Onset Of Acute Respiratory Distress Syndrome Research Articles

Timing and Clinical Significance of Fluid Overload in Pediatric Acute Respiratory Distress Syndrome.

Fluid overload is associated with worse outcomes in adult and pediatric acute respiratory distress syndrome. However, the time-course of fluid overload and its relationship to outcome has not been described. We aimed to determine the relationship between the timing of fluid overload and outcomes over the first 7 days after acute respiratory distress syndrome onset in children. Retrospective cohort study. Single tertiary care PICU. Intubated children with acute respiratory distress syndrome between 2011 and 2019. None. Daily and cumulative total fluid intake, total output, urine output, and fluid balance were collected for each 24-hour period from days 1 to 7 after acute respiratory distress syndrome onset. We tested the association between daily cumulative fluid metrics with PICU mortality and probability of extubation by 28 days using multivariable logistic and competing risk regression, respectively. In a subset of children, plasma was collected on day 1 and day 3 of acute respiratory distress syndrome and angiopoietin-2 quantified. Of 723 children with acute respiratory distress syndrome, 132 died (18%). In unadjusted analysis, nonsurvivors had higher cumulative fluid balance starting on day 3. In multivariable analysis, a positive cumulative fluid balance on days 5 through 7 was associated with increased mortality. Higher cumulative fluid balance on days 4 to 7 was associated with lower probability of extubation. Elevated angiopoietin-2 on day 1 predicted early (within 3 d) fluid overload greater than or equal to 10%, and elevated angiopoietin-2 on day 3 predicted late (between days 4 and 7) fluid overload. Fluid overload after day 4 of acute respiratory distress syndrome, but not before, was associated with worse outcomes. Higher angiopoietin-2 predicted subsequent fluid overload. Our results suggest that future interventions aimed at managing fluid overload may have differential efficacy depending on when in the time-course of acute respiratory distress syndrome they are initiated.

Novel criteria to classify ARDS severity using a machine learning approach

BackgroundUsually, arterial oxygenation in patients with the acute respiratory distress syndrome (ARDS) improves substantially by increasing the level of positive end-expiratory pressure (PEEP). Herein, we are proposing a novel variable [PaO2/(FiO2xPEEP) or P/FPE] for PEEP ≥ 5 to address Berlin’s definition gap for ARDS severity by using machine learning (ML) approaches.MethodsWe examined P/FPE values delimiting the boundaries of mild, moderate, and severe ARDS. We applied ML to predict ARDS severity after onset over time by comparing current Berlin PaO2/FiO2 criteria with P/FPE under three different scenarios. We extracted clinical data from the first 3 ICU days after ARDS onset (N = 2738, 1519, and 1341 patients, respectively) from MIMIC-III database according to Berlin criteria for severity. Then, we used the multicenter database eICU (2014–2015) and extracted data from the first 3 ICU days after ARDS onset (N = 5153, 2981, and 2326 patients, respectively). Disease progression in each database was tracked along those 3 ICU days to assess ARDS severity. Three robust ML classification techniques were implemented using Python 3.7 (LightGBM, RF, and XGBoost) for predicting ARDS severity over time.ResultsP/FPE ratio outperformed PaO2/FiO2 ratio in all ML models for predicting ARDS severity after onset over time (MIMIC-III: AUC 0.711–0.788 and CORR 0.376–0.566; eICU: AUC 0.734–0.873 and CORR 0.511–0.745).ConclusionsThe novel P/FPE ratio to assess ARDS severity after onset over time is markedly better than current PaO2/FiO2 criteria. The use of P/FPE could help to manage ARDS patients with a more precise therapeutic regimen for each ARDS category of severity.

HFOV vs CMV for neonates with moderate-to-severe perinatal onset acute respiratory distress syndrome (NARDS): a propensity score analysis.

