RESUMO
Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN-, type II IFN-, and NF-κB-dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients' first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.
Assuntos
COVID-19/imunologia , COVID-19/mortalidade , Corticosteroides/uso terapêutico , Adulto , Idoso , Antibacterianos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Azitromicina/uso terapêutico , Biomarcadores , COVID-19/genética , COVID-19/terapia , Calgranulina B/genética , Calgranulina B/imunologia , Estudos de Casos e Controles , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Quimiocina CXCL9/genética , Quimiocina CXCL9/imunologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Ferritinas/genética , Ferritinas/imunologia , Perfilação da Expressão Gênica , Humanos , Hidroxicloroquina/uso terapêutico , Fatores Imunológicos/uso terapêutico , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interferon gama/genética , Interferon gama/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-15/genética , Interleucina-15/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Lactoferrina/genética , Lactoferrina/imunologia , Lipocalina-2/genética , Lipocalina-2/imunologia , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/imunologia , Pessoa de Meia-Idade , Análise Multivariada , NF-kappa B/genética , NF-kappa B/imunologiaRESUMO
The World Health Organization considers the discovery of new treatments for P. aeruginosa a top priority. Virulence attenuating combination therapy (VACT) is a pragmatic strategy to improve bacterial clearance, repurpose outmoded antibiotics, improve drug efficacy at lower doses, and reduce the evolution of resistance. In vitro and in vivo studies have shown that adding a quorum sensing inhibitor or an extracellular polymeric substance repressor to classical antibiotics synergistically improves antipseudomonal activity. This review highlights why VACT could specifically benefit cystic fibrosis patients harboring chronic P. aeruginosa infections, outlines the current landscape of synergistic combinations between virulence-targeting small-molecules and anti-pseudomonal drugs, and suggests future directions for VACT research.