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The soluble receptor for advanced glycation end-products (sRAGE) is a marker of alveolar type I cell injury associated with outcomes COVID-19 pneumonia. How plasma sRAGE changes over time and whether it remains associated with long-term clinical outcomes beyond a single measurement in COVID-19 has not been well-studied. We studied two cohorts in randomized clinical trials of monoclonal antibody treatment for COVID-19 (bamlanivimab and tixagevimab/cilgavimab). We first studied the association between baseline plasma sRAGE and 90-day clinical outcomes, which had been previously demonstrated in the bamlanivimab cohort, among hospitalized patients with COVID-19 supported with high flow nasal oxygen (HFNO) or non-invasive ventilation (NIV) in the tixagevimab/cilgavimab study. Next, we investigated the relationship between day 3 sRAGE and 90-day outcomes and how plasma sRAGE changes over the first 3 days of hospitalization in both clinical trial cohorts. We found that plasma sRAGE in the highest quartile in the HFNO/NIV participants in the tixagevimab/cilgavimab trial was associated with a significantly lower rate of 90-day sustained recovery (recovery rate ratio 0.31, 95% CI 0.14-0.71, p=0.005) and with a significantly higher rate of 90-day mortality (HR 2.49, 95% CI 1.15-5.43, p = 0.021) compared with the lower three quartiles. Day 3 plasma sRAGE in both clinical trial cohorts remained associated with 90-day clinical outcomes. The trajectory of sRAGE was not influenced by treatment assignment. Our results indicate that plasma sRAGE is a valuable prognostic marker in COVID-19 up to three days after initial hospital presentation.
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BACKGROUND: Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of viral replication and immune dysregulation. We aimed to characterise biomarker trajectories and their associations with clinical outcomes. METHODS: In this international, prospective cohort study, patients admitted to hospital with COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 platform trial within the Accelerating COVID-19 Therapeutic Interventions and Vaccines programme between Aug 5, 2020 and Sept 30, 2021 were included. Participants were included from 108 sites in Denmark, Greece, Poland, Singapore, Spain, Switzerland, Uganda, the UK, and the USA, and randomised to placebo or one of four neutralising monoclonal antibodies: bamlanivimab (Aug 5 to Oct 13, 2020), sotrovimab (Dec 16, 2020, to March 1, 2021), amubarvimab-romlusevimab (Dec 16, 2020, to March 1, 2021), and tixagevimab-cilgavimab (Feb 10 to Sept 30, 2021). This trial included an analysis of 2149 participants with plasma nucleocapsid antigen, anti-nucleocapsid antibody, C-reactive protein (CRP), IL-6, and D-dimer measured at baseline and day 1, day 3, and day 5 of enrolment. Day-90 follow-up status was available for 1790 participants. Biomarker trajectories were evaluated for associations with baseline characteristics, a 7-day pulmonary ordinal outcome, 90-day mortality, and 90-day rate of sustained recovery. FINDINGS: The study included 2149 participants. Participant median age was 57 years (IQR 46-68), 1246 (58·0%) of 2149 participants were male and 903 (42·0%) were female; 1792 (83·4%) had at least one comorbidity, and 1764 (82·1%) were unvaccinated. Mortality to day 90 was 172 (8·0%) of 2149 and 189 (8·8%) participants had sustained recovery. A pattern of less favourable trajectories of low anti-nucleocapsid antibody, high plasma nucleocapsid antigen, and high inflammatory markers over the first 5 days was observed for high-risk baseline clinical characteristics or factors related to SARS-CoV-2 infection. For example, participants with chronic kidney disease demonstrated plasma nucleocapsid antigen 424% higher (95% CI 319-559), CRP 174% higher (150-202), IL-6 173% higher (144-208), D-dimer 149% higher (134-165), and anti-nucleocapsid antibody 39% lower (60-18) to day 5 than those without chronic kidney disease. Participants in the highest quartile for plasma nucleocapsid antigen, CRP, and IL-6 at baseline and day 5 had worse clinical outcomes, including 90-day all-cause mortality (plasma nucleocapsid antigen hazard ratio (HR) 4·50 (95% CI 3·29-6·15), CRP HR 3·37 (2·30-4·94), and IL-6 HR 5·67 (4·12-7·80). This risk persisted for plasma nucleocapsid antigen and CRP after adjustment for baseline biomarker values and other baseline factors. INTERPRETATION: Patients admitted to hospital with less favourable 5-day biomarker trajectories had worse prognosis, suggesting that persistent viral burden might drive inflammation in the pathogenesis of COVID-19, identifying patients that might benefit from escalation of antiviral or anti-inflammatory treatment. FUNDING: US National Institutes of Health.
