The preclinical and phase 1 development of the novel oral cathepsin C inhibitor BI 1291583.

Preclinical and phase 1 study results indicate that BI 1291583 is a reversible, highly potent and highly selective CatC inhibitor that markedly inhibits active NSP production in a dose-dependent manner, supporting phase 2 trials in bronchiectasis patients https://bit.ly/47PZ8E5.

Alveolar membrane and capillary function in COVID-19 convalescents: insights from chest MRI.

OBJECTIVES: To investigate potential presence and resolution of longer-term pulmonary diffusion limitation and microvascular perfusion impairment in COVID-19 convalescents. MATERIALS AND METHODS: This prospective, longitudinal study was carried out between May 2020 and April 2023. COVID-19 convalescents repeatedly and age/sex-matched healthy controls once underwent MRI including hyperpolarized 129Xe MRI. Blood samples were obtained in COVID-19 convalescents for immunophenotyping. Ratios of 129Xe in red blood cells (RBC), tissue/plasma (TP), and gas phase (GP) as well as lung surface-volume ratio were quantified and correlations with CD4+/CD8+ T cell frequencies were assessed using Pearson's correlation coefficient. Signed-rank tests were used for longitudinal and U tests for group comparisons. RESULTS: Thirty-five participants were recruited. Twenty-three COVID-19 convalescents (age 52.1 ± 19.4 years, 13 men) underwent baseline MRI 12.6 ± 4.2 weeks after symptom onset. Fourteen COVID-19 convalescents underwent follow-up MRI and 12 were included for longitudinal comparison (baseline MRI at 11.5 ± 2.7 weeks and follow-up 38.0 ± 5.5 weeks). Twelve matched controls were included for comparison. In COVID-19 convalescents, RBC-TP was increased at follow-up (p = 0.04). Baseline RBC-TP was lower in patients treated on intensive care unit (p = 0.03) and in patients with severe/critical disease (p = 0.006). RBC-TP correlated with CD4+/CD8+ T cell frequencies (R = 0.61/ - 0.60) at baseline. RBC-TP was not significantly different compared to matched controls at follow-up (p = 0.25). CONCLUSION: Impaired microvascular pulmonary perfusion and alveolar membrane function persisted 12 weeks after symptom onset and resolved within 38 weeks after COVID-19 symptom onset. CLINICAL RELEVANCE STATEMENT: 129Xe MRI shows improvement of microvascular pulmonary perfusion and alveolar membrane function between 11.5 ± 2.7 weeks and 38.0 ± 5.5 weeks after symptom onset in patients after COVID-19, returning to normal in subjects without significant prior disease. KEY POINTS: • The study aims to investigate long-term effects of COVID-19 on lung function, in particular gas uptake efficiency, and on the cardiovascular system. • In COVID-19 convalescents, the ratio of 129Xe in red blood cells/tissue plasma increased longitudinally (p = 0.04), but was not different from matched controls at follow-up (p = 0.25). • Microvascular pulmonary perfusion and alveolar membrane function are impaired 11.5 weeks after symptom onset in patients after COVID-19, returning to normal in subjects without significant prior disease at 38.0 weeks.

Feasibility, Repeatability, and Correlation to Lung Function of Phase-Resolved Functional Lung (PREFUL) MRI-derived Pulmonary Artery Pulse Wave Velocity Measurements.

