scholarly journals Analysis of pulmonary vascular injury and repair during Pseudomonas aeruginosa infection-induced pneumonia and acute respiratory distress syndrome

2019 ◽  
Vol 9 (1) ◽  
pp. 204589401982694 ◽  
Author(s):  
Ashley S. Lindsey ◽  
Lydia M. Sullivan ◽  
Nicole A. Housley ◽  
Anna Koloteva ◽  
Judy A. King ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Vascular Injury ◽  
Post Infection ◽  
Vascular Function ◽  
Distress Syndrome ◽  
Proliferative Phase ◽  
Injury And Repair

Herein we describe lung vascular injury and repair using a rodent model of Pseudomonas aeruginosa pneumonia-induced acute respiratory distress syndrome (ARDS) during: 1) the exudative phase (48-hour survivors) and 2) the reparative/fibro-proliferative phase (1-week survivors). Pneumonia was induced by intratracheal instillation of P. aeruginosa strain PA103, and lung morphology and pulmonary vascular function were determined subsequently. Pulmonary vascular function was assessed in mechanically ventilated animals in vivo (air dead space, PaO2, and lung mechanics) and lung permeability was determined in isolated perfused lungs ex vivo (vascular filtration coefficient and extravascular lung water). At 48 hours post infection, histological analyses demonstrated capillary endothelial disruption, diffuse alveolar damage, perivascular cuffs, and neutrophil influx into lung parenchyma. Infected animals displayed clinical hallmarks of ARDS, including increased vascular permeability, increased dead space, impaired gas exchange, and decreased lung compliance. Overall, the animal infection model recapitulated the morphological and functional changes typically observed in lungs from patients during the exudative phase of ARDS. At 1 week post infection, there was lung histological and pulmonary vascular functional evidence of repair when compared with 48 hours post infection; however, some parameters were still impaired when compared with uninfected controls. Importantly, lungs displayed increased fibrosis and cellular hyperplasia reminiscent of lungs from patients during the fibro-proliferative phase of ARDS. Control, sham inoculated animals showed normal lung histology and function. These data represent the first comprehensive assessment of lung pathophysiology during the exudative and reparative/fibro-proliferative phases of P. aeruginosa pneumonia-induced ARDS, and position this pre-clinical model for use in interventional studies aimed at advancing clinical care.

scholarly journals Ventilator-associated pneumonia in patients with SARS-CoV-2-associated acute respiratory distress syndrome requiring ECMO: a retrospective cohort study

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Charles-Edouard Luyt ◽  
Tarek Sahnoun ◽  
Melchior Gautier ◽  
Pauline Vidal ◽  
Sonia Burrel ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acute Respiratory Distress Syndrome ◽  
Cohort Study ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Retrospective Cohort Study ◽  
Retrospective Cohort ◽  
Distress Syndrome ◽  
Ventilator Associated Pneumonia ◽  
Historical Cohort

Abstract Background The data on incidence, clinical presentation, and outcomes of ventilator-associated pneumonia (VAP) in patients with severe coronavirus disease 2019 (COVID-19) pneumonia requiring mechanical ventilation (MV) are limited. We performed this retrospective cohort study to assess frequency, clinical characteristics, responsible pathogens, and outcomes of VAP in patients COVID-19 pneumonia requiring MV between March 12th and April 24th, 2020 (all had RT-PCR-confirmed SARS-CoV-2 infection). Patients with COVID-19-associated acute respiratory distress syndrome (ARDS) requiring ECMO were compared with an historical cohort of 45 patients with severe influenza-associated ARDS requiring ECMO admitted to the same ICU during the preceding three winter seasons. Results Among 50 consecutive patients with Covid-19-associated ARDS requiring ECMO included [median (IQR) age 48 (42–56) years; 72% male], 43 (86%) developed VAP [median (IQR) MV duration before the first episode, 10 (8–16) days]. VAP-causative pathogens were predominantly Enterobacteriaceae (70%), particularly inducible AmpC-cephalosporinase producers (40%), followed by Pseudomonas aeruginosa (37%). VAP recurred in 34 (79%) patients and 17 (34%) died. Most recurrences were relapses (i.e., infection with the same pathogen), with a high percentage occurring on adequate antimicrobial treatment. Estimated cumulative incidence of VAP, taking into account death and extubation as competing events, was significantly higher in Covid-19 patients than in influenza patients (p = 0.002). Despite a high P. aeruginosa-VAP rate in patients with influenza-associated ARDS (54%), the pulmonary infection recurrence rate was significantly lower than in Covid-19 patients. Overall mortality was similar for the two groups. Conclusions Patients with severe Covid-19-associated ARDS requiring ECMO had a very high late-onset VAP rate. Inducible AmpC-cephalosporinase-producing Enterobacteriaceae and Pseudomonas aeruginosa frequently caused VAP, with multiple recurrences and difficulties eradicating the pathogen from the lung.