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Biomarcadores , COVID-19 , Hospitalización , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/mortalidad , COVID-19/sangre , Estudios Prospectivos , Masculino , Femenino , Biomarcadores/sangre , Persona de Mediana Edad , SARS-CoV-2/inmunología , Anciano , Hospitalización/estadística & datos numéricos , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Anticuerpos Monoclonales Humanizados/uso terapéutico , Interleucina-6/sangre , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Pandemias , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Neumonía Viral/inmunología , Neumonía Viral/sangre , Neumonía Viral/mortalidad , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/virología , Resultado del TratamientoRESUMEN
Neutrophils are the first leukocytes to be recruited to sites of inflammation in response to chemotactic factors released by activated macrophages and pulmonary epithelial and endothelial cells in bacterial pneumonia, a common cause of acute respiratory distress syndrome (ARDS). Although neutrophilic inflammation facilitates the elimination of pathogens, neutrophils also may cause bystander tissue injury. Even though the presence of neutrophils in alveolar spaces is a key feature of acute lung injury and ARDS especially from pneumonia, their contribution to the pathogenesis of lung injury is uncertain. The goal of this study was to elucidate the role of neutrophils in a clinically relevant model of bacterial pneumonia. We investigated the effect of reducing neutrophils in a mouse model of pneumococcal pneumonia treated with antibiotics. Neutrophils were reduced with anti-lymphocyte antigen 6 complex locus G6D (Ly6G) monoclonal antibody 24 h before and immediately preceding infection. Mice were inoculated intranasally with Streptococcus pneumoniae and received ceftriaxone 12 h after bacterial inoculation. Neutrophil reduction in mice treated with ceftriaxone attenuated hypoxemia, alveolar permeability, epithelial injury, pulmonary edema, and inflammatory biomarker release induced by bacterial pneumonia, even though bacterial loads in the distal air spaces of the lung were modestly increased as compared with antibiotic treatment alone. Thus, when appropriate antibiotics are administered, lung injury in the early phase of bacterial pneumonia is mediated in part by neutrophils. In the early phase of bacterial pneumonia, neutrophils contribute to the severity of lung injury, although they also participate in host defense.NEW & NOTEWORTHY Neutrophil accumulation is a key feature of ARDS, but their contribution to the pathogenesis is still uncertain. We investigated the effect of reducing neutrophils in a clinically relevant mouse model of pneumococcal pneumonia treated with antibiotics. When appropriate antibiotics were administered, neutrophil reduction with Ly6G antibody markedly attenuated lung injury and improved oxygenation. In the early phase of bacterial pneumonia, neutrophils contribute to the severity of lung injury, although they also participate in host defense.
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Ratones Endogámicos C57BL , Neutrófilos , Neumonía Neumocócica , Animales , Neumonía Neumocócica/inmunología , Neumonía Neumocócica/patología , Neumonía Neumocócica/tratamiento farmacológico , Neumonía Neumocócica/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Ratones , Streptococcus pneumoniae/patogenicidad , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/microbiología , Modelos Animales de Enfermedad , Pulmón/patología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/efectos de los fármacos , Lesión Pulmonar/patología , Lesión Pulmonar/inmunología , Lesión Pulmonar/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/patología , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/inmunología , MasculinoRESUMEN
BACKGROUND: Streptococcus pneumoniae is the most common bacterial cause of community acquired pneumonia and the acute respiratory distress syndrome (ARDS). Some clinical trials have demonstrated a beneficial effect of corticosteroid therapy in community acquired pneumonia, COVID-19, and ARDS, but the mechanisms of this benefit remain unclear. The primary objective of this study was to investigate the effects of corticosteroids on the pulmonary biology of pneumococcal pneumonia in a mouse model. A secondary objective was to identify shared transcriptomic features of pneumococcal pneumonia and steroid treatment in the mouse model and clinical samples. METHODS: We carried out comprehensive physiologic, biochemical, and histological analyses in mice to identify the mechanisms of lung injury in Streptococcus pneumoniae with and without adjunctive steroid therapy. We also studied lower respiratory tract gene expression from a cohort of 15 mechanically ventilated patients (10 with Streptococcus pneumoniae and 5 controls) to compare with the transcriptional studies in the mice. RESULTS: In mice with pneumonia, dexamethasone in combination with ceftriaxone reduced (1) pulmonary edema formation, (2) alveolar protein permeability, (3) proinflammatory cytokine release, (4) histopathologic lung injury score, and (5) hypoxemia but did not increase bacterial burden. Transcriptomic analyses identified effects of steroid therapy in mice that were also observed in the clinical samples. CONCLUSIONS: In combination with appropriate antibiotic therapy in mice, treatment of pneumococcal pneumonia with steroid therapy reduced hypoxemia, pulmonary edema, lung permeability, and histologic criteria of lung injury, and also altered inflammatory responses at the protein and gene expression level. The transcriptional studies in patients suggest that the mouse model replicates some of the features of pneumonia in patients with Streptococcus pneumoniae and steroid treatment. Overall, these studies provide evidence for the mechanisms that may explain the beneficial effects of glucocorticoid therapy in patients with community acquired pneumonia from Streptococcus Pneumoniae.