BACKGROUND: Pulse wave velocity (PWV) in the pulmonary arteries (PA) is a marker of vascular stiffening. Currently, only phase-contrast (PC) MRI-based options exist to measure PA-PWV. PURPOSE: To test feasibility, repeatability, and correlation to clinical data of Phase-Resolved Functional Lung (PREFUL) MRI-based calculation of PA-PWV. STUDY TYPE: Retrospective. SUBJECTS: 79 (26 female) healthy subjects (age range 19-78), 58 (24 female) patients with chronic obstructive pulmonary disease (COPD, age range 40-77), 60 (33 female) patients with suspected pulmonary hypertension (PH, age range 28-85). SEQUENCE: 2D spoiled gradient echo, 1.5T. ASSESSMENT: PA-PWV was measured from PREFUL-derived cardiac cycles based on the determination of temporal and spatial distance between lung vasculature voxels using a simplified (sPWV) method and a more comprehensive (cPWV) method including more elaborate distance calculation. For 135 individuals, PC MRI-based PWV (PWV-QA) was measured. STATISTICAL TESTS: Intraclass-correlation-coefficient (ICC) and coefficient of variation (CoV) were used to test repeatability. Nonparametric tests were used to compare cohorts. Correlation of sPWV/cPWV, PWV-QA, forced expiratory volume in 1 sec (FEV1 ) %predicted, residual volume (RV) %predicted, age, and right heart catheterization (RHC) data were tested. Significance level α = 0.05 was used. RESULTS: sPWV and cPWV showed no significant differences between repeated measurements (P-range 0.10-0.92). CoV was generally lower than 15%. COPD and PH patients had significantly higher sPWV and cPWV than healthy subjects. Significant correlation was found between sPWV or cPWV and FEV1 %pred. (R = -0.36 and R = -0.44), but not with RHC (P-range -0.11 - 0.91) or age (P-range 0.23-0.89). Correlation to RV%pred. was significant for cPWV (R = 0.42) but not for sPWV (R = 0.34, P = 0.055). For all cohorts, sPWV and cPWV were significantly correlated with PWV-QA (R = -0.41 and R = 0.48). DATA CONCLUSION: PREFUL-derived PWV is feasible and repeatable. PWV is increased in COPD and PH patients and correlates to airway obstruction and hyperinflation. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Quantifying Exhaled Particles in Healthy Humans During Various Respiratory Activities Under Realistic Conditions.

Background: Quantitatively collecting and characterizing exhaled aerosols is vital for infection risk assessment, but the entire droplet size spectrum has often been neglected. We analyzed particle number and size distribution of healthy participants in various respiratory activities, considering inter-individual variability, and deployed a simplified far-field model to inform on infection risks. Methods: Participants repeated the same respiratory activities on two visits. Particles were collected using an airtight extraction helmet supplied with High Efficiency Particulate Air (HEPA) filtered air. The sampling volume flow was transported to two particle counters covering the small and large particle spectrum. The applied simple mass balance model included respiratory activity, viral load, room size, and air exchange rates. Results: Thirty participants completed the study. The major fraction of the number-based size distribution was <5 µm in all respiratory activities. In contrast, the major fraction of the volume-based size distribution was 2-12 µm in tidal breathing, but >60 µm in all other activities. Aerosol volume flow was lowest in tidal breathing, 10-fold higher in quiet/normal speaking, deep breathing, coughing, and 100-fold higher in loud speaking/singing. Intra-individual reproducibility was high. Between participants, aerosol volume flow varied by two orders of magnitude in droplets <80 µm, and three orders of magnitude in droplets >80 µm. Simple model calculations not accounting for potential particle size-dependent differences in viral load and infection-related differences were used to model airborne pathogen concentrations. Conclusions: Quantitative analysis of exhaled aerosols for the entire droplet size spectrum as well as the variability in aerosol emission between individuals provides information that can support infection research. Clinical Trial Registration number: NCT04771585.

Transcriptomic characterization of the human segmental endotoxin challenge model.

Segmental instillation of lipopolysaccharide (LPS) by bronchoscopy safely induces transient airway inflammation in human lungs. This model enables investigation of pulmonary inflammatory mechanisms as well as pharmacodynamic analysis of investigational drugs. The aim of this work was to describe the transcriptomic profile of human segmental LPS challenge with contextualization to major respiratory diseases. Pre-challenge bronchoalveolar lavage (BAL) fluid and biopsies were sampled from 28 smoking, healthy participants, followed by segmental instillation of LPS and saline as control. Twenty-four hours post instillation, BAL and biopsies were collected from challenged lung segments. Total RNA of cells from BAL and biopsy samples were sequenced and analysed for differentially expressed genes (DEGs). After challenge with LPS compared with saline, 6316 DEGs were upregulated and 241 were downregulated in BAL, but only one DEG was downregulated in biopsy samples. Upregulated DEGs in BAL were related to molecular functions such as "Inflammatory response" or "chemokine receptor activity", and upregulated pro-inflammatory pathways such as "Wnt-"/"Ras-"/"JAK-STAT" "-signaling pathway". Furthermore, the segmental LPS challenge model resembled aspects of the five most prevalent respiratory diseases chronic obstructive pulmonary disease (COPD), asthma, pneumonia, tuberculosis and lung cancer and featured similarities with acute exacerbations in COPD (AECOPD) and community-acquired pneumonia. Overall, our study provides extensive information about the transcriptomic profile from BAL cells and mucosal biopsies following LPS challenge in healthy smokers. It expands the knowledge about the LPS challenge model providing potential overlap with respiratory diseases in general and infection-triggered respiratory insults such as AECOPD in particular.

