Background COVID-19 patients can develop a cytokine release syndrome that eventually leads to acute respiratory distress syndrome (ARDS) requiring invasive mechanical ventilation (IMV). Since interleukin-6 (IL-6) is a relevant cytokine in ARDS, the blockade of its receptor with Tocilizumab (TCZ) could reduce mortality and/or morbidity in severe COVID-19. Objective To determine whether baseline IL-6 serum levels can predict the need for IMV and the response to TCZ. Methods Retrospective observational study performed in hospitalized patients diagnosed of COVID-19. Clinical information and laboratory findings, including IL-6 levels, were collected approximately 3 and 9 days after admission to be matched with pre- and post-administration of TCZ. Multivariable logistic and linear regressions, and survival analysis were performed depending on outcomes: need for IMV, evolution of arterial oxygen tension/fraction of inspired oxygen ratio (PaO 2 /FiO 2 ) or mortality. Results One hundred and forty-six patients were studied, predominantly male (66%); median age was 63 years. Forty-four patients (30%) required IMV, and 58 patients (40%) received treatment with TCZ. IL-6 levels>30 pg/ml was the best predictor for IMV (OR:7.1; p<0.001). Early administration of TCZ was associated with improvement of oxygenation (PaO 2 /FiO 2 ) in patients with high IL-6 (p=0.048). Patients with high IL-6 not treated with TCZ showed high mortality (HR: 4.6; p=0.003), as well as those with low IL-6 treated with TCZ (HR: 3.6; p=0.016). No relevant serious adverse events were observed in TCZ-treated patients. Conclusion Baseline IL-6>30 pg/ml predicts IMV requirement in patients with COVID-19 and contributes to establish an adequate indication for TCZ administration.
The SARS-CoV-2 is responsible for the pandemic COVID-19 in infected individuals, who can either exhibit mild symptoms or progress towards a life-threatening acute respiratory distress syndrome (ARDS). It is known that exacerbated inflammation and dysregulated immune responses involving T and myeloid cells occur in COVID-19 patients with severe clinical progression. However, the differential contribution of specific subsets of dendritic cells and monocytes to ARDS is still poorly understood. In addition, the role of CD8 + T cells present in the lung of COVID-19 patients and relevant for viral control has not been characterized. With the aim to improve the knowledge in this area, we developed a cross-sectional study, in which we have studied the frequencies and activation profiles of dendritic cells and monocytes present in the blood of COVID-19 patients with different clinical severity in comparison with healthy control individuals. Furthermore, these subpopulations and their association with antiviral effector CD8 + T cell subsets were also characterized in lung infiltrates from critical COVID-19 patients.Collectively, our results suggest that inflammatory transitional and non-classical monocytes preferentially migrate from blood to lungs in patients with severe COVID-19. CD1c + conventional dendritic cells also followed this pattern, whereas CD141 + conventional and CD123 hi plasmacytoid dendritic cells were depleted from blood but were absent in the lungs. Thus, this study increases the knowledge on the pathogenesis of COVID-19 disease and could be useful for the design of therapeutic strategies to fight SARS-CoV-2 infection.