This study aimed to evaluate whether high-frequency oscillatory ventilation (HFOV) could reduce mortality and the incidence of bronchopulmonary dysplasia (BPD) of perinatal-onset neonatal acute respiratory distress syndrome (NARDS) compared with conventional mechanical ventilation (CMV). Medical records were collected and retrospectively analyzed. Among the 700 neonates with NARDS who needed invasive ventilation, 501 (71.6%) received CMV, while 199 (28.4%) received HFOV. One-to-one propensity score matching (127:127) was used to match the baseline characteristics of patients who received CMV and HFOV. The results showed that birth weight and oxygenation index (OI) were independently associated with mortality in the multivariate logistic regression. No significant differences were observed in mortality or the incidence of BPD between the two groups. The incidence of intraventricular hemorrhage (IVH) and ventilation-free days were significantly lower in the HFOV group than in the CMV group (3.9 vs 11.80%, p=0.02; 15.226 vs 20.967 days, p=0.01). There were no significant differences between the two groups regarding other secondary outcomes.Conclusion: HFOV was associated with a decreased incidence of IVH in infants with NARDS compared with CMV. However, there were significantly more VFDs in the CMV group than in the HFOV group, and HFOV did not appear to be superior to CMV in decreasing the mortality and incidence of BPD in infants with NARDS.What is Known:• The diagnostic criteria of neonatal acute respiratory distress syndrome (Montreux criteria) were established in 2017.• To date, studies comparing high-frequency oscillatory ventilation and conventional mechanical ventilation in the treatment of neonatal acute respiratory distress syndrome are insufficient.What is New:• High-frequency oscillatory ventilation did not appear to be superior to conventional mechanical ventilation in decreasing the mortality and incidence of bronchopulmonary dysplasia in infants with moderate-to-severe perinatal-onset neonatal acute respiratory distress syndrome.• High-frequency oscillatory ventilation was associated with a decreased incidence of intraventricular hemorrhage in infants with moderate-to-severe perinatal-onset acute respiratory distress syndrome compared with conventional mechanical ventilation.

Plasma Nucleosomes Are Associated With Mortality in Pediatric Acute Respiratory Distress Syndrome.

Circulating nucleosomes and their component histones have been implicated as pathogenic in sepsis and acute respiratory distress syndrome in adults. However, their role in pediatric acute respiratory distress syndrome is unknown. We performed a prospective cohort study in children with acute respiratory distress syndrome, with plasma collection within 24 hours of acute respiratory distress syndrome onset. We associated nucleosome levels with severity of acute respiratory distress syndrome and with nonpulmonary organ failures and tested for association of nucleosomes with PICU mortality and ventilator-free days at 28 days in univariate and multivariable analyses. We also performed proteomics of DNA-bound plasma proteins in a matched case-control study of septic children with and without acute respiratory distress syndrome in order to identify specific histone proteins elevated in acute respiratory distress syndrome. Large academic tertiary-care PICU. Intubated children meeting Berlin criteria for acute respiratory distress syndrome. None. We enrolled 333 children with acute respiratory distress syndrome, with 69 nonsurvivors (21%). Plasma nucleosomes were correlated with acute respiratory distress syndrome severity and with the number of nonpulmonary organ failures at acute respiratory distress syndrome onset. Nucleosomes were higher (p < 0.001) in nonsurvivors (0.40 [interquartile range, 0.20-0.71] arbitrary units) relative to survivors (0.10 [interquartile range, 0.04-0.25] arbitrary units). Nucleosomes were associated with PICU mortality in multivariable analysis (adjusted odds ratio 1.84 per 1 sd increase; 95% CI, 1.38-2.45; p < 0.001). Nucleosomes were also associated with a lower probability of being extubated alive by day 28 after multivariable adjustment (adjusted subdistribution hazard ratio, 0.74; 95% CI, 0.63-0.88; p = 0.001). Proteomic analysis demonstrated higher levels of the core nucleosome histones H2A, H2B, H3, and H4 in septic children with acute respiratory distress syndrome, relative to septic children without acute respiratory distress syndrome. Plasma nucleosomes are associated with acute respiratory distress syndrome severity, nonpulmonary organ failures, and worse outcomes in pediatric acute respiratory distress syndrome.