scholarly journals Interleukin-1RA Mitigates SARS-CoV-2–Induced Inflammatory Lung Vascular Leakage and Mortality in Humanized K18-hACE-2 Mice

2021 ◽  
Author(s):  
Shiqin Xiong ◽  
Lianghui Zhang ◽  
Justin M. Richner ◽  
Jake Class ◽  
Jalees Rehman ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Failure ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Vascular Injury ◽  
Distress Syndrome ◽  
Lung Edema ◽  
Edema Formation ◽  
Caspase 1 ◽  
Junction Protein

Objective: SARS-CoV-2 infection is a major cause of morbidity and mortality, often as a result of acute respiratory distress syndrome. Respiratory failure is characterized by a hyperinflammatory immune response, lung vascular injury, and edema formation. The potential for immunomodulatory therapy to prevent lung vascular injury and edema formation is not well understood. Approach and Results: We show that SARS-CoV-2 infection in humanized K18-hACE-2 mice activated inflammatory NLRP3–caspase-1 pyroptotic signaling in lungs, release of IL (interleukin)-1β, and downregulation of the lung endothelial adherens junction protein VE-cadherin. Primary human lung microvascular endothelial cells were susceptible to SARS-CoV-2 infection and displayed pyroptosis-like injury. We observed profound lung vascular injury post–SARS-CoV-2 infection and resultant protein-rich lung edema formation. Selective blockade of IL-1 receptor signaling by IL-1RA (IL-1 receptor antagonist) anakinra prevented downregulation of VE-cadherin, as well as accompanying lung vascular hyperpermeability. IL-1RA also significantly increased survival. Conclusions: These results provide insights into the central role of NLRP3–caspase-1 pyroptotic innate immune signaling and loss of lung endothelial adherens junctions in the mechanism of acute respiratory distress syndrome induced by SARS-CoV-2. Our data show that treatment with IL-1RA during activation of inflammasome provides the ideal scenario for preventing lung vascular injury and respiratory failure in coronavirus disease 2019 (COVID-19).

scholarly journals Pseudomonas Aeruginosa Induced Cell Death in Acute Lung Injury and Acute Respiratory Distress Syndrome

2020 ◽  
Vol 21 (15) ◽  
pp. 5356
Author(s):  
Rushikesh Deshpande ◽  
Chunbin Zou
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Cell Death ◽  
Acute Respiratory Distress Syndrome ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Lung Epithelial ◽  
Epithelial Cell Death

Pseudomonas aeruginosa is an important opportunistic pathogen responsible for the cause of acute lung injury and acute respiratory distress syndrome. P. aeruginosa isthe leading species isolated from patients with nosocomial infection and is detected in almost all the patients with long term ventilation in critical care units. P. aeruginosa infection is also the leading cause of deleterious chronic lung infections in patients suffering from cystic fibrosis as well as the major reason for morbidity in people with chronic obstructive pulmonary disease. P. aeruginosa infections are linked to diseases with high mortality rates and are challenging for treatment, for which no effective remedies have been developed. Massive lung epithelial cell death is a hallmark of severe acute lung injury and acute respiratory distress syndrome caused by P. aeruginosa infection. Lung epithelial cell death poses serious challenges to air barrier and structural integrity that may lead to edema, cytokine secretion, inflammatory infiltration, and hypoxia. Here we review different types of cell death caused by P. aeruginosa serving as a starting point for the diseases it is responsible for causing. We also review the different mechanisms of cell death and potential therapeutics in countering the serious challenges presented by this deadly bacterium.

