RESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown. The aim of this study was to obtain insight into the association between ageing, the host response and mortality in patients with COVID-19. METHODS: We determined 43 biomarkers reflective of alterations in four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We used mediation analysis to associate ageing-driven alterations in the host response with 30-day mortality. Biomarkers associated with both ageing and mortality were validated in an intensive care unit and external cohort. RESULTS: 464 general ward patients with COVID-19 were stratified according to age decades. Increasing age was an independent risk factor for 30-day mortality. Ageing was associated with alterations in each of the host response domains, characterised by greater activation of the endothelium and coagulation system and stronger elevation of inflammation and organ damage markers, which was independent of an increase in age-related comorbidities. Soluble tumour necrosis factor receptor 1, soluble triggering receptor expressed on myeloid cells 1 and soluble thrombomodulin showed the strongest correlation with ageing and explained part of the ageing-driven increase in 30-day mortality (proportion mediated: 13.0%, 12.9% and 12.6%, respectively). CONCLUSIONS: Ageing is associated with a strong and broad modification of the host response to COVID-19, and specific immune changes likely contribute to increased mortality in older patients. These results may provide insight into potential age-specific immunomodulatory targets in COVID-19.
Assuntos
COVID-19 , Humanos , Idoso , Biomarcadores , Inflamação , Citocinas , EnvelhecimentoRESUMO
BACKGROUND: Mortality rates are high among hospitalized patients with COVID-19, especially in those intubated on the ICU. Insight in pathways associated with unfavourable outcome may lead to new treatment strategies. METHODS: We performed a prospective cohort study of patients with COVID-19 admitted to general ward or ICU who underwent serial blood sampling. To provide insight in the pathways involved in disease progression, associations were estimated between outcome risk and serial measurements of 64 biomarkers in potential important pathways of COVID-19 infection (inflammation, tissue damage, complement system, coagulation and fibrinolysis) using joint models combining Cox regression and linear mixed-effects models. For patients admitted to the general ward, the primary outcome was admission to the ICU or mortality (unfavourable outcome). For patients admitted to the ICU, the primary outcome was 12-week mortality. FINDINGS: A total of 219 patients were included: 136 (62%) on the ward and 119 patients (54%) on the ICU; 36 patients (26%) were included in both cohorts because they were transferred from general ward to ICU. On the general ward, 54 of 136 patients (40%) had an unfavourable outcome and 31 (23%) patients died. On the ICU, 54 out of 119 patients (45%) died. Unfavourable outcome on the general ward was associated with changes in concentrations of IL-6, IL-8, IL-10, soluble Receptor for Advanced Glycation End Products (sRAGE), vascular cell adhesion molecule 1 (VCAM-1) and Pentraxin-3. Death on the ICU was associated with changes in IL-6, IL-8, IL-10, sRAGE, VCAM-1, Pentraxin-3, urokinase-type plasminogen activator receptor, IL-1-receptor antagonist, CD14, procalcitonin, tumor necrosis factor alfa, tissue factor, complement component 5a, Growth arrest-specific 6, angiopoietin 2, and lactoferrin. Pathway analysis showed that unfavourable outcome on the ward was mainly driven by chemotaxis and interleukin production, whereas death on ICU was associated with a variety of pathways including chemotaxis, cell-cell adhesion, innate host response mechanisms, including the complement system, viral life cycle regulation, angiogenesis, wound healing and response to corticosteroids. INTERPRETATION: Clinical deterioration in patients with severe COVID-19 involves multiple pathways, including chemotaxis and interleukin production, but also endothelial dysfunction, the complement system, and immunothrombosis. Prognostic markers showed considerable overlap between general ward and ICU patients, but we identified distinct differences between groups that should be considered in the development and timing of interventional therapies in COVID-19. FUNDING: Amsterdam UMC, Amsterdam UMC Corona Fund, and Dr. C.J. Vaillant Fonds.
Assuntos
Biomarcadores/sangue , COVID-19/mortalidade , Admissão do Paciente/estatística & dados numéricos , Idoso , COVID-19/sangue , Quimiotaxia , Feminino , Humanos , Unidades de Terapia Intensiva , Interleucinas/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos ProspectivosRESUMO
Immunoglobulin G (IgG) antibodies are crucial for protection against invading pathogens. A highly conserved N-linked glycan within the IgG-Fc tail, which is essential for IgG function, shows variable composition in humans. Afucosylated IgG variants are already used in anticancer therapeutic antibodies for their increased activity through Fc receptors (FcγRIIIa). Here, we report that afucosylated IgG (approximately 6% of total IgG in humans) are specifically formed against enveloped viruses but generally not against other antigens. This mediates stronger FcγRIIIa responses but also amplifies brewing cytokine storms and immune-mediated pathologies. Critically ill COVID-19 patients, but not those with mild symptoms, had high concentrations of afucosylated IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), amplifying proinflammatory cytokine release and acute phase responses. Thus, antibody glycosylation plays a critical role in immune responses to enveloped viruses, including COVID-19.
Assuntos
Anticorpos Antivirais/imunologia , COVID-19/imunologia , Imunoglobulina G/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Anticorpos Antivirais/sangue , Anticorpos Antivirais/química , COVID-19/fisiopatologia , Células Cultivadas , Estado Terminal , Citomegalovirus/imunologia , Feminino , Fucose/análise , Glicosilação , HIV/imunologia , Vacinas contra Hepatite B/imunologia , Humanos , Fragmentos Fc das Imunoglobulinas/química , Fragmentos Fc das Imunoglobulinas/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/química , Inflamação , Interleucina-6/biossíntese , Interleucina-6/imunologia , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Parvovirus B19 Humano/imunologia , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Adulto JovemRESUMO
OBJECTIVES: The primary objectives of this meta-analysis in critically ill adult patients admitted to the intensive care unit (ICU) were to analyse whether erythropoiesis-stimulating agents (ESAs) reduced the number of patients receiving red blood cell (RBC) transfusion and resulted in a change in haemoglobin (Hb) concentration. Our secondary objectives were adverse events and mortality. BACKGROUND: Anaemia is common in ICU patients, and currently, the standard therapy is RBC transfusion, which is known to be associated with adverse events. ESA could potentially reduce the need for RBC transfusion. METHODS: EMBASE, Cochrane and PubMed were searched up to January 2020. RESULTS: A total of 1357 articles were identified, of which 18 articles met the inclusion criteria for the qualitative synthesis. Eight of these studies were used in the meta-analyses. Comparing ESA vs control group, there was a small reduction in the proportion of patients who received one or more RBC transfusions (relative risk [RR] 0.88; confidence interval [CI] 0.78-1.00, moderate certainty). The change in Hb concentration was trivial (mean difference -0.31 g/dL; CI -0.51 to -0.05, high certainty). The number of serious adverse events (RR 1.02; 0.90-1.15, low certainty) and the overall short-term mortality were similar (RR 0.80; CI 0.61-1.05, low certainty) between the groups. CONCLUSION: ESA resulted in a small reduction in the proportion of patients transfused and a trivial increase in haemoglobin concentration, both of questionable clinical relevance, without impacting adverse events or mortality. These results do not support the routine use of ESA to treat anaemia in critically ill adults.