ABO blood type: a window into the genetics of acute respiratory distress syndrome susceptibility.

The genetic factors that determine a patient's risk for developing the acute respiratory distress syndrome (ARDS) remain understudied. In this issue of the JCI, Reilly and colleagues analyzed data from three cohorts of critically ill patients and observed an association between the ABO allele A1 and the onset of moderate-severe ARDS. This association was most notable in patients with non-pulmonary sepsis (an indirect, vasculature-targeted mechanism of lung injury) and persisted in patients who lacked epithelial expression of the A antigen, suggesting an endothelial mechanism of A1-associated ARDS susceptibility. Critically ill patients with blood type A had increased circulating concentrations of endothelium-derived glycoproteins such as von Willebrand factor and soluble thrombomodulin, and marginal lungs from blood type A donors were less likely to recover function during ex vivo perfusion. These findings implicate A antigen glycosylation of endothelial cells as a critical, genetically determined risk factor for indirect lung injury that may contribute to the mechanistic heterogeneity of ARDS.

Early high dose corticosteroid therapy in hematopoietic stem cell transplantation patients with acute respiratory distress syndrome: a propensity score matched study.

Background:Acute respiratory distress syndrome (ARDS) is one of the pulmonary complications after hematopoietic cell transplantation (HSCT) with a poor prognosis. The effects of corticosteroid therapy in HSCT patients with ARDS have never been described. In this study, we aim to evaluate the effect of corticosteroid on hospital mortality and other outcomes in patients with HSCT and ARDS.Methods:In this bicenter retrospective study, data were collected from patients diagnosed with ARDS and HSCT. Patients were divided into an early high dose steroids group (receiving a cumulative dose ⩾480 mg of methylprednisolone or its equivalent within the first 3 days after ARDS onset) and a no early high dose steroids group. Univariate and multivariate analyses were used to determine the risk factors of hospital mortality. Cox regression was performed to assess the effect of early high dose steroids on patient survival. A propensity score matched cohort was built to validate the results from the original study cohort.Results:Two hundred and sixty-four patients were included in the original study cohort; 89 (33.71%) patients received early high dose steroids; these patients had higher ventilator free days at day 28 (7.68 ± 4.32 versus 6.48 ± 4.76, p = 0.046); there was no difference in hospital mortality (64.04% versus 53.14%, p = 0.091). Patients with early high dose steroids had a higher incidence of new onset bacteremia (17.98% versus 4%, p < 0.001) and viremia (13.48% versus 3.43%, p = 0.002). The results were further confirmed in the propensity score matched cohort, except for the improvement of ventilator free days (6.02 ± 5.51 versus 5.57 ± 5.54, p = 0.643).Conclusion:In this cohort of HSCT patients with ARDS, early high dose coticosteroids had no effect on hospital mortality. In addition, the incidences of new onset bacteremia and viremia were increased after early high dose steroids. The reviews of this paper are available via the supplemental material section.

Early fibroproliferative signs on high-resolution CT are associated with mortality in COVID-19 pneumonia patients with ARDS: a retrospective study.