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Corticoesteroides , Modelos Animales de Enfermedad , Neumonía Neumocócica , Animales , Neumonía Neumocócica/tratamiento farmacológico , Ratones , Corticoesteroides/uso terapéutico , Corticoesteroides/farmacología , Humanos , Dexametasona/farmacología , Dexametasona/uso terapéutico , Femenino , Masculino , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/patogenicidadRESUMEN
Background: Streptococcus pneumoniae is the most common bacterial cause of community acquired pneumonia and the acute respiratory distress syndrome (ARDS). Some clinical trials have demonstrated a beneficial effect of corticosteroid therapy in community acquired pneumonia, COVID-19, and ARDS, but the mechanisms of this benefit remain unclear. The objective of this study was to investigate the effects of corticosteroids on the pulmonary biology of pneumococcal pneumonia in an observational cohort of mechanically ventilated patients and in a mouse model of bacterial pneumonia with Streptococcus pneumoniae. Methods: We studied gene expression with lower respiratory tract transcriptomes from a cohort of mechanically ventilated patients and in mice. We also carried out comprehensive physiologic, biochemical, and histological analyses in mice to identify the mechanisms of lung injury in Streptococcus pneumoniae with and without adjunctive steroid therapy. Results: Transcriptomic analysis identified pleiotropic effects of steroid therapy on the lower respiratory tract in critically ill patients with pneumococcal pneumonia, findings that were reproducible in mice. In mice with pneumonia, dexamethasone in combination with ceftriaxone reduced (1) pulmonary edema formation, (2) alveolar protein permeability, (3) proinflammatory cytokine release, (4) histopathologic lung injury score, and (5) hypoxemia but did not increase bacterial burden. Conclusions: The gene expression studies in patients and in the mice support the clinical relevance of the mouse studies, which replicate several features of pneumococcal pneumonia and steroid therapy in humans. In combination with appropriate antibiotic therapy in mice, treatment of pneumococcal pneumonia with steroid therapy reduced hypoxemia, pulmonary edema, lung permeability, and histologic criteria of lung injury, and also altered inflammatory responses at the protein and gene expression level. The results from these studies provide evidence for the mechanisms that may explain the beneficial effects of glucocorticoid therapy in patients with community acquired pneumonia from Streptococcus Pneumoniae.
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BACKGROUND: Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood. METHODS: Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), anti-nucleocapsid antibody, C-reactive protein, interleukin-6, and D-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models. RESULTS: Analysis included 2149 participants enrolled between August 2020 and September 2021. Treatment resulted in 20% lower levels of plasma N-Ag compared with placebo (95% confidence interval, 12%-27%; P < .001), and a steeper rate of decline through the first 5 days (P < .001). The treatment difference did not vary between subgroups, and no difference was observed in trajectories of other biomarkers or the day 5 pulmonary ordinal scale. CONCLUSIONS: Our study suggests that nmAb has an antiviral effect assessed by plasma N-Ag among hospitalized patients with COVID-19, with no blunting of the endogenous anti-nucleocapsid antibody response. No effect on systemic inflammation or day 5 clinical status was observed. CLINICAL TRIALS REGISTRATION: NCT04501978.
