Search

Background: Analyses of blood biomarkers involved in the host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection can reveal distinct biological pathways and inform development and testing of therapeutics for COVID-19. Our objective was to evaluate host endothelial, epithelial and inflammatory biomarkers in COVID-19., Methods: We prospectively enrolled 171 ICU patients, including 78 (46%) patients positive and 93 (54%) negative for SARS-CoV-2 infection from April to September, 2020. We compared 22 plasma biomarkers in blood collected within 24 h and 3 days after ICU admission., Results: In critically ill COVID-19 and non-COVID-19 patients, the most common ICU admission diagnoses were respiratory failure or pneumonia, followed by sepsis and other diagnoses. Similar proportions of patients in both groups received invasive mechanical ventilation at the time of study enrollment. COVID-19 and non-COVID-19 patients had similar rates of acute respiratory distress syndrome, severe acute kidney injury, and in-hospital mortality. While concentrations of interleukin 6 and 8 were not different between groups, markers of epithelial cell injury (soluble receptor for advanced glycation end products, sRAGE) and acute phase proteins (serum amyloid A, SAA) were significantly higher in COVID-19 compared to non-COVID-19, adjusting for demographics and APACHE III scores. In contrast, angiopoietin 2:1 (Ang-2:1 ratio) and soluble tumor necrosis factor receptor 1 (sTNFR-1), markers of endothelial dysfunction and inflammation, were significantly lower in COVID-19 (p < 0.002). Ang-2:1 ratio and SAA were associated with mortality only in non-COVID-19 patients., Conclusions: These studies demonstrate that, unlike other well-studied causes of critical illness, endothelial dysfunction may not be characteristic of severe COVID-19 early after ICU admission. Pathways resulting in elaboration of acute phase proteins and inducing epithelial cell injury may be promising targets for therapeutics in COVID-19.

Background: Neutrophils release neutrophil extracellular traps (NETs) in response to invading pathogens. Although NETs play an important role in host defense against microbial pathogens, they have also been shown to play a contributing mechanistic role in pathologic inflammation in the absence of infection. Although a role for NETs in bacterial pneumonia and acute respiratory distress syndrome (ARDS) is emerging, a comprehensive evaluation of NETs in the alveolar space of critically ill patients has yet to be reported. In this study, we evaluated whether markers of NET formation in mechanically ventilated patients are associated with ventilator-associated pneumonia (VAP)., Methods: We collected bronchoalveolar lavage fluid from 100 critically ill patients undergoing bronchoscopy for clinically suspected VAP. Subjects were categorized by the absence or presence of VAP and further stratified by ARDS status. NETs (myeloperoxidase (MPO)-DNA complexes) and the NET-associated markers peroxidase activity and cell-free DNA were analyzed by enzyme-linked immunosorbent assay and colorimetric assays, respectively. Quantitative polymerase chain reaction of nuclear and mitochondrial DNA was used to determine the origin of the extruded DNA. Interleukin (IL)-8 and calprotectin were assayed as measures of alveolar inflammation and neutrophil activation. Correlations between NETs and markers of neutrophil activation were determined using Spearman's correlation. We tested for associations with VAP and bacterial burden by logistic and linear regression, respectively, using log 10 -transformed NETs., Results: MPO-DNA concentrations were highly correlated with other measures of NET formation in the alveolar space, including cell-free DNA and peroxidase activity (r = 0.95 and r = 0.87, p < 0.0001, respectively). Alveolar concentrations of MPO-DNA were higher in subjects with VAP and ARDS compared with those with ARDS alone (p < 0.0001), and higher MPO-DNA was associated with increased odds of VAP (odds ratio 3.03, p < 0.0001). In addition, NET concentrations were associated with bacterial burden (p < 0.0001) and local alveolar inflammation as measured by IL-8 (r = 0.89, p < 0.0001)., Conclusions: Alveolar NETs measured by MPO-DNA complex are associated with VAP, and markers of NETosis are associated with local inflammation and bacterial burden in the lung. These results suggest that NETs contribute to inflammatory responses involved in the pathogenesis of VAP.