Objectives:To investigate the chest high-resolution computed tomography (HRCT) findings in coronavirus disease 2019 (COVID-19) pneumonia patients with acute respiratory distress syndrome (ARDS) and to evaluate its relationship with clinical outcome.Materials and methods:In this retrospective study, 79 COVID-19 patients with ARDS were recruited. Clinical data were extracted from electronic medical records and analyzed. HRCT scans, obtained within 3 days before clinical ARDS onset, were evaluated by three independent observers and graded into six findings according to the extent of fibroproliferation. Multivariable Cox proportional hazard regression analysis was used to assess the independent predictive value of the computed tomography (CT) score and radiological fibroproliferation. Patient survival was determined by Kaplan–Meier analysis.Results:Compared with survivors, non-survivors showed higher rates of lung fibroproliferation, whereas there were no significant differences in the area of increased attenuation without traction bronchiolectasis or bronchiectasis. A HRCT score <230 enabled the prediction of survival with 73.5% sensitivity and 93.3% specificity, 100% negative predictive value (NPP), 83.3% positive predictive value (PPV) and 88.6% accuracy (Area Under the Curve [AUC] = 0.9; 95% confidence Interval [CI] 0.831–0.968). A multivariate Cox proportional hazards model showed that the HRCT score is a significant independent risk factor for mortality (Hazard Ratio [HR] 9.94; 95% CI 4.10–24.12). Kaplan–Meier analysis revealed that a HRCT score ⩾230 was associated with a higher fatality rate. Organ injury occurred less frequently in patients with a HRCT score <230 compared to those with a HRCT score ⩾230.Conclusion:Early pulmonary fibroproliferative signs on HRCT are associated with increased mortality and susceptibility to organ injury in COVID-19 pneumonia patients with early ARDS.

Animal models of COVID-19 hyper-inflammation.

Animal models of COVID-19 hyper-inflammation.

Lower versus higher hemoglobin threshold for transfusion in ARDS patients with and without ECMO

BackgroundEfficacy and safety of different hemoglobin thresholds for transfusion of red blood cells (RBCs) in adults with an acute respiratory distress syndrome (ARDS) are unknown. We therefore assessed the effect of two transfusion thresholds on short-term outcome in patients with ARDS.MethodsPatients who received transfusions of RBCs were identified from a cohort of 1044 ARDS patients. After propensity score matching, patients transfused at a hemoglobin concentration of 8 g/dl or less (lower-threshold) were compared to patients transfused at a hemoglobin concentration of 10 g/dl or less (higher-threshold). The primary endpoint was 28-day mortality. Secondary endpoints included ECMO-free, ventilator-free, sedation-free, and organ dysfunction-free composites.Measurements and main resultsOne hundred ninety-two patients were eligible for analysis of the matched cohort. Patients in the lower-threshold group had similar baseline characteristics and hemoglobin levels at ARDS onset but received fewer RBC units and had lower hemoglobin levels compared with the higher-threshold group during the course on the ICU (9.1 [IQR, 8.7–9.7] vs. 10.4 [10–11] g/dl, P < 0.001). There was no difference in 28-day mortality between the lower-threshold group compared with the higher-threshold group (hazard ratio, 0.94 [95%-CI, 0.59–1.48], P = 0.78). Within 28 days, 36.5% (95%-CI, 27.0–46.9) of the patients in the lower-threshold group compared with 39.5% (29.9–50.1) of the patients in the higher-threshold group had died. While there were no differences in ECMO-free, sedation-free, and organ dysfunction-free composites, the chance for successful weaning from mechanical ventilation within 28 days after ARDS onset was lower in the lower-threshold group (subdistribution hazard ratio, 0.36 [95%-CI, 0.15–0.86], P = 0.02).ConclusionsTransfusion at a hemoglobin concentration of 8 g/dl, as compared with a hemoglobin concentration of 10 g/dl, was not associated with an increase in 28-day mortality in adults with ARDS. However, a transfusion at a hemoglobin concentration of 8 g/dl was associated with a lower chance for successful weaning from the ventilator during the first 28 days after ARDS onset.Trial Registration: ClinicalTrials.gov NCT03871166.