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COVID-19 , Humanos , SARS-CoV-2 , Anticuerpos Neutralizantes , Anticuerpos Monoclonales/uso terapéutico , BiomarcadoresRESUMEN
Background: Since publication of the 2012 Berlin definition of acute respiratory distress syndrome (ARDS), several developments have supported the need for an expansion of the definition, including the use of high-flow nasal oxygen, the expansion of the use of pulse oximetry in place of arterial blood gases, the use of ultrasound for chest imaging, and the need for applicability in resource-limited settings. Methods: A consensus conference of 32 critical care ARDS experts was convened, had six virtual meetings (June 2021 to March 2022), and subsequently obtained input from members of several critical care societies. The goal was to develop a definition that would 1) identify patients with the currently accepted conceptual framework for ARDS, 2) facilitate rapid ARDS diagnosis for clinical care and research, 3) be applicable in resource-limited settings, 4) be useful for testing specific therapies, and 5) be practical for communication to patients and caregivers. Results: The committee made four main recommendations: 1) include high-flow nasal oxygen with a minimum flow rate of ⩾30 L/min; 2) use PaO2:FiO2 ⩽ 300 mm Hg or oxygen saturation as measured by pulse oximetry SpO2:FiO2 ⩽ 315 (if oxygen saturation as measured by pulse oximetry is ⩽97%) to identify hypoxemia; 3) retain bilateral opacities for imaging criteria but add ultrasound as an imaging modality, especially in resource-limited areas; and 4) in resource-limited settings, do not require positive end-expiratory pressure, oxygen flow rate, or specific respiratory support devices. Conclusions: We propose a new global definition of ARDS that builds on the Berlin definition. The recommendations also identify areas for future research, including the need for prospective assessments of the feasibility, reliability, and prognostic validity of the proposed global definition.
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Síndrome de Dificultad Respiratoria , Humanos , Estudios Prospectivos , Reproducibilidad de los Resultados , Síndrome de Dificultad Respiratoria/diagnóstico , Síndrome de Dificultad Respiratoria/terapia , Oximetría , OxígenoRESUMEN
BACKGROUND: Inflammatory subphenotypes have been identified in acute respiratory distress syndrome (ARDS). Hyperferritinaemia in sepsis is associated with hyperinflammation, worse clinical outcomes, and may predict benefit with immunomodulation. Our aim was to determine if raised ferritin identified a subphenotype in patients with ARDS. METHODS: Baseline plasma ferritin concentrations were measured in patients with ARDS from two randomised controlled trials of simvastatin (Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary Dysfunction-2 (HARP-2); discovery cohort, UK) and neuromuscular blockade (ROSE; validation cohort, USA). Results were analysed using a logistic regression model with restricted cubic splines, to determine the ferritin threshold associated with 28-day mortality. RESULTS: Ferritin was measured in 511 patients from HARP-2 (95% of patients enrolled) and 847 patients (84% of patients enrolled) from ROSE. Ferritin was consistently associated with 28-day mortality in both studies and following a meta-analysis, a log-fold increase in ferritin was associated with an OR 1.71 (95% CI 1.01 to 2.90) for 28-day mortality. Patients with ferritin >1380 ng/mL (HARP-2 28%, ROSE 24%) had a significantly higher 28-day mortality and fewer ventilator-free days in both studies. Mediation analysis, including confounders (acute physiology and chronic health evaluation-II score and ARDS aetiology) demonstrated a statistically significant contribution of interleukin (IL)-18 as an intermediate pathway between ferritin and mortality. CONCLUSIONS: Ferritin is a clinically useful biomarker in ARDS and is associated with worse patient outcomes. These results provide support for prospective interventional trials of immunomodulatory agents targeting IL-18 in this hyperferritinaemic subgroup of patients with ARDS.
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Interleucina-18 , Síndrome de Dificultad Respiratoria , Humanos , Estudios Prospectivos , Simvastatina , Síndrome de Dificultad Respiratoria/etiología , InflamaciónRESUMEN
Angiopoietin-2 (Ang-2) is associated with vascular endothelial injury and permeability in the acute respiratory distress syndrome (ARDS) and sepsis. Elevated circulating Ang-2 levels may identify critically ill patients with distinct pathobiology amenable to targeted therapy. We hypothesized that plasma Ang-2 measured shortly after hospitalization among patients with sepsis would be associated with the development of ARDS and poor clinical outcomes. To test this hypothesis, we measured plasma Ang-2 in a cohort of 757 patients with sepsis, including 267 with ARDS, enrolled in the emergency department or early in their ICU course before the COVID-19 pandemic. Multivariable models were used to test the association of Ang-2 with the development of ARDS and 30-day morality. We found that early plasma Ang-2 in sepsis was associated with higher baseline severity of illness, the development of ARDS, and mortality risk. The association between Ang-2 and mortality was strongest among patients with ARDS and sepsis as compared to those with sepsis alone (OR 1.81 vs. 1.52 per log Ang-2 increase). These findings might inform models testing patient risk prediction and strengthen the evidence for Ang-2 as an appealing biomarker for patient selection for novel therapeutic agents to target vascular injury in sepsis and ARDS.