Sepsis is a major contributor to the global burden of disease. The majority of sepsis cases and deaths are estimated to occur in low and middle-income countries. Barriers to reducing the global burden of sepsis include difficulty quantifying attributable morbidity and mortality, low awareness, poverty and health inequity, and under-resourced and low-resilience public health and acute health care delivery systems. Important differences in the populations at risk, infecting pathogens, and clinical capacity to manage sepsis in high and low-resource settings necessitate context-specific approaches to this significant problem. We review these challenges and propose strategies to overcome them. These strategies include strengthening health systems, accurately identifying and quantifying sepsis cases, conducting inclusive research, establishing data-driven and context-specific management guidelines, promoting creative clinical interventions, and advocacy.

Introduction: In low-resource settings it is not always possible to acquire the information required to diagnose acute respiratory distress syndrome (ARDS). Ultrasound and pulse oximetry, however, may be available in these settings. This study was designed to test whether pulmonary ultrasound and pulse oximetry could be used in place of traditional radiographic and oxygenation evaluation for ARDS., Methods: This study was a prospective, single-center study in the ICU of Harborview Medical Center, a referral hospital in Seattle, Washington, USA. Bedside pulmonary ultrasound was performed on ICU patients receiving invasive mechanical ventilation. Pulse oximetric oxygen saturation (SpO2), partial pressure of oxygen (PaO2), fraction of inspired oxygen (FiO2), provider diagnoses, and chest radiograph closest to time of ultrasound were recorded or interpreted., Results: One hundred and twenty three ultrasound assessments were performed on 77 consecutively enrolled patients with respiratory failure. Oxygenation and radiographic criteria for ARDS were met in 35 assessments. Where SpO2 ≤ 97%, the Spearman rank correlation coefficient between SpO2/FiO2 and PaO2/FiO2 was 0.83, p < 0.0001. The sensitivity and specificity of the previously reported threshold of SpO2/FiO2 ≤ 315 for PaO2/FiO2 ≤ 300 was 83% (95% confidence interval (CI) 68-93), and 50% (95% CI 1-99), respectively. Sensitivity and specificity of SpO2/FiO2 ≤ 235 for PaO2/FiO2 ≤ 200 was 70% (95% CI 47-87), and 90% (95% CI 68-99), respectively. For pulmonary ultrasound assessments interpreted by the study physician, the sensitivity and specificity of ultrasound interstitial syndrome bilaterally and involving at least three lung fields were 80% (95% CI 63-92) and 62% (95% CI 49-74) for radiographic criteria for ARDS. Combining SpO2/FiO2 with ultrasound to determine oxygenation and radiographic criteria for ARDS, the sensitivity was 83% (95% CI 52-98) and specificity was 62% (95% CI 38-82). For moderate-severe ARDS criteria (PaO2/FiO2 ≤ 200), sensitivity was 64% (95% CI 31-89) and specificity was 86% (95% CI 65-97). Excluding repeat assessments and independent interpretation of ultrasound images did not significantly alter the sensitivity measures., Conclusions: Pulse oximetry and pulmonary ultrasound may be useful tools to screen for, or rule out, impaired oxygenation or lung abnormalities consistent with ARDS in under-resourced settings where arterial blood gas testing and chest radiography are not readily available.

In their article, Baelani and colleagues surveyed anesthesia providers from African low- and middle-income countries (LMICs) to evaluate whether or not the current Surviving Sepsis Campaign (SSC) guidelines are feasible in such resource-constrained settings. The authors report that an alarmingly low percentage of hospitals have the capacity to implement the SSC guidelines in their entirety but a higher percentage are able to implement the majority of SSC guidelines and grade 1 recommendations. In reality, the probability of adherence to SSC guidelines for septic management is even lower than reported, given that the majority of sepsis management in African LMICs is likely performed by non-intensivists outside of intensive care units. Efforts to address the challenges of managing severely ill patients in LMICs have recently been taken on by the World Health Organization. After reviewing available evidence for sepsis management predominantly from high-income countries, a panel of experts developed a consensus-based strategy tailored for resource-limited settings. However, more research that can evaluate the challenges specific to sepsis management in LMICs and not currently addressed by the SSC guidelines is needed. Comprehensive, evidence-based guidelines combined with innovative approaches to sepsis management in LMICs are required to make a meaningful impact on worldwide sepsis survival.