Short Term Metformin Intervention Inhibits IL-6 and IL-1β Secretion and Prevents Acute Respiratory Distress Syndrome-Implications for COVID-19

Acute respiratory distress syndrome (ARDS) is a leading cause of COVID-19 death. Long-term metformin usage decreases COVID-19 mortality through an obscure mechanism unrelated to glycemic control. It is unclear whether and how short-term metformin-based intervention can block acute inflammation. We show that metformin inhibits IL-6 and IL-1β secretion from LPS or SARS-CoV-2 Spike protein primed macrophages undergoing NLRP3 inflammasome activation, a key to ARDS initiation. Reduced IL-6 production correlates with blunted NFAT and C/EBPβ/NFIL-6 activation, whereas inhibition of IL-1β secretion reflects interference with NLRP3 inflammasome activation. By targeting electron transfer chain complex 1, but independently of AMPK and mitophagy, metformin inhibits ATP-dependent mitochondrial DNA synthesis and blocks generation of oxidized mitochondrial DNA, a trigger of inflammasome assembly. Correspondingly, short-term metformin treatment abrogates LPS-induced ARDS, lung macrophage recruitment, damage and mortality. We suggest that metformin, a cheap and safe drug, can be used to prevent ARDS onset in COVID-19 patients.Funding: The UCSD Tissue Technology Shared Resource supported by a National Cancer Institute Cancer Center Support Grant (CCSG P30CA23100). M.A. was supported by NIH (R01AI072726). E.S-L. was supported by NIAMS (K01AR077111). Research was supported by NIH grant awards to M.K. and M.A. (U54CA260591), and M.K. (R01A1043477, P42ES010337), who is an American Cancer Research Society Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases. Conflict of Interest: M.K. is a founder of Elgia Pharmaceuticals and receives research support from Gossamer Bio and Jansen Pharmaceuticals. All other authors declare no competing interests.Ethical Approval: All mouse studies were conducted in accordance with UCSD and NIH guidelines and regulations for the housing and treatment of laboratory animals using protocols approved by the UCSD Institutional Animal Care and Use Committee.

May the neutrophil-to-lymphocyte ratio at admission predict the occurrence and the severity of ARDS after blunt chest trauma patients? A retrospective study.

In blunt chest trauma patients, the activation of inflammatory response is thought to be one of the pathophysiological pathways leading to delayed acute respiratory distress syndrome(ARDS). The main objective of the study was to assess the performance of the neutrophil-lymphocyte ratio(NLR) for prediction of delayed ARDS. The secondary objective was to compare NLR in patients with traumarelated focal and non-focal ARDS. Over a 2-year period, every adult patient triaged to our level 1 trauma center with multiple rib fractures and PaO 2 /FiO 2 ratio>200 at admission were retrospectively included. The NLR was recorded at admission in the Emergency Department(ED). The main study outcome was the occurrence of moderate to severe ARDS within 5days after admission according to Berlin criteria. Two phenotypes (focal and non-focal ARDS) were determined based on the closest chest CT regarding the ARDS onset. 216 patients were included and 42(19%) underwent moderate to severe ARDS within 5days after ED admission (focal, N=26 [12%] and non-focal, N=16 [7%]). The NLR at ED admission was not statistically different between patients who developed or not a delayed ARDS (14±13 vs. 11±8,p=0.095), although patients with non-focal ARDS presented higher NLR ratio than focal ARDS (21±18 p<0.0001). The AUC for NLR at ED in predicting delayed ARDS was 0.53. In blunt chest trauma patients, the NLR at ED admission was unable to predict delayed ARDS over the five first days post-injury. Although not clinically relevant, the NLR was higher in patients with non focal ARDS.

Air pollution impairs recovery and tissue remodeling in a murine model of acute lung injury

Evidence regarding the impact of air pollution on acute respiratory distress syndrome (ARDS) is limited, and most studies focus on ARDS onset. Our study aimed to evaluate whether exposure to fine particulate matter interferes with lung recovery and remodeling in a murine model of acute lung injury. Forty-eight mice received nebulized LPS or the vehicle (controls). Blood, BALF, lungs and spleen were collected after 5 weeks of exposure to either PM2.5 (PM and LPS + PM group) or filtered air (control and LPS5w groups). Inflammatory cells and cytokines were assessed in the blood, BALF, lungs and spleen. Stereological analyses and remodeling assessments were performed by histology. The LPS + PM group showed increased BALF leukocytes, characterized by increased macrophages, increased IL-1β and IL-6 levels, anemia and thrombocytopenia. Moreover, we also observed septal thickening, decreased alveolar air space total volume and, septa surface density. Finally, regarding tissue remodeling, we observed elastosis of the lung parenchyma, and unlike in the LPS5w group, we did not observe fibrosis in the LPS + PM group. In conclusion, the delayed inflammation resolution due to subchronic exposure to PM2.5 could be influenced by low systemic and local lymphocyte counts, which lead to impaired lung injury recovery and tissue remodeling.