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COVID-19 , Síndrome de Dificultad Respiratoria , Sepsis , Humanos , Angiopoyetina 2 , Enfermedad Crítica , Pandemias , PronósticoRESUMEN
Introduction: There remains a need to better identify patients at highest risk for developing severe Coronavirus Disease 2019 (COVID-19) as additional waves of the pandemic continue to impact hospital systems. We sought to characterize the association of receptor for advanced glycation end products (RAGE), SARS-CoV-2 nucleocapsid viral antigen, and a panel of thromboinflammatory biomarkers with development of severe disease in patients presenting to the emergency department with symptomatic COVID-19. Methods: Blood samples were collected on arrival from 77 patients with symptomatic COVID-19, and plasma levels of thromboinflammatory biomarkers were measured. Results: Differences in biomarkers between those who did and did not develop severe disease or death 7 days after presentation were analyzed. After adjustment for multiple comparisons, RAGE, SARS-CoV-2 nucleocapsid viral antigen, interleukin (IL)-6, IL-10 and tumor necrosis factor receptor (TNFR)-1 were significantly elevated in the group who developed severe disease (all p<0.05). In a multivariable regression model, RAGE and SARS-CoV-2 nucleocapsid viral antigen remained significant risk factors for development of severe disease (both p<0.05), and each had sensitivity and specificity >80% on cut-point analysis. Discussion: Elevated RAGE and SARS-CoV-2 nucleocapsid viral antigen on emergency department presentation are strongly associated with development of severe disease at 7 days. These findings are of clinical relevance for patient prognostication and triage as hospital systems continue to be overwhelmed. Further studies are warranted to determine the feasibility and utility of point-of care measurements of these biomarkers in the emergency department setting to improve patient prognostication and triage.
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COVID-19 , Humanos , SARS-CoV-2 , Receptor para Productos Finales de Glicación Avanzada , Nucleocápside , Antígenos , Biomarcadores , Antígenos ViralesRESUMEN
Introduction: Thromboinflammatory complications are well described sequalae of Coronavirus Disease 2019 (COVID-19), and there is evidence of both hyperreactive platelet and inflammatory neutrophil biology that contributes to the thromoinflammatory milieu. It has been demonstrated in other thromboinflammatory diseases that the circulating environment may affect cellular behavior, but what role this environment exerts on platelets and neutrophils in COVID-19 remains unknown. We tested the hypotheses that 1) plasma from COVID-19 patients can induce a prothrombotic platelet functional phenotype, and 2) contents released from platelets (platelet releasate) from COVID-19 patients can induce a proinflammatory neutrophil phenotype. Methods: We treated platelets with COVID-19 patient and disease control plasma, and measured their aggregation response to collagen and adhesion in a microfluidic parallel plate flow chamber coated with collagen and thromboplastin. We exposed healthy neutrophils to platelet releasate from COVID-19 patients and disease controls and measured neutrophil extracellular trap formation and performed RNA sequencing. Results: We found that COVID-19 patient plasma promoted auto-aggregation, thereby reducing response to further stimulation ex-vivo. Neither disease condition increased the number of platelets adhered to a collagen and thromboplastin coated parallel plate flow chamber, but both markedly reduced platelet size. COVID-19 patient platelet releasate increased myeloperoxidasedeoxyribonucleic acid complexes and induced changes to neutrophil gene expression. Discussion: Together these results suggest aspects of the soluble environment circulating platelets, and that the contents released from those neutrophil behavior independent of direct cellular contact.
