RESUMEN
Since the outbreak of COVID-19 in China in December 2019, a pandemic has rapidly developed on a scale that has overwhelmed health services in a number of countries. COVID-19 has the potential to lead to severe hypoxia; this is usually the cause of death if it occurs. In a substantial number of patients, adequate arterial oxygenation cannot be achieved with supplementary oxygen therapy alone. To date, there has been no clear guideline endorsement of ward-based non-invasive pressure support (NIPS) for severely hypoxic patients who are deemed unlikely to benefit from invasive ventilation. We established a ward-based NIPS service for COVID-19 PCR-positive patients, with severe hypoxia, and in whom escalation to critical care for invasive ventilation was not deemed appropriate. A retrospective analysis of survival in these patients was undertaken. Twenty-eight patients were included. Ward-based NIPS for severe hypoxia was associated with a 50% survival in this cohort. This compares favourably with Intensive Care National Audit and Research Centre survival data following invasive ventilation in a less frail, less comorbid and younger population. These results suggest that ward-based NIPS should be considered as a treatment option in an integrated escalation strategy in all units managing respiratory failure secondary to COVID-19.
Asunto(s)
Presión de las Vías Aéreas Positiva Contínua/métodos , Infecciones por Coronavirus , Fragilidad , Evaluación Geriátrica/métodos , Pandemias , Neumonía Viral , Unidades de Cuidados Respiratorios , Insuficiencia Respiratoria , Anciano de 80 o más Años , Betacoronavirus/aislamiento & purificación , COVID-19 , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/fisiopatología , Infecciones por Coronavirus/terapia , Femenino , Fragilidad/diagnóstico , Fragilidad/fisiopatología , Fragilidad/terapia , Humanos , Pulmón/diagnóstico por imagen , Masculino , Evaluación de Procesos y Resultados en Atención de Salud , Oximetría/métodos , Oximetría/estadística & datos numéricos , Consumo de Oxígeno , Neumonía Viral/epidemiología , Neumonía Viral/fisiopatología , Neumonía Viral/terapia , Unidades de Cuidados Respiratorios/métodos , Unidades de Cuidados Respiratorios/organización & administración , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/mortalidad , Insuficiencia Respiratoria/fisiopatología , Insuficiencia Respiratoria/terapia , SARS-CoV-2 , Análisis de Supervivencia , Tomografía Computarizada por Rayos X/métodos , Reino Unido/epidemiologíaRESUMEN
Inflammation is a key feature in the pathogenesis of sepsis and acute respiratory distress syndrome (ARDS). Sepsis and ARDS continue to be associated with high mortality. A key contributory factor is the rudimentary understanding of the early events in pulmonary and systemic inflammation in humans, which are difficult to study in clinical practice, as they precede the patient's presentation to medical services. Lipopolysaccharide (LPS), a constituent of the outer membrane of Gram-negative bacteria, is a trigger of inflammation and the dysregulated host response in sepsis. Human LPS models deliver a small quantity of LPS to healthy volunteers, triggering an inflammatory response and providing a window to study early inflammation in humans. This allows biological/mechanistic insights to be made and new therapeutic strategies to be tested in a controlled, reproducible environment from a defined point in time. We review the use of human LPS models, focussing on the underlying mechanistic insights that have been gained by studying the response to intravenous and pulmonary LPS challenge. We discuss variables that may influence the response to LPS before considering factors that should be considered when designing future human LPS studies.
Asunto(s)
Neumonía , Síndrome de Dificultad Respiratoria , Humanos , Inflamación , Lipopolisacáridos , Pulmón , Síndrome de Dificultad Respiratoria/terapiaRESUMEN
Mononuclear phagocytes (MPs) including monocytes, macrophages and dendritic cells (DCs) are critical innate immune effectors and initiators of the adaptive immune response. MPs are present in the alveolar airspace at steady state, however little is known about DC recruitment in acute pulmonary inflammation. Here we use lipopolysaccharide inhalation to induce acute inflammation in healthy volunteers and examine the impact on bronchoalveolar lavage fluid and blood MP repertoire. Classical monocytes and two DC subsets (DC2/3 and DC5) are expanded in bronchoalveolar lavage fluid 8 h after lipopolysaccharide inhalation. Surface phenotyping, gene expression profiling and parallel analysis of blood indicate recruited DCs are blood-derived. Recruited monocytes and DCs rapidly adopt typical airspace-resident MP gene expression profiles. Following lipopolysaccharide inhalation, alveolar macrophages strongly up-regulate cytokines for MP recruitment. Our study defines the characteristics of human DCs and monocytes recruited into bronchoalveolar space immediately following localised acute inflammatory stimulus in vivo.
Asunto(s)
Células Dendríticas/efectos de los fármacos , Lipopolisacáridos/farmacología , Macrófagos Alveolares/efectos de los fármacos , Monocitos/efectos de los fármacos , Líquido del Lavado Bronquioalveolar , Citocinas/metabolismo , Humanos , Lipopolisacáridos/administración & dosificaciónRESUMEN
BACKGROUND: Critically ill patients with impaired neutrophil phagocytosis have significantly increased risk of nosocomial infection. Granulocyte-macrophage colony-stimulating factor (GM-CSF) improves phagocytosis by neutrophils ex vivo. This study tested the hypothesis that GM-CSF improves neutrophil phagocytosis in critically ill patients in whom phagocytosis is known to be impaired. METHODS: This was a multicentre, phase IIa randomised, placebo-controlled clinical trial. Using a personalised medicine approach, only critically ill patients with impaired neutrophil phagocytosis were included. Patients were randomised 1:1 to subcutaneous GM-CSF (3 µg/kg/day) or placebo, once daily for 4 days. The primary outcome measure was neutrophil phagocytosis 2 days after initiation of GM-CSF. Secondary outcomes included neutrophil phagocytosis over time, neutrophil functions other than phagocytosis, monocyte HLA-DR expression and safety. RESULTS: Thirty-eight patients were recruited from five intensive care units (17 randomised to GM-CSF). Mean neutrophil phagocytosis at day 2 was 57.2% (SD 13.2%) in the GM-CSF group and 49.8% (13.4%) in the placebo group, p=0.73. The proportion of patients with neutrophil phagocytosis≥50% at day 2, and monocyte HLA-DR, appeared significantly higher in the GM-CSF group. Neutrophil functions other than phagocytosis did not appear significantly different between the groups. The most common adverse event associated with GM-CSF was fever. CONCLUSIONS: GM-CSF did not improve mean neutrophil phagocytosis at day 2, but was safe and appeared to increase the proportion of patients with adequate phagocytosis. The study suggests proof of principle for a pharmacological effect on neutrophil function in a subset of critically ill patients.
Asunto(s)
Enfermedad Crítica/terapia , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Neutrófilos/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/efectos adversos , Antígenos HLA-DR/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Neutrófilos/fisiología , Resultado del TratamientoRESUMEN
BACKGROUND: The homozygous K108E mutation of interferon regulatory factor 8 (IRF8) is reported to cause dendritic cell (DC) and monocyte deficiency. However, more widespread immune dysfunction is predicted from the multiple roles ascribed to IRF8 in immune cell development and function. OBJECTIVE: We sought to describe the effect on hematopoiesis and immunity of the compound heterozygous R83C/R291Q mutation of IRF8, which is present in a patient with recurrent viral infection, granuloproliferation, and intracerebral calcification. METHODS: Variant IRF8 alleles were identified by means of exome sequencing, and their function was tested by using reporter assays. The cellular phenotype was studied in detail by using flow cytometry, functional immunologic assay transcriptional profiling, and antigen receptor profiling. RESULTS: Both mutations affected conserved residues, and R291Q is orthologous to R294, which is mutated in the BXH2 IRF8-deficient mouse. R83C showed reduced nuclear translocation, and neither mutant was able to regulate the Ets/IRF composite element or interferon-stimulated response element, whereas R291Q retained BATF/JUN interactions. DC deficiency and monocytopenia were observed in blood, dermis, and lung lavage fluid. Granulocytes were consistently increased, dysplastic, and hypofunctional. Natural killer cell development and maturation were arrested. TH1, TH17, and CD8+ memory T-cell differentiation was significantly reduced, and T cells did not express CXCR3. B-cell development was impaired, with fewer memory cells, reduced class-switching, and lower frequency and complexity of somatic hypermutation. Cell-specific gene expression was widely disturbed in interferon- and IRF8-regulated transcripts. CONCLUSIONS: This analysis defines the clinical features of human biallelic IRF8 deficiency, revealing a complex immunodeficiency syndrome caused by DC and monocyte deficiency combined with widespread immune dysregulation.
Asunto(s)
Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Factores Reguladores del Interferón/genética , Células Dendríticas/patología , Humanos , Masculino , Monocitos/patología , MutaciónRESUMEN
BACKGROUND: Neutrophils play a role in the pathogenesis of asthma, chronic obstructive pulmonary disease, and pulmonary infection. Impaired neutrophil phagocytosis predicts hospital-acquired infection. Despite this, remarkably few neutrophil-specific treatments exist. OBJECTIVES: We sought to identify novel pathways for the restoration of effective neutrophil phagocytosis and to activate such pathways effectively in neutrophils from patients with impaired neutrophil phagocytosis. METHODS: Blood neutrophils were isolated from healthy volunteers and patients with impaired neutrophil function. In healthy neutrophils phagocytic impairment was induced experimentally by using ß2-agonists. Inhibitors and activators of cyclic AMP (cAMP)-dependent pathways were used to assess the influence on neutrophil phagocytosis in vitro. RESULTS: ß2-Agonists and corticosteroids inhibited neutrophil phagocytosis. Impairment of neutrophil phagocytosis by ß2-agonists was associated with significantly reduced RhoA activity. Inhibition of protein kinase A (PKA) restored phagocytosis and RhoA activity, suggesting that cAMP signals through PKA to drive phagocytic impairment. However, cAMP can signal through effectors other than PKA, such as exchange protein directly activated by cyclic AMP (EPAC). An EPAC-activating analog of cAMP (8CPT-2Me-cAMP) reversed neutrophil dysfunction induced by ß2-agonists or corticosteroids but did not increase RhoA activity. 8CPT-2Me-cAMP reversed phagocytic impairment induced by Rho kinase inhibition but was ineffective in the presence of Rap-1 GTPase inhibitors. 8CPT-2Me-cAMP restored function to neutrophils from patients with known acquired impairment of neutrophil phagocytosis. CONCLUSIONS: EPAC activation consistently reverses clinical and experimental impairment of neutrophil phagocytosis. EPAC signals through Rap-1 and bypasses RhoA. EPAC activation represents a novel potential means by which to reverse impaired neutrophil phagocytosis.
Asunto(s)
Corticoesteroides/farmacología , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Enfermedad Crítica , Neutrófilos/inmunología , Neutrófilos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Citotoxicidad Inmunológica , Femenino , Factores de Intercambio de Guanina Nucleótido , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Activación Neutrófila/efectos de los fármacos , Activación Neutrófila/inmunología , Neutrófilos/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Fagocitosis/inmunología , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
BACKGROUND: Excessive use of empirical antibiotics is common in critically ill patients. Rapid biomarker-based exclusion of infection may improve antibiotic stewardship in ventilator-acquired pneumonia (VAP). However, successful validation of the usefulness of potential markers in this setting is exceptionally rare. OBJECTIVES: We sought to validate the capacity for specific host inflammatory mediators to exclude pneumonia in patients with suspected VAP. METHODS: A prospective, multicentre, validation study of patients with suspected VAP was conducted in 12 intensive care units. VAP was confirmed following bronchoscopy by culture of a potential pathogen in bronchoalveolar lavage fluid (BALF) at >10(4) colony forming units per millilitre (cfu/mL). Interleukin-1 beta (IL-1ß), IL-8, matrix metalloproteinase-8 (MMP-8), MMP-9 and human neutrophil elastase (HNE) were quantified in BALF. Diagnostic utility was determined for biomarkers individually and in combination. RESULTS: Paired BALF culture and biomarker results were available for 150 patients. 53 patients (35%) had VAP and 97 (65%) patients formed the non-VAP group. All biomarkers were significantly higher in the VAP group (p<0.001). The area under the receiver operator characteristic curve for IL-1ß was 0.81; IL-8, 0.74; MMP-8, 0.76; MMP-9, 0.79 and HNE, 0.78. A combination of IL-1ß and IL-8, at the optimal cut-point, excluded VAP with a sensitivity of 100%, a specificity of 44.3% and a post-test probability of 0% (95% CI 0% to 9.2%). CONCLUSIONS: Low BALF IL-1ß in combination with IL-8 confidently excludes VAP and could form a rapid biomarker-based rule-out test, with the potential to improve antibiotic stewardship.
Asunto(s)
Líquido del Lavado Bronquioalveolar/química , Citocinas/metabolismo , Neumonía Asociada al Ventilador/diagnóstico , Biomarcadores/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neumonía Asociada al Ventilador/metabolismo , Estudios Prospectivos , Reproducibilidad de los ResultadosRESUMEN
Lung transplantation is a well-established treatment option for selected patients with end-stage lung disease, leading to improved survival and improved quality of life. The last 20 years have seen a steady growth in number of lung transplantation procedures performed worldwide. The increase in clinical activity has been associated with tremendous progress in the understanding of cellular and molecular processes that limit both short- and long-term outcomes. This review gives a comprehensive overview of the current status of lung transplantation for the referring physician. It demonstrates that careful selection of potential recipients, optimisation of their condition prior to transplant, use of carefully assessed donor organs, excellent surgery and meticulous long-term follow-up are all essential ingredients in determining a successful outcome.