Outcomes of COVID-19 in Patients With Lung Cancer Treated in a Tertiary Hospital in Madrid

Background: Cancer patients represent a vulnerable population for COVID-19 illness. We aimed to analyze outcomes of lung cancer patients affected by COVID-19 in a tertiary hospital of a high-incidence region during the pandemic.Methods: We annotated 23 lung cancer patients consecutively diagnosed with COVID-19 at our institution (HGUGM; Madrid, Spain) between March 4th, 2020 and May 12th, 2020. Only patients with a confirmatory SARS-CoV-2 RT-PCR were included in the study.Results: All patients had at least 1 COVID-19 related symptom; cough (48%), shortness of breath (48%), fever (39%), and low-grade fever (30%) were the most common. Time from symptoms onset to first positive SARS-CoV-2 PCR was 5.5 days (range 1–17), with 13% of cases needed from a 2nd PCR to confirm diagnosis. There was a high variability on thoracic imaging findings, with multilobar pneumonia as the most commonly found pattern (74%). Main lab test abnormalities were low lymphocytes count (87%), high neutrophil to lymphocyte ratio -NLR- (78%), and elevated inflammatory markers: fibrinogen (91%), c-reactive protein -CRP- (87%), and D-dimer (70%). In our series, hospitalization rate was 74%, 39% of patients developed acute respiratory distress syndrome (ARDS), and the case-fatality rate was 35% (8/23). 87% of patients received anti-viral treatment (87% hydroxychloroquine, 74% lopinavir/ritonavir, 13% azithromycin), 43% corticosteroids, 26% interferon-β, 4% tocilizumab, and 82% of hospitalized patients received anticoagulation. High-oxygen requirements were needed in 39% of patients, but only 1 pt was admitted for invasive MV and was discharged 42 days after admission. Multiple variables related to tumor status, clinical baseline conditions, and inflammation markers were associated with mortality but did not remain statistically significant in a multivariate model. In patients with lung cancer receiving systemic therapy (n = 242) incidence and mortality from COVID-19 were 4.5, and 2.1%, respectively, with no differences found by type of treatment.Conclusions: Lung cancer patients represent a vulnerable population for COVID-19, according to the high rate of hospitalization, onset of ARDS, and high mortality rate. Although larger series are needed, no differences in mortality were found by type of cancer treatment. Measures to minimize the risk of SARS-CoV-2 infection remain key to protect lung cancer patients.

Clinical characteristics and risk factors for mortality in obstetric patients with severe COVID-19 in Brazil: a surveillance database analysis.

ObjectiveTo describe clinical characteristics of pregnant and postpartum women with severe COVID‐19 in Brazil and to examine risk factors for mortality.DesignCross‐sectional study based on secondary surveillance database analysis.SettingNationwide Brazil.Population or sample978 Brazilian pregnant and postpartum women notified as COVID‐19 Acute Respiratory Distress Syndrome (ARDS) cases with complete outcome (death or cure) up to 18 June 2020.MethodsData was abstracted from the Brazilian ARDS Surveillance System (ARDS‐SS) database. All eligible cases were included. Data on demographics, clinical characteristics, intensive care resources use and outcomes were collected. Risk factors for mortality were examined by multivariate logistic regression.Main outcome measuresCase fatality rate.ResultsWe identified 124 maternal deaths, corresponding to a case fatality rate among COVID‐19 ARDS cases in the obstetric population of 12.7%. At least one comorbidity was present in 48.4% of fatal cases compared with 24.9% in survival cases. Among women who died, 58.9% were admitted to ICU, 53.2% had invasive ventilation and 29.0% had no respiratory support. The multivariate logistic regression showed that the main risk factors for maternal death by COVID‐19 were being postpartum at onset of ARDS, obesity, diabetes and cardiovascular disease, whereas white ethnicity had a protective effect.ConclusionsNegative outcomes of COVID‐19 in this population are affected by clinical characteristics but social determinants of health also seem to play a role. It is urgent to reinforce containment measures targeting the obstetric population and ensure high quality care throughout pregnancy and the postpartum period.Tweetable abstractA total of 124 COVID‐19 maternal deaths were identified in Brazil. Symptoms onset at postpartum and comorbidities are risk factors.