Aerosol Plumes of Inhalers Used in COPD.

INTRODUCTION: The selection of inhaler device is of critical importance in chronic obstructive pulmonary disease (COPD) as the interaction between a patient's inhalation profile and the aerosol characteristics of an inhaler can affect drug delivery and lung deposition. This study assessed the in vitro aerosol characteristics of inhaler devices approved for the treatment of COPD, including a soft mist inhaler (SMI), pressurized metered-dose inhalers (pMDIs), and dry powder inhalers (DPIs). METHODS: High-speed video recording was used to visualize and measure aerosol velocity and spray duration for nine different inhalers (one SMI, three pMDIs, and five DPIs), each containing dual or triple fixed-dose combinations of long-acting muscarinic receptor antagonists and long-acting ß2-agonists, with or without an inhaled corticosteroid. Measurements were taken in triplicate at experimental flow rates of 30, 60, and 90 l/min. Optimal flow rates were defined based on pharmacopoeial testing requirements: 30 l/min for pMDIs and SMIs, and the rate achieving a 4-kPa pressure drop against internal inhaler resistance for DPIs. Comparison of aerosol plumes was based on the experimental flow rates closest to the optimal flow rates. RESULTS: The Respimat SMI had the slowest plume velocity (0.99 m/s) and longest spray duration (1447 ms) compared with pMDIs (velocity: 3.65-5.09 m/s; duration: 227-270 ms) and DPIs (velocity: 1.43-4.60 m/s; duration: 60-757 ms). With increasing flow rates, SMI aerosol duration was unaffected, but velocity increased (maximum 2.63 m/s), pMDI aerosol velocity and duration were unaffected, and DPI aerosol velocity tended to increase, with a more variable impact on duration. CONCLUSIONS: Aerosol characteristics (velocity and duration of aerosol plume) vary by inhaler type. Plume velocity was lower and spray duration longer for the SMI compared with pMDIs and DPIs. Increasing experimental flow rate was associated with faster plume velocity for DPIs and the SMI, with no or variable impact on plume duration, whereas pMDI aerosol velocity and duration were unaffected by increasing flow rate.

Exhaled breath particles as a novel tool to study lipid composition of epithelial lining fluid from the distal lung.

BACKGROUND: Surfactant phospholipid (PL) composition plays an important role in lung diseases. We compared the PL composition of non-invasively collected exhaled breath particles (PEx) with bronchoalveolar lavage (BAL) and induced sputum (ISP) at baseline and following endotoxin (LPS) challenges. METHODS: PEx and BAL were collected from ten healthy nonsmoking participants before and after segmental LPS challenge. Four weeks later, PEx and ISP were sampled in the week before and after a whole lung LPS inhalation challenge. PL composition was analysed using mass spectrometry. RESULTS: The overall PL composition of BAL, ISP and PEx was similar, with PC(32:0) and PC(34:1) representing the largest fractions in all three sample types (baseline PC(32:0) geometric mean mol%: 52.1, 56.9, and 51.7, PC(34:1) mol%: 11.7, 11.9 and 11.4, respectively). Despite this similarity, PEx PL composition was more closely related to BAL than to ISP. For most lipids comparable inter-individual differences in BAL, ISP, and PEx were found. PL composition of PEx was repeatable. The most pronounced increase following segmental LPS challenge was detected for SM(d34:1) in BAL (0.24 to 0.52 mol%) and following inhalation LPS challenge in ISP (0.45 to 0.68 mol%). An increase of SM(d34:1) following segmental LPS challenge was also detectable in PEx (0.099 to 0.103 mol%). The inhalation challenge did not change PL composition of PEx. CONCLUSION: Our data supports the peripheral origin of PEx. The lack of PL changes in PEx after inhalation challenge might to be due to the overall weaker response of inhaled LPS which primarily affects the larger airways. Compared with BAL, which always contains lining fluid from both peripheral lung and central airways, PEx analysis might add value as a selective and non-invasive method to investigate peripheral airway PL composition. TRIAL REGISTRATION: NCT03044327, first posted 07/02/2017.

