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Lethal COVID-19 outcomes are attributed to classic cytokine storm. We revisit this using RNA sequencing of nasopharyngeal and 40 autopsy samples from patients dying of SARS-CoV-2. Subsets of the 100 top-upregulated genes in nasal swabs are upregulated in the heart, lung, kidney, and liver, but not mediastinal lymph nodes. Twenty-two of these are "noncanonical" immune genes, which we link to components of the renin-angiotensin-activation-system that manifest as increased fibrin deposition, leaky vessels, thrombotic tendency, PANoptosis, and mitochondrial dysfunction. Immunohistochemistry of mediastinal lymph nodes reveals altered architecture, excess collagen deposition, and pathogenic fibroblast infiltration. Many of the above findings are paralleled in animal models of SARS-CoV-2 infection and human peripheral blood mononuclear and whole blood samples from individuals with early and later SARS-CoV-2 variants. We then redefine cytokine storm in lethal COVID-19 as driven by upstream immune gene and mitochondrial signaling producing downstream RAAS (renin-angiotensin-aldosterone system) overactivation and organ damage, including compromised mediastinal lymph node function. [ABSTRACT FROM AUTHOR]

Introduction We report an Intervention/outcome study of 33 severe COVID-19 subjects who received Seraph100 Microbind Affinity Blood Filter (Seraph 100) hemoperfusion therapy (15 survivors, 18 non-survivors) under emergency authorization from the FDA. Our objective was to determine if Seraph 100 hemoperfusion reduces SARS-CoV-2 RNA titers and/or markers of inflammation and/or epi/endothelial damage.a Methods Viral RNA and 78 protein analytes related to endothelial/epithelial damage and/or inflammation were quantified in systemic blood samples from 33 severe COVID-19 subjects collected upon ICU admission and then immediately before and after blood passed through the heparin-based Seraph 100 filter at two time points on the first day of hemoperfusion. Viral RNA titers were quantified using droplet-digital PCR. Protein analytes were quantified using multiplex/multi-analyte panels on MesoScale Discovery and ProteinSimple-Ella platforms. Results A total of 15/33 subjects had detectable viral RNA in baseline samples (shortly after ICU admission). These initial viremia levels were low, and they did not change uniformly post-perfusion. Five of 55 protein analytes that were up-regulated 1.4-120X at ICU admission relative to healthy controls showed significant decreases across the filter during the indicated time points on the first day of hemoperfusion: IP-10/CXCL10, fms-like tyrosine kinase (Flt-1), MIG/CXCL9, Hepatocyte Growth Factor (HGF) and receptor for advanced glycosylation end-products (RAGE). Paired t-tests identified 25 additional analytes that showed significant decreases (p<0.05) only without Bonferroni correction. Conclusion Initial freely circulating SARS-CoV-2 RNA levels of ICU-admitted subjects were low or undetectable. The Seraph 100 filter did not significantly reduce viral RNA titers in their plasma. However, multiple circulating proteins with roles in inflammation, endothelial/epithelial damage and/or angiogenesis decreased significantly across the filter. Larger prospective trials will be required to determine if such transient reductions translate into improved patient outcomes. However, this study did not demonstrate a direct reduction of free SARS-CoV-2 viral RNA by the Seraph 100., (S. Karger AG, Basel.)

Background: Blood biomarkers of neurological injury could provide a rapid diagnosis of central nervous system (CNS) injury caused by infections. An FDA-approved assay for mild traumatic brain injury (TBI) measures glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which signal astrocyte and neuronal injury, respectively. Here, we assessed the applicability of this biomarker assay for determining infection-induced brain injury., Methods: We measured serum levels of GFAP and UCH-L1 retrospectively in serum samples from three study populations: 1) human cases infected with Venezuelan equine encephalitis virus (VEEV) and Madariaga virus (MADV) (n = 73), 2) human sepsis patients who were severely ill or diagnosed with encephalitis (n = 66), and 3) sepsis cases that were subsequently evaluated for cognitive impairment (n = 64)., Results: In the virus infection group, we found elevated GFAP for VEEV (p = 0.014) and MADV (p = 0.011) infections, which correlated with seizures (p = 0.006). In the bacterial sepsis group, GFAP was elevated in cases diagnosed with encephalitis (p = 0.0007) and correlated with headaches (p = 0.0002). In the bacterial sepsis cases with a later cognitive assessment, elevated GFAP (p = 0.0057) at study enrollment was associated with cognitive impairment six months later with a positive prognostic capacity of 79% (CI: 66-95%; p = 0.0068)., Conclusions: GFAP and UCH-L1 levels measured using an FDA-approved assay for TBI may indicate brain injury resulting from viral or bacterial infections and could predict the development of neurological sequelae., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Background: Post-COVID conditions (PCC) are difficult to characterize, diagnose, predict, and treat due to overlapping symptoms and poorly understood pathology. Identifying inflammatory profiles may improve clinical prognostication and trial endpoints., Methods: 1,988 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative post-COVID symptom scores were included in this analysis. Among participants who reported moderate-to-severe symptoms on surveys collected 6-months post-SARS-CoV-2 infection, principal component analysis (PCA) followed by K-means clustering identified distinct clusters of symptoms., Results: Three symptom-based clusters were identified: a sensory cluster (loss of smell and/or taste), a fatigue/difficulty thinking cluster, and a difficulty breathing/exercise intolerance cluster. Individuals within the sensory cluster were all outpatients during their initial COVID-19 presentation. The difficulty breathing cluster had a higher likelihood of obesity and COVID-19 hospitalization compared to those with no/mild symptoms at 6-months post-infection. Multinomial regression linked early post-infection D-dimer and IL-1RA elevation to fatigue/difficulty thinking, and elevated ICAM-1 concentrations to sensory symptoms., Conclusions: We identified three distinct symptom-based PCC phenotypes with specific clinical risk factors and early post-infection inflammatory predictors. With further validation and characterization, this framework may allow more precise classification of PCC cases and potentially improve the diagnosis, prognostication, and treatment of PCC., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)