Dexamethasone in Acute Respiratory Distress Syndrome

Synopsis: In patients with moderate-to-severe acute respiratory distress syndrome (ARDS), defined as an arterial oxygen partial pressure/ fractional inspired oxygen (PaO2/FiO2) of 200 mm Hg or less with a positive end-expiratory pressure (PEEP) of 10 cm H2O or greater and FiO2 >0.5, administration of dexamethasone within 24 hours of ARDS onset led to more ventilator-free days, and a reduction of all-cause mortality with no difference in adverse events. Source: Villar, J, Ferrando, C, Martínez, D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicenter, randomised controlled trial. Lancet Respir Med. 2020;8:267–276.

Impact of Polytrauma and Acute Respiratory Distress Syndrome on Markers of Fibrinolysis: A Prospective Pilot Study.

Acute respiratory distress syndrome (ARDS), which is associated with major morbidity and high mortality, is commonly developed by polytraumatized patients. Its pathogenesis is complex, and its development is difficult to anticipate, as candidate biomarkers for the prediction of ARDS were found not to be reliable for clinical use. In this prospective study, we assessed the serum antigen levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor type-1 (PAI-1) of 28 survivors of blunt polytrauma (age ≥18 years; injury severity score ≥16) at admission and on days 1, 3, 5, 7, 10, 14, and 21 of hospitalization. Our results show that these patients presented high mean tPA and PAI-1 antigen levels at admission; despite their decline, these parameters remained elevated for 3 weeks. Over this period, the mean tPA antigen level was higher in polytrauma victims suffering from ARDS than in those without ARDS, whereas the mean PAI-1 level was higher in polytrauma victims sustaining pneumonia than in those without pneumonia. Moreover, in each individual developing ARDS, the polytrauma-related elevated tPA antigen level either continued to rise after admission or suffered a second increase up to the onset of ARDS, declining immediately thereafter. Therefore, our findings support the assessment of serum tPA antigen levels after the initial treatment of polytraumatized patients, as this parameter shows potential as a biomarker for the development of ARDS and for the consequent identification of high-risk individuals.

A pharmacological interactome between COVID-19 patient samples and human sensory neurons reveals potential drivers of neurogenic pulmonary dysfunction

The SARS-CoV-2 virus infects cells of the airway and lungs in humans causing the disease COVID-19. This disease is characterized by cough, shortness of breath, and in severe cases causes pneumonia and acute respiratory distress syndrome (ARDS) which can be fatal. Bronchial alveolar lavage fluid (BALF) and plasma from mild and severe cases of COVID-19 have been profiled using protein measurements and bulk and single cell RNA sequencing. Onset of pneumonia and ARDS can be rapid in COVID-19, suggesting a potential neuronal involvement in pathology and mortality. We hypothesized that SARS-CoV-2 infection drives changes in immune cell-derived factors that then interact with receptors expressed by the sensory neuronal innervation of the lung to further promote important aspects of disease severity, including ARDS. We sought to quantify how immune cells might interact with sensory innervation of the lung in COVID-19 using published data from patients, existing RNA sequencing datasets from human dorsal root ganglion neurons and other sources, and a genome-wide ligand-receptor pair database curated for pharmacological interactions relevant for neuro-immune interactions. Our findings reveal a landscape of ligand-receptor interactions in the lung caused by SARS-CoV-2 viral infection and point to potential interventions to reduce the burden of neurogenic inflammation in COVID-19 pulmonary disease. In particular, our work highlights opportunities for clinical trials with existing or under development rheumatoid arthritis and other (e.g. CCL2, CCR5 or EGFR inhibitors) drugs to treat high risk or severe COVID-19 cases.

