters involved in immune system processes, and two aspects of gene expression-spliceosome and transcription. These results were compared with an earlier dataset of 346 differentially regulated proteins in PBMC’s from ME/CFS patients analysed by the same methodology.

There were overlapping protein clusters and enriched molecular pathways particularly in immune functions, suggesting the two conditions have similar immune pathophysiology as a prominent feature, and mitochondrial functions involved in energy production were affected in both conditions.

Source: Katie Peppercorn, Christina D. Edgar, Torsten Kleffmann, Warren. P Tate. Immune cell proteomes of Long COVID patients have functional changes similar to those in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Research Square preprint https://doi.org/10.21203/rs.3.rs-3335919/v1 https://www.researchsquare.com/article/rs-3335919/v1 (Full text) https://www.nature.com/articles/s41598-023-49402-9 (Final full text)

Understanding, diagnosing, and treating Myalgic encephalomyelitis/chronic fatigue syndrome – State of the art: Report of the 2nd international meeting at the Charité fatigue center

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a devastating disease affecting millions of people worldwide. Due to the 2019 pandemic of coronavirus disease (COVID-19), we are facing a significant increase of ME/CFS prevalence. On May 11th to 12th, 2023, the second international ME/CFS conference of the Charité Fatigue Center was held in Berlin, Germany, focusing on pathomechanisms, diagnosis, and treatment.

During the two-day conference, more than 100 researchers from various research fields met on-site and over 700 attendees participated online to discuss the state of the art and novel findings in this field. Key topics from the conference included: the role of the immune system, dysfunction of endothelial and autonomic nervous system, and viral reactivation. Furthermore, there were presentations on innovative diagnostic measures and assessments for this complex disease, cutting-edge treatment approaches, and clinical studies.

Despite the increased public attention due to the COVID-19 pandemic, the subsequent rise of Long COVID-19 cases, and the rise of funding opportunities to unravel the pathomechanisms underlying ME/CFS, this severe disease remains highly underresearched. Future adequately funded research efforts are needed to further explore the disease etiology and to identify diagnostic markers and targeted therapies.

Source: Steiner S, Fehrer A, Hoheisel F, Schoening S, Aschenbrenner A, Babel N, Bellmann-Strobl J, Finke C, Fluge Ø, Froehlich L, Goebel A, Grande B, Haas JP, Hohberger B, Jason LA, Komaroff AL, Lacerda E, Liebl M, Maier A, Mella O, Nacul L, Paul F, Prusty BK, Puta C, Riemekasten G, Ries W, Rowe PC, Sawitzki B, Shoenfeld Y, Schultze JL, Seifert M, Sepúlveda N, Sotzny F, Stein E, Stingl M, Ufer F, Veauthier C, Westermeier F, Wirth K, Wolfarth B, Zalewski P, Behrends U, Scheibenbogen C. Understanding, diagnosing, and treating Myalgic encephalomyelitis/chronic fatigue syndrome – State of the art: Report of the 2nd international meeting at the Charité fatigue center. Autoimmun Rev. 2023 Sep 22:103452. doi: 10.1016/j.autrev.2023.103452. Epub ahead of print. PMID: 37742748. https://www.sciencedirect.com/science/article/abs/pii/S1568997223001866

Bone marrow alterations in COVID-19 infection: The root of hematological problems

Abstract:

Introduction: The 2019 coronavirus disease (COVID-19) is a respiratory infection caused by the SARS-CoV-2 virus with a significant impact on the hematopoietic system and homeostasis. The effect of the virus on blood cells indicates the involvement of the bone marrow (BM) as the place of production and maturation of these cells by the virus and it reminds the necessity of investigating the effect of the virus on the bone marrow.

Method: To investigate the effects of COVID-19 infection in BM, we reviewed literature from the Google Scholar search engine and PubMed database up to 2022 using the terms “COVID-19; SARS-CoV-2; Bone marrow; Thrombocytopenia; Hemophagocytosis; Pancytopenia and Thrombocytopenia.

Results: Infection with the SARS-CoV-2 virus is accompanied by alterations such as single-line cytopenia, pancytopenia, hemophagocytosis, and BM necrosis. The presence of factors such as cytokine release syndrome, the direct effect of the virus on cells through different receptors, and the side effects of current treatments such as corticosteroids are some of the important mechanisms in the occurrence of these alterations.

Conclusion: To our knowledge, this review is the first study to comprehensively investigate BM alterations caused by SAR-CoV-2 virus infection. The available findings show that the significant impact of this viral infection on blood cells and the clinical consequences resulting from them are deeper than previously thought and it may be rooted in the changes that the virus causes in the BM of patients.

Source: Zeylabi F, Nameh Goshay Fard N, Parsi A, Pezeshki SMS. Bone marrow alterations in COVID-19 infection: The root of hematological problems. Curr Res Transl Med. 2023 Jul 25;71(3):103407. doi: 10.1016/j.retram.2023.103407. Epub ahead of print. PMID: 37544028. https://www.sciencedirect.com/science/article/abs/pii/S2452318623000314 (Full text)