ABSTRACT
With an estimated 65 million individuals suffering from Long COVID, validated therapeutic strategies as well as non-invasive biomarkers are direly needed to guide clinical management. We used blood digital transcriptomics in search of viral persistence and Long COVID diagnostic biomarkers in a real-world, general practice-based setting with a long clinical follow-up. We demonstrate systemic SARS-CoV-2 persistence for more than 2 years after acute COVID-19 infection. A 2-gene biomarker, including FYN and SARS-CoV-2 antisense RNA, correctly classifies Long COVID with 93.8% sensitivity and 91.7% specificity. Specific immune transcripts and immunometabolism score correlate to systemic viral load and patient-reported anxiety/depression, providing mechanistic links as well as therapeutic targets to tackle Long COVID.
Subject(s)
COVID-19 , Anxiety DisordersABSTRACT
COVID-19 vaccination has resulted in excellent protection against fatal disease, including in the elderly. However, risk factors for post-vaccination fatal COVID-19 are largely unknown. We comprehensively studied three large nursing home outbreaks (20-35% fatal cases) by combining SARS-CoV-2 aerosol monitoring, whole-genome phylogenetic analysis, and immunovirological profiling by digital nCounter transcriptomics. Phylogenetic investigations indicated each outbreak stemmed from a single introduction event, though with different variants (Delta, Gamma, and Mu). SARS-CoV-2 was detected in aerosol samples up to 52 days after the initial infection. Combining demographic, immune and viral parameters, the best predictive models for mortality comprised IFNB1 or age, viral ORF7a and ACE2 receptor transcripts. Comparison with published pre-vaccine fatal COVID-19 signatures and reanalysis of single-cell RNAseq data highlights the unique immune signature in post-vaccine fatal COVID-19 outbreaks. A multi-layered strategy including environmental sampling, immunomonitoring, and early antiviral therapy should be considered to prevent post-vaccination COVID-19 mortality in nursing homes.
Subject(s)
COVID-19ABSTRACT
Although the subject of intensive preclinical and clinical research, controversy on the protective vs. deleterious effect of interferon (IFN) in COVID-19 remains. Some apparently conflicting results are likely due to the intricacy of IFN subtypes (type I: IFN-alpha/beta, type III: IFN-lambda), timing and mode of administration (nebulized/subcutaneous) and clinical groups targeted (asymptomatic/mild, moderate, severe/critical COVID-19). Within the COntAGIouS (COvid-19 Advanced Genetic and Immunologic Sampling) clinical trial, we investigated endogenous type I and type III IFNs in nasal mucosa as possible predictors of clinical outcome in critical patients, as well as their correlation to SARS-CoV-2 viral load, using nCounter technology. We found that endogenous IFN-beta expression in the nasal mucosa predicts clinical outcome, independent of viral replication or Apache II score, and should be considered as a prognostic tool in a precision medicine approach of IFN therapy in COVID-19 clinical management.
Subject(s)
COVID-19ABSTRACT
Understanding the pathology of COVID-19 is a global research priority. Early evidence suggests that the microbiome may be playing a role in disease progression, yet current studies report contradictory results. Here, we examine potential confounders in COVID-19 microbiome studies by analyzing the upper (n=58) and lower (n=35) respiratory tract microbiome in well-phenotyped COVID-19 patients and controls combining microbiome sequencing, viral load determination, and immunoprofiling. We found that time in the intensive care unit and the type of oxygen support explained the most variation within the upper respiratory tract microbiome, dwarfing (non-significant) effects from viral load, disease severity, and immune status. Specifically, mechanical ventilation was linked to altered community structure, lower species- and higher strain-level diversity, and significant shifts in oral taxa previously associated with COVID-19. Single-cell transcriptomic analysis of the lower respiratory tract of ventilated COVID-19 patients identified increased oral microbiota compared to controls. These oral microbiota were found physically associated with proinflammatory immune cells, which showed higher levels of inflammatory markers. Overall, our findings suggest confounders are driving contradictory results in current COVID-19 microbiome studies and careful attention needs to be paid to ICU stay and type of oxygen support, as bacteria favored in these conditions may contribute to the inflammatory phenotypes observed in severe COVID-19 patients.