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Principal Investigator: Timothy E Corcoran
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $198,750
Funding agency: National Heart Lung and Blood Institute
ABSTRACT:
Ventilator associated pneumonias (VAP) are a common complication in mechanically ventilated patients,
occurring more than 250,000 times annually. VAPs occur in a high percentage of mechanically ventilated
patients with acute respiratory distress syndrome (ARDS, 29%) and COVID-19 (>50%). Timely detection and
identification of the pathogen is key to effective treatment, as is differentiating colonization from acute infection.
The most common options for microbiological diagnosis are cultures of endotracheal aspirate or bronchoalveolar
lavage. Sampling aspirate is non-invasive, but the samples are prone to contamination from the proximal
airways. Bronchoalveolar lavage (BAL) allows for sample collection from the distal lung without proximal airway
contamination, but this technique is invasive and cannot be repeated frequently for surveillance. Here we
propose to develop and test a non-invasive, high-efficiency system for collecting exhaled respiratory aerosols
from mechanically ventilated patients. This system will collect large aerosols, typically generated in the proximal
airways, separately from smaller aerosols, which are typically generated in the very distal airways, thus providing
independent samples from these two distinct compartments of the lung. The collection of a sample from the
distal lung will facilitate the correct diagnosis VAP. The system will allow for short sample collection times,
facilitating repeated measures and timely surveillance, and will be developed and tested in an ex vivo human
lung model using culture and non-culture-based methods. We will also evaluate the utility of collected aerosol
samples for surveying the microbial, fungal, and viral community members in the lung (the lung microbiome).
Misbalances in the bacterial communities (respiratory dysbiosis) have been associated with decreased survival
in mechanically ventilated patients and may play a role in both local and systemic inflammation. Finally, we will
evaluate the use of exhaled aerosol samples to indicate host response to infection and lung injury through the
analysis of biomarkers related to endothelial and epithelial permeability, inflammation, and infection. Markers of
host response and lung injury may help to differentiate simple bacterial colonization from acute infection and
VAP. Pneumonia is the leading cause of Acute Respiratory Distress Syndrome (ARDS), an often-lethal
complication involving a complex dysregulated inflammatory response that causes loss of endothelial and
epithelial barrier integrity, resulting in pulmonary edema and respiratory failure. Serial biomarker measurements
from distal lung samples may also elucidate the etiology of ARDS after lung infection.
Terms: <3-10C><42 kDa TNF-inducible gene product><AMCF-I><ARDS><Acute><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Aerosols><Airway failure><Albumins><Assay><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Bacterial Infections><Bioassay><Biological><Biological Assay><Biological Markers><Bronchioalveolar Lavage><Bronchoalveolar Lavage><Bronchopulmonary Lavage><CD 120a Antigen><CD120a Antigens><COPD><COVID-19><CSIF><CSIF-10><CV-19><CXCL8><Causality><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Collection><Communities><Complex><Complication><Coronavirus Infectious Disease 2019><Cytokine Synthesis Inhibitory Factor><Da Nang Lung><Detection><Devices><Diagnosis><Distal><Dysfunction><Early Diagnosis><Early identification><Endothelium><Epithelium><Etiology><Evolution><Exhalation><Exhaling><Fibrosing Alveolitis><Functional Metagenomics><Functional disorder><GCP1><GDF15><GDF15 gene><Gene Transcription><Genetic Transcription><Goals><HPGF><Hepatocyte-Stimulating Factor><Human><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-10><IL-6><IL-8><IL10><IL10A><IL6 Protein><IL8><IL8 gene><Immune response><Immunological response><Infection><Inflammation><Inflammatory><Inflammatory Response><Interleukin 10 Precursor><Interleukin-10><Interleukin-6><K60><Label><Lung><Lung Lavage><Lung Respiratory System><Lung damage><Lung infections><MGI-2><MIC-1 gene product><MIC1><Macrophage Inhibitory Cytokine-1><Measurement><Measures><Mechanical ventilation><Metagenomics><Methods><Modeling><Modern Man><Myeloid Differentiation-Inducing Protein><NAG-1 protein><NAG1><NSAID activated gene-1 product><NSAID-Activated Protein 1><NSAID-Regulated Protein 1><Nonsteroidal Anti-Inflammatory Drug-Activated Protein 1><PLAB><PLAB Protein><PTGF-Beta><PTX3 protein><Pathogen detection><Patients><Performance><Perfusion><Permeability><Physiopathology><Placental Bone Morphogenic Protein><Placental TGF-Beta><Plasmacytoma Growth Factor><Pneumonia><Prostate Differentiation Factor><Pulmonary Edema><RNA Expression><Radiolabeled><Recovery><Respiratory Expiration><Respiratory Failure><Ribosomal RNA Genes><SCYB8><Sampling><Shock Lung><Stiff lung><Survey Instrument><Surveys><System><TNF Receptor p55><TNF-sR55><TNF-stimulated gene 14 product><TNF-α receptor><TNFAR><TNFR p60><TNFR, 55-kD><TNFR, 60-kD><TNFR-I><TNFR1><TNFR55><TNFR60><TNFRSF1A><TNFRSF1A Receptor><TNFRSF1A gene><TNFalpha receptor><TNFα receptor><TSG-1><TSG-14 protein><Techniques><Testing><Transcription><Tube><Tumor Necrosis Factor Receptor 1><Tumor Necrosis Factor Receptor 55><Ventilator><Viral><acute infection><airway aerosol><aspirate><b-ENAP><bacteria infection><bacterial community><bacterial disease><bio-markers><biologic><biologic marker><biomarker><bronchopulmonary lavage therapy><calcitonin precursor polyprotein><candidate biomarker><candidate marker><causation><chronic obstructive pulmonary disorder><clinical decision-making><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cytokine><design><designing><diffuse interstitial pulmonary fibrosis><disease causation><dysbacteriosis><dysbiosis><dysbiotic><early detection><effective therapy><effective treatment><endothelial dysfunction><endotracheal><experiment><experimental research><experimental study><experiments><growth differentiation factor 15><host response><idiopathic pulmonary fibrosis><immune system response><immunoresponse><interferon beta 2><lung edema><lung injury><lung microbiome><mechanical respiratory assist><mechanically ventilated><member><microbial><microbial imbalance><pathogen><pathophysiology><pentraxin 3><pentraxin-related protein 3><potential biological marker><potential biomarker><pro-calcitonin><procalcitonin><pulmonary><pulmonary damage><pulmonary infections><pulmonary injury><pulmonary microbiome><pulmonary tissue damage><pulmonary tissue injury><rRNA Genes><radiolabeling><radiologically labeled><respiratory><respiratory aerosol><sample collection><specimen collection><systemic inflammation><systemic inflammatory response><tumor necrosis factor alpha receptor><tumor necrosis factor receptor 1A><tumor necrosis factor α receptor><ventilation><ventilator-acquired pneumonia><ventilator-associated pneumonia><wet lung>