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Plaquetas , COVID-19 , Humanos , Plaquetas/metabolismo , Neutrófilos/metabolismo , COVID-19/metabolismo , Tromboplastina/metabolismo , Colágeno/metabolismoRESUMEN
BACKGROUND: Opioid overuse is a substantial cause of morbidity and mortality in the United States, and orthopaedic surgeons are the third highest prescribers of opioids. Postoperative prescribing patterns vary widely, and there is a paucity of data evaluating patient and surgical factors associated with discharge opioid prescribing patterns after elective anterior cervical surgery (ACS). The purpose of this study was to evaluate the volume of postoperative opioids prescribed and factors associated with discharge opioid prescription volumes after elective ACS. METHODS: We retrospectively identified patients aged 18 years and older who underwent elective primary anterior cervical diskectomy and fusion (ACDF), cervical disk arthroplasty (CDA), or hybrid procedure (ACDF and CDA at separate levels) at a single institution between 2015 and 2021. Demographic, surgical, and opioid prescription data were obtained from patients' electronic medical records. Univariate and multivariate analyses were conducted to assess for independent associations with discharge opioid volumes. RESULTS: A total of 313 patients met inclusion criteria, including 226 (72.2%) ACDF, 69 (22.0%) CDA, and 18 (5.8%) hybrid procedure patients. Indications included radiculopathy in 63.6%, myelopathy in 19.2%, and myeloradiculopathy in 16.3%. The average age was 57.2 years, and 50.2% of patients were male. Of these, 88 (28.1%) underwent one-level, 137 (43.8%) underwent two-level, 83 (26.5%) underwent three-level, and 5 (1.6%) underwent four-level surgery. Younger age (P = 0.010), preoperative radiculopathy (P = 0.029), procedure type (ACDF, P < 0.001), preoperative opioid use (P = 0.012), and discharge prescription written by a midlevel provider (P = 0.010) were independently associated with greater discharge opioid prescription volumes. CONCLUSION: We identified wide variability in prescription opioid discharge volumes after ACS and patient, procedure, and perioperative factors associated with greater discharge opioid volumes. These factors should be considered when designing protocols and interventions to reduce and optimize postoperative opioid use after ACS.
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Trastornos Relacionados con Opioides , Radiculopatía , Enfermedades de la Médula Espinal , Fusión Vertebral , Humanos , Masculino , Estados Unidos , Persona de Mediana Edad , Femenino , Analgésicos Opioides/uso terapéutico , Estudios Retrospectivos , Radiculopatía/cirugía , Pautas de la Práctica en Medicina , Prescripciones , Enfermedades de la Médula Espinal/cirugía , Vértebras Cervicales/cirugía , Derivados de la Morfina , Dolor Postoperatorio/tratamiento farmacológico , DiscectomíaRESUMEN
BACKGROUND: The ventilatory ratio (VR, [minute ventilation × PaCO2]/[predicted body weight × 100 × 37.5]) is associated with mortality in ARDS. The aims of this study were to test whether baseline disease severity or neuromuscular blockade (NMB) modified the relationship between VR and mortality. METHODS: This was a post hoc analysis of the PETAL-ROSE trial, which randomized moderate-to-severe ARDS patients to NMB or control. Survival among patients with different VR trajectories or VR cutoff above and below the median was assessed by Kaplan-Meier analysis. The relationships between single-day or 48-h VR trajectories with 28- or 90-day mortality were tested by logistic regression. Randomization allocation to NMB and markers of disease severity were tested as confounders by multivariable regression and interaction term analyses. RESULTS: Patients with worsening VR trajectories had significantly lower survival compared to those with improving VR (n = 602, p < 0.05). Patients with VR > 2 (median) at day 1 had a significantly lower 90-day survival compared to patients with VR ≤ 2 (HR 1.36, 95% CI 1.10-1.69). VR at day 1 was significantly associated with 28-day mortality (OR = 1.40, 95% CI 1.15-1.72). There was no interaction between NMB and VR for 28-day mortality. APACHE-III had a significant interaction with VR at baseline for the outcome of 28-day mortality, such that the relationship between VR and mortality was stronger among patients with lower APACHE-III. There was a significant association between rising VR trajectory and mortality that was independent of NMB, baseline PaO2/FiO2 ratio and generalized markers of disease severity (Adjusted OR 1.81, 95% CI 1.28-2.84 for 28-day and OR 2.07 95% CI 1.41-3.10 for 90-day mortality). APACHE-III and NMB were not effect modifiers in the relationship between VR trajectory and mortality. CONCLUSIONS: Elevated baseline and day 1 VR were associated with higher 28-day mortality. The relationship between baseline VR and mortality was stronger among patients with lower APACHE-III. APACHE-III was not an effect modifier for the relationship between VR trajectory and mortality, so that the VR trajectory may be optimally suited for prognostication and predictive enrichment. VR was not different between patients randomized to NMB or control, indicating that VR can be utilized without correcting for NMB.