Novel paediatric presentation of COVID-19 with ARDS and cytokine storm syndrome without respiratory symptoms.

Novel paediatric presentation of COVID-19 with ARDS and cytokine storm syndrome without respiratory symptoms.

Hyperglycemia, hydroxychloroquine, and the COVID-19 pandemic.

Coronavirus disease‐2019 (COVID‐19) infection and its severity can be explained by the concentration of glycosylated severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) viral particles in the lung epithelium, the concentration of glycosylated angiotensin‐converting enzyme receptor 2 (ACE2) in the lung epithelium, and the degree and control of the pulmonary immune response to the SARS‐CoV‐2 spike protein at approximately day 8 to 10 after symptom onset, which may be related to both. Binding of ACE2 by SARS‐CoV‐2 in COVID‐19 also suggests that prolonged uncontrolled hyperglycemia, and not just a history of diabetes mellitus, may be important in the pathogenesis of the disease. It is tempting to consider that the same mechanism acts in COVID‐19 as in SARS, where an overactive macrophage M1 inflammatory response, as neutralizing antibodies to the SARS‐CoV‐2 spike protein form at day 7 to 10, results in acute respiratory distress syndrome (ARDS) in susceptible patients. It also allows consideration of agents, such as hydroxychloroquine, which may interfere with this overly brisk macrophage inflammatory response and perhaps influence the course of the disease, in particular, those that blunt but do not completely abrogate the M1 to M2 balance in macrophage polarization, as well as viral load, which in SARS appears to be temporally related to the onset of ARDS.

Pulmonary microbiome patterns correlate with the course of disease in patients with sepsis-induced ARDS following major abdominal surgery

Patients with sepsis-induced Acute Respiratory Distress Syndrome (ARDS) are hallmarked by high mortality rates. Early, targeted antibiotic therapy is crucial for patients' survival. The clinical use of a Next Generation Sequencing (NGS)-based approach for pathogen identification may lead to an improved diagnostic performance. Therefore, the objective of this study was to examine changes in the pulmonary-microbiome and resulting influences on patients' outcome in septic ARDS, but also to compare NGS- and culture-based diagnostic methods for pathogen identification. In total, 30 patients in two groups were enrolled in the study: (1) 15 septic ARDS patients following major abdominal surgery and (2) 15 patients undergoing oesophageal resection serving as controls. In the ARDS group, blood samples were collected at ARDS onset as well as 5 days and 10 days afterwards. At the same timepoints, bronchoalveolar lavages (BAL) were performed to collect epithelial lining fluid for culture-, as well as NGS-based analyses and to evaluate longitudinal changes in the pulmonary microbiome. In the control group, only one BAL and one blood sample were collected. ARDS patients showed a significantly reduced α-diversity (p=0.007**) and an increased dominance (p=0.012*) in their pulmonary-microbiome. The α-diversity-index correlated with the length of stay in the intensive care unit (p-value=0.015) and the need for mechanical ventilation (p-value=0.009). In 42.9% of all ARDS patients, culture-based results were negative, while NGS findings indicated bacterial colonization. Sepsis-induced ARDS is associated with a significant dysbiosis of patients' pulmonary-microbiome, which is closely correlated with the clinical course of the disease. This prospective, observational pilot study was approved by the Ethics Committee of the Medical Faculty of Heidelberg (trial code no. S-063/2015) and was prospectively registered in the German clinical trials register (DRKS-ID: DRKS00008317 prospectively registered: 28.10.2015). All study patients or their legal representatives signed written informed consent.