Daily Respiratory Research Analysis

Inhaled therapies or delivery of pharmacological aerosols to the respiratory tract are central to medicine and more specifically, respiratory diseases. As such, in vitro aerosol exposure systems have become indispensable for initial drug screening and toxicity evaluation. While differentiated airway epithelial cell cultures at air-liquid interface (ALI) effectively model the respiratory tract, conventional exposure methods, such as adding dissolved compounds to culture media or bulk application to the apical surface, fail to replicate physiological aerosol deposition. These approaches either ignore polarized cellular responses or disrupt the ALI, causing hypoxic conditions that may alter toxicity and efficacy outcomes. While several commercial in vitro aerosol exposure systems are available, they can be cost-prohibitive, contain proprietary components, have limited throughput, and are not adaptable to different conditions. Therefore, open-source, standardized methods for in vitro aerosol delivery are urgently needed to accelerate innovation in respiratory toxicology and drug development. To address these limitations, we developed OPADA (On-Plate Aerosol Delivery Array), a novel open-source system for in vitro evaluation of inhaled drugs and toxicants. OPADA advances previous open-source designs by increasing deposition efficiency and enabling simultaneous multi-well, multi-compound exposures, enhancing throughput and experimental flexibility. We validated OPADA through proof-of-principle experiments demonstrating uniform and reproducible deposition. Furthermore, we confirmed OPADA's biological relevance using inhaled delivery of a nutraceutical (calcitriol) in airway epithelial cells at ALI, and pharmacokinetic evaluation of aerosolized pirfenidone in a complex donor-matched co-culture system. These findings establish OPADA as an effective, reproducible platform for in vitro evaluation of inhaled compounds.

BACKGROUND: To enhance biological understanding of acute respiratory distress syndrome (ARDS), pneumonia, and sepsis and accelerate therapeutic development in these areas, the National Institutes of Health developed the ARDS, Pneumonia, and Sepsis (APS) Consortium. RESEARCH QUESTION: Is the APS Consortium study rapidly generating data and biospecimens from a large cohort of critically ill adults with ARDS, pneumonia, and sepsis that will facilitate phenotyping of these syndromes? STUDY DESIGN AND METHODS: The APS Consortium Phenotyping Study is a multicenter longitudinal prospective observational cohort study aimed at enrolling 4,000 critically ill adults with ARDS, pneumonia, and/or sepsis over 4 years. Data and biospecimens are collected to characterize many aspects of each participant's chronic health, acute illness, and long-term recovery to facilitate phenotyping-that is, subclassifying ARDS, pneumonia, and sepsis into precise biologically-based subsets with shared pathophysiology. Feasibility of the study was assessed by evaluating the first 1,000 participants in terms of recruitment pace, participant characteristics, biospecimen collection, and proportion with confirmed ARDS, pneumonia, and sepsis based on expert adjudication. RESULTS: The first 1,000 participants were recruited ahead of schedule in less than 13 months. Median age was 64 years, 75% received vasopressors, 50% received invasive mechanical ventilation, and 25% died in the hospital within 4 weeks of enrollment. Biospecimen collection rates were high, with 99% of participants with blood, 98% with upper respiratory swabs, 37% with lower respiratory samples, 80% with urine, and 65% with gastrointestinal samples. Expert adjudication resulted in 40% classified with ARDS, 52% with pneumonia, and 89% with sepsis. INTERPRETATION: The APS Consortium Phenotyping Study is producing a cohort of critically ill adults with ARDS, pneumonia, and sepsis with high severity of disease and a rich set of data and biospecimens. The study will continue to full enrollment of 4,000 participants. REGISTRATION: Clinicaltrials.gov NCT06521502.

Acute exacerbations (AEs) occur both in patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic interstitial lung disease (fILD). These events confer high morbidity and mortality, with a lack of proven effective therapeutic interventions. The objective of this state-of-the-art document is to summarize latest evidence since the 2016 international working group report on AE-IPF, expanding it across the spectrum of all fILDs. A comprehensive literature review on the epidemiology, associated and risk factors, prognosis, and management of AE-fILD is summarized. In addition to revising the AE definition and diagnostic criteria for broad application across different fILDs, a conceptual framework for acute respiratory worsening (ARW) has been proposed to encompass a variety of acute respiratory deteriorations, both related and unrelated to AE. This allows structured evaluation in both clinical and research settings. The proposed revised definition for AE-fILD is an acute respiratory event characterized by increased respiratory symptoms or signs and associated with radiologic or histologic features consistent with diffuse alveolar damage (with or without superimposed organizing pneumonia) in a patient with known or newly diagnosed fILD. On the other hand, ARW refers to a heterogeneous group of clinical events with acute symptom worsening not attributable to DAD in patients with fILD, such as pulmonary edema, bronchitis, and pneumonia, although severe pneumonia can trigger AE-fILD. Additionally, we discuss considerations for inclusion of AE as a clinical trial endpoint, as well as research priorities for advancing knowledge on the pathogenic mechanisms, event prediction, risk stratification, and development of drugs and supportive treatments.