Compartment-specific 129Xe HyperCEST z spectroscopy and chemical shift imaging of cucurbit[6]uril in spontaneously breathing rats.

129Xe hyperpolarized gas chemical exchange saturation transfer (HyperCEST) MRI has been suggested as molecular imaging modality but translation to in vivo imaging has been slow, likely due to difficulties of synthesizing suitable molecules. Cucurbit[6]uril-either in readily available non-functionalized or potentially in functionalized form-may, combined with 129Xe HyperCEST MRI, prove useful as a switchable 129Xe MR contrast agent but the likely differential properties of contrast generation in individual chemical compartments as well as the influence of 129Xe signal drifts encountered in vivo on HyperCEST MRI are unknown. Here, HyperCEST z spectroscopy and chemical shift imaging with compartment-specific analysis are performed in a total of 10 rats using cucurbit[6]uril injected i.v. and under a protocol employing spontaneous respiration. Differences in intensity of the HyperCEST effect between chemical compartments and anatomical regions are investigated. Strategies to mitigate influence of signal instabilities associated with drifts in physiological parameters are developed. It is shown that presence of cucurbit[6]uril can be readily detected under spontaneous 129Xe inhalation mostly in aqueous tissues further away from the lung. Differences of effect intensity in individual regions and compartments must be considered in HyperCEST data interpretation. In particular, there seems to be almost no effect in lipids. 129Xe HyperCEST MR measurements utilizing spontaneous respiration protocols and extended measurement times are feasible. HyperCEST MRI of non-functionalized cucurbit[6]uril may create contrast between anatomical structures in vivo.

Sodium Chloride versus Lactose as a Carrier for House Dust Mite Allergen in Allergen Chamber Studies: A Clinical Study to Assess Noninferiority.

INTRODUCTION: In the Fraunhofer allergen challenge chamber (ACC), a standardized, universal, good manufacturing practice-conforming technology using a spray dried solution of lactose (L) and allergen extract has been established. In this study, we investigated the noninferiority of hypertonic sodium chloride (S) versus L as a carrier for house dust mite (HDM) allergen to simplify manufacturing, reduce costs, and allow for wider use. METHODS: Using a participant-blinded, sham exposure-controlled, single-arm, sequential intervention study, we challenged adults with HDM allergic rhinitis five times in the ACC. Participants were first exposed to S, L, and clean air (block 1), followed by S + HDM and L + HDM (block 2). Primary endpoints were mean total nasal symptom score (TNSS) and mean nasal secretion weight. RESULTS: 19 participants were enrolled in the study (10 females; mean age 32 years [22-49], 4 with mild allergic asthma). The safety profile of S + HDM and L + HDM was similar; eight participants experienced mild procedure-related adverse events including tiredness, cough, and dyspnea. Due to dropouts, 13 participants completed the study and were evaluated. Mean TNSS and nasal secretion were as follows: S 0.98, 0.28 g; L 1.1, 0.20 g; clean air 1.1, 0.23 g; S + HDM 5.7, 4.8 g; L + HDM 5.1, 5.1 g. Separate block 1/block 2 MANOVAs with TNSS and nasal secretion as dependent variables revealed no significant differences between the carriers, neither alone and compared with clean air (p = 0.2059, Wilk's λ = 0.78) nor combined with HDM (p = 0.3474, Wilk's λ = 0.89). Noninferiority of S was established using a meta-analysis-based minimal clinical important difference of -0.55: mean TNSS difference between S + HDM and L + HDM was 0.62 (90% CI: -0.51 to 1.74). CONCLUSION: S as an HDM carrier was safe and well tolerated. It was noninferior to L which makes it an adequate and easy-to-use carrier substitute.

The effect of bradykinin 1 receptor antagonist BI 1026706 on pulmonary inflammation after segmental lipopolysaccharide challenge in healthy smokers.

BACKGROUND: Bradykinin 1 receptor (B1R) signalling pathways may be involved in the inflammatory pathophysiology of chronic obstructive pulmonary disease (COPD). B1R signalling is induced by inflammatory stimuli or tissue injury and leads to activation and increased migration of pro-inflammatory cells. Lipopolysaccharide (LPS) lung challenge in