scholarly journals Rescue therapy with inhaled nitric oxide and almitrine in COVID-19 patients with severe acute respiratory distress syndrome

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
François Bagate ◽  
Samuel Tuffet ◽  
Paul Masi ◽  
François Perier ◽  
Keyvan Razazi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Acute Respiratory Distress Syndrome ◽  
Pilot Study ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Vascular Function ◽  
Distress Syndrome ◽  
Rescue Therapy ◽  
Blood Gases ◽  
Inhaled Nitric Oxide

Abstract Background In COVID-19 patients with severe acute respiratory distress syndrome (ARDS), the relatively preserved respiratory system compliance despite severe hypoxemia, with specific pulmonary vascular dysfunction, suggests a possible hemodynamic mechanism for VA/Q mismatch, as hypoxic vasoconstriction alteration. This study aimed to evaluate the capacity of inhaled nitric oxide (iNO)–almitrine combination to restore oxygenation in severe COVID-19 ARDS (C-ARDS) patients. Methods We conducted a monocentric preliminary pilot study in intubated patients with severe C-ARDS. Respiratory mechanics was assessed after a prone session. Then, patients received iNO (10 ppm) alone and in association with almitrine (10 μg/kg/min) during 30 min in each step. Echocardiographic and blood gases measurements were performed at baseline, during iNO alone, and iNO–almitrine combination. The primary endpoint was the variation of oxygenation (PaO2/FiO2 ratio). Results Ten severe C-ARDS patients were assessed (7 males and 3 females), with a median age of 60 [52–72] years. Combination of iNO and almitrine outperformed iNO alone for oxygenation improvement. The median of PaO2/FiO2 ratio varied from 102 [89–134] mmHg at baseline, to 124 [108–146] mmHg after iNO (p = 0.13) and 180 [132–206] mmHg after iNO and almitrine (p < 0.01). We found no correlation between the increase in oxygenation caused by iNO–almitrine combination and that caused by proning. Conclusion In this pilot study of severe C-ARDS patients, iNO–almitrine combination was associated with rapid and significant improvement of oxygenation. These findings highlight the role of pulmonary vascular function in COVID-19 pathophysiology.

scholarly journals The maladaptive vascular response in COVID-19 acute respiratory distress syndrome and recovery

2021 ◽  
Author(s):  
David R Price ◽  
Elisa Benedetti ◽  
Katherine Hoffman ◽  
Luis Gomez-Escobar ◽  
Sergio Alvarez-Mulett ◽  
...  
Keyword(s):  
At Risk ◽  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Vascular Injury ◽  
Distress Syndrome ◽  
Vascular Response ◽  
Early Signal ◽  
One Year

Vascular injury is a menacing element of acute respiratory distress syndrome (ARDS) pathogenesis. To better understand the role of vascular injury in COVID-19 ARDS, we used lung autopsy immunohistochemistry and blood proteomics from COVID-19 subjects at distinct timepoints in disease pathogenesis, including a hospitalized cohort at risk of ARDS development ("at risk", N=59), an intensive care unit cohort with ARDS ("ARDS", N=31), and a cohort recovering from ARDS ("recovery", N=12). COVID-19 ARDS lung autopsy tissue revealed an association between vascular injury and platelet-rich microthrombi. This link guided the derivation of a protein signature in the at risk cohort characterized by lower expression of vascular proteins in subjects who died, an early signal of vascular limitation termed the maladaptive vascular response. These findings were replicated in COVID-19 ARDS subjects, as well as when bacterial and influenza ARDS patients (N=29) were considered, hinting at a common final pathway of vascular injury that is more disease (ARDS) then cause (COVID-19) specific, and may be related to vascular cell death. Among recovery subjects, our vascular signature identified patients with good functional recovery one year later. This vascular injury signature could be used to identify ARDS patients most likely to benefit from vascular targeted therapies.

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