SARS‐CoV‐2 infection causes an abrupt response by the host immune system, which is largely responsible for the outcome of COVID‐19. We investigated whether the specific immune responses in the peripheral blood of 276 patients associated to severity and progression of COVID‐19. At admission, dramatic lymphopenia of T, B and NK cells associated to severity. Conversely, the proportion of B cells, plasmablasts, circulating follicular helper T cells (cTfh) and CD56‐CD16+ NK‐cells increased. Regarding humoral immunity, levels of IgM, IgA and IgG were unaffected, but when degrees of severity were considered, IgG was lower in severe patients. Compared to healthy donors, complement C3 and C4 protein levels were higher in mild and moderate, but not in severe patients, while the activation peptide of C5 (C5a) increased from the admission in every patient, regardless their severity. Moreover, total IgG, the IgG1 and IgG3 isotypes and C4 decreased from day 0 to day 10 in patients who were hospitalized for more than two weeks, but not in patients who were discharged earlier. Our study provides important clues to understand the immune response observed in COVID‐19 patients, associating severity with an imbalanced humoral response and identifying new targets for therapeutic intervention. This article is protected by copyright. All rights reserved
COVID-19 has overloaded national health services worldwide. Thus, early identification of patients at risk of poor outcomes is critical. Our objective was to analyse SARS-CoV-2 RNA detection in serum as a severity biomarker in COVID-19. Retrospective observational study including 193 patients admitted for COVID-19. Detection of SARS-CoV-2 RNA in serum (viremia) was performed with samples collected at 48–72 h of admission by two techniques from Roche and Thermo Fischer Scientific (TFS). Main outcome variables were mortality and need for ICU admission during hospitalization for COVID-19. Viremia was detected in 50–60% of patients depending on technique. The correlation of Ct in serum between both techniques was good (intraclass correlation coefficient: 0.612; p < 0.001). Patients with viremia were older (p = 0.006), had poorer baseline oxygenation (PaO2/FiO2; p < 0.001), more severe lymphopenia (p < 0.001) and higher LDH (p < 0.001), IL-6 (p = 0.021), C-reactive protein (CRP; p = 0.022) and procalcitonin (p = 0.002) serum levels. We defined "relevant viremia" when detection Ct was < 34 with Roche and < 31 for TFS. These thresholds had 95% sensitivity and 35% specificity. Relevant viremia predicted death during hospitalization (OR 9.2 [3.8–22.6] for Roche, OR 10.3 [3.6–29.3] for TFS; p < 0.001). Cox regression models, adjusted by age, sex and Charlson index, identified increased LDH serum levels and relevant viremia (HR = 9.87 [4.13–23.57] for TFS viremia and HR = 7.09 [3.3–14.82] for Roche viremia) as the best markers to predict mortality. Viremia assessment at admission is the most useful biomarker for predicting mortality in COVID-19 patients. Viremia is highly reproducible with two different techniques (TFS and Roche), has a good consistency with other severity biomarkers for COVID-19 and better predictive accuracy.
The individual contribution of specific myeloid subsets such as CD1c + conventional dendritic cells (cDC) to perpetuation of Rheumatoid Arthritis (RA) pathology remains unclear. In addition, the specific innate sensors driving pathogenic activation of CD1c + cDCs in RA patients and their functional implications have not been characterized. Here, we assessed phenotypical, transcriptional and functional characteristics of CD1c + and CD141 + cDCs and monocytes from the blood and synovial fluid of RA patients. Increased levels of CCR2 and the IgG receptor CD64 on circulating CD1c + cDC associated with the presence of this DC subset in the synovial membrane in RA patients. Moreover, synovial CD1c + cDCs are characterized by increased expression of proinflammatory cytokines and high abilities to induce pathogenic IFNg + IL-17 + CD4 + T cells in vitro.Finally, we identified the crosstalk between Fcg Receptors and NLRC4 as a new potential molecular mechanism mediating pathogenic activation, CD64 upregulation and functional specialization of CD1c + cDCs in response to dsDNA-IgG in RA patients.
Background: SARS-CoV-2 infection causes an abrupt response by the host immune system, which is largely responsible for the pathogenesis and outcome of COVID-19. We aimed to investigate which specific responses from either cellular or humoral immunity associate to severity and progression of COVID-19. Methods: A cohort of 276 patients classified in mild, moderate and severe, was studied. Peripheral blood lymphocyte subpopulations were quantified by flow cytometry, and immunoglobulins and complement proteins by nephelometry. Results: At admission, dramatic lymphopenia of T, B and NK cells associated to severity. However, only the proportion of B cells increased, while T and NK cells appeared unaffected. Accordingly, the number of plasma cells and circulating follicular helper T cells (cTfh) increased, but levels of IgM, IgA and IgG were unaffected. When degrees of severity were considered, IgG was lower in severe patients, suggesting an IgG consumption by complement activation or antibody-dependent cellular cytotoxicity (ADCC). Activated CD56-CD16+ NK-cells, which mediate ADCC, were increased. Regarding complement, C3 and C4 protein levels were higher in mild and moderate, but not in severe patients, compared to healthy donors. Moreover, IgG and C4 decreased from day 0 to day 10 in patients who were hospitalized for more than two weeks, but not in patients who were discharged earlier. Conclusion: Our study provides important clues to understand the immune response observed in COVID-19 patients, which is probably related to viral clearance, but also underlies its pathogenesis and severity. This study associates for the first time COVID-19 severity with an imbalanced humoral immune response characterized by excessive consumption of IgG and C4, identifying new targets for therapeutic intervention.
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