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Bloqueo Neuromuscular , Síndrome de Dificultad Respiratoria , APACHE , Humanos , Estimación de Kaplan-Meier , Pronóstico , Síndrome de Dificultad Respiratoria/terapiaRESUMEN
BACKGROUND: Studies quantifying SARS-CoV-2 have focused on upper respiratory tract or plasma viral RNA with inconsistent association with clinical outcomes. The association between plasma viral antigen levels and clinical outcomes has not been previously studied. Our aim was to investigate the relationship between plasma SARS-CoV-2 nucleocapsid antigen (N-antigen) concentration and both markers of host response and clinical outcomes. METHODS: SARS-CoV-2 N-antigen concentrations were measured in the first study plasma sample (D0), collected within 72 h of hospital admission, from 256 subjects admitted between March 2020 and August 2021 in a prospective observational cohort of hospitalized patients with COVID-19. The rank correlations between plasma N-antigen and plasma biomarkers of tissue damage, coagulation, and inflammation were assessed. Multiple ordinal regression was used to test the association between enrollment N-antigen plasma concentration and the primary outcome of clinical deterioration at one week as measured by a modified World Health Organization (WHO) ordinal scale. Multiple logistic regression was used to test the association between enrollment plasma N-antigen concentration and the secondary outcomes of ICU admission, mechanical ventilation at 28 days, and death at 28 days. The prognostic discrimination of an externally derived "high antigen" cutoff of N-antigen ≥ 1000 pg/mL was also tested. RESULTS: N-antigen on D0 was detectable in 84% of study participants. Plasma N-antigen levels significantly correlated with RAGE (r = 0.61), IL-10 (r = 0.59), and IP-10 (r = 0.59, adjusted p = 0.01 for all correlations). For the primary outcome of clinical status at one week, each 500 pg/mL increase in plasma N-antigen level was associated with an adjusted OR of 1.05 (95% CI 1.03-1.08) for worse WHO ordinal status. D0 plasma N-antigen ≥ 1000 pg/mL was 77% sensitive and 59% specific (AUROC 0.68) with a positive predictive value of 23% and a negative predictive value of 93% for a worse WHO ordinal scale at day 7 compared to baseline. D0 N-antigen concentration was independently associated with ICU admission and 28-day mechanical ventilation, but not with death at 28 days. CONCLUSIONS: Plasma N-antigen levels are readily measured and provide important insight into the pathogenesis and prognosis of COVID-19. The measurement of N-antigen levels early in-hospital course may improve risk stratification, especially for identifying patients who are unlikely to progress to severe disease.
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COVID-19 , SARS-CoV-2 , Humanos , Nucleocápside , ARN ViralRESUMEN
The diagnosis of acute respiratory distress syndrome (ARDS) traditionally requires calculation of the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) using arterial blood, which can be costly and is not possible in many resource-limited settings. By contrast, pulse oximetry is continuously available, accurate, inexpensive, and non-invasive. Pulse oximetry-based indices, such as the ratio of pulse-oximetric oxygen saturation to FiO2 (SpO2/FiO2), have been validated in clinical studies for the diagnosis and risk stratification of patients with ARDS. Limitations of the SpO2/FiO2 ratio include reduced accuracy in poor perfusion states or above oxygen saturations of 97%, and the potential for reduced accuracy in patients with darker skin pigmentation. Application of pulse oximetry to the diagnosis and management of ARDS, including formal adoption of the SpO2/FiO2 ratio as an alternative to PaO2/FiO2 to meet the diagnostic criterion for hypoxaemia in ARDS, could facilitate increased and earlier recognition of ARDS worldwide to advance both clinical practice and research.
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Oximetría , Síndrome de Dificultad Respiratoria , Humanos , Síndrome de Dificultad Respiratoria/diagnóstico , Síndrome de Dificultad Respiratoria/terapia , OxígenoRESUMEN
The acute respiratory distress syndrome (ARDS) is a common critical illness syndrome with high morbidity and mortality. There are no proven pharmacological therapies for ARDS. The current definition of ARDS is based on shared clinical characteristics but does not capture the heterogeneity in clinical risk factors, imaging characteristics, physiology, timing of onset and trajectory, and biology of the syndrome. There is increasing interest within the ARDS clinical trialist community to design clinical trials that reduce heterogeneity in the trial population. This effort must be balanced with ongoing work to craft an inclusive, global definition of ARDS, with important implications for trial design. Ultimately, the two aims-to design trials that are applicable to the diverse global ARDS population while also advancing opportunities to identify targetable traits-should coexist. In this Personal View, we recommend two primary strategies to improve future ARDS trials: the development of new methods to target treatable traits in clinical trial populations, and improvements in the representativeness of ARDS trials, with the inclusion of global populations. We emphasise that these two strategies are complementary. We also discuss how a proposed expansion of the definition of ARDS could affect the future of clinical trials.
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Síndrome de Dificultad Respiratoria , Ensayos Clínicos como Asunto , Humanos , Fenotipo , Síndrome de Dificultad Respiratoria/terapia , Factores de RiesgoRESUMEN
Electronic cigarettes (e-cigarettes) are designed to simulate combustible cigarette smoking and to aid in smoking cessation. Although the number of e-cigarette users has been increasing, the potential health impacts and biological effects of e-cigarettes are still not fully understood. Previous research has focused on the biological effects of e-cigarettes on lung cancer cell lines and distal airway epithelial cells; however, there have been few published studies on the effect of e-cigarettes on primary lung alveolar epithelial cells. The primary purpose of this study was to investigate the direct effect of e-cigarette aerosol on primary human lung alveolar epithelial type 2 (AT2) cells, both alone and in the presence of viral infection. The Melo-3 atomizer caused direct AT2 cell toxicity, whereas the more popular Juul pod's aerosol did not have a detectable cytotoxic effect on AT2 cells. Juul nicotine aerosol also did not increase short-term susceptibility to viral infection. However, 3 days of exposure upregulated genes central to the generation of reactive oxygen species, lipid peroxidation, and carcinogen metabolism and downregulated key innate immune system genes related to cytokine and chemokine signaling. These findings have implications for the potentially injurious impact of long-term use of popular low-power e-cigarette pods on the human alveolar epithelium. Gene expression data might be an important endpoint for evaluating the potential harmful effects of vaping devices that do not cause overt toxicity.
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Sistemas Electrónicos de Liberación de Nicotina , Vapeo , Células Epiteliales Alveolares , Humanos , Nicotina/efectos adversos , Aerosoles y Gotitas Respiratorias , Vapeo/efectos adversosRESUMEN
BACKGROUND: How indices specific to respiratory compromise contribute to prognostication in patients with ARDS is not well characterized in general clinical populations. The primary objective of this study was to identify variables specific to respiratory failure that might add prognostic value to indicators of systemic illness severity in an observational cohort of subjects with ARDS. METHODS: Fifty subjects with ARDS were enrolled in a single-center, prospective, observational cohort. We tested the contribution of respiratory variables (oxygenation index, ventilatory ratio [VR], and the radiographic assessment of lung edema score) to logistic regression models of 28-d mortality adjusted for indicators of systemic illness severity (the Acute Physiology and Chronic Health Evaluation [APACHE] III score or severity of shock as measured by the number of vasopressors required at baseline) using likelihood ratio testing. We also compared a model utilizing APACHE III with one including baseline number of vasopressors by comparing the area under the receiver operating curve (AUROC). RESULTS: VR significantly improved model performance by likelihood ratio testing when added to APACHE III (P = .036) or the number of vasopressors at baseline (P = .01). Number of vasopressors required at baseline had similar prognostic discrimination to the APACHE III. A model including the number of vasopressors and VR (AUROC 0.77 [95% CI 0.64-0.90]) was comparable to a model including APACHE III and VR (AUROC 0.81 [95% CI 0.68-0.93]; P for comparison = .58.). CONCLUSIONS: In this observational cohort of subjects with ARDS, the VR significantly improved discrimination for mortality when combined with indicators of severe systemic illness. The number of vasopressors required at baseline and APACHE III had similar discrimination for mortality when combined with VR. VR is easily obtained at the bedside and offers promise for clinical prognostication.
Asunto(s)
Síndrome de Dificultad Respiratoria , APACHE , Estudios de Cohortes , Humanos , Unidades de Cuidados Intensivos , Pronóstico , Estudios Prospectivos , Curva ROCRESUMEN
Although vitamin E acetate (VEA) is suspected to play a causal role in the development of electronic-cigarette, or vaping, product use-associated lung injury (EVALI), the underlying biological mechanisms of pulmonary injury are yet to be determined. In addition, no study has replicated the systemic inflammation observed in humans in a murine EVALI model, nor investigated potential additive toxicity of viral infection in the setting of exposure to vaping products. To identify the mechanisms driving VEA-related lung injury and test the hypothesis that viral infection causes additive lung injury in the presence of aerosolized VEA, we exposed mice to aerosolized VEA for extended times, followed by influenza infection in some experiments. We used mass spectrometry to evaluate the composition of aerosolized VEA condensate and the VEA deposition in murine or human alveolar macrophages. Extended vaping for 28 days versus 15 days did not worsen lung injury but caused systemic inflammation in the murine EVALI model. Vaping plus influenza increased lung water compared with virus alone. Murine alveolar macrophages exposed to vaped VEA hydrolyzed the VEA to vitamin E with evidence of oxidative stress in the alveolar space and systemic circulation. Aerosolized VEA also induced cell death and chemokine release and reduced efferocytotic function in human alveolar macrophages in vitro. These findings provide new insights into the biological mechanisms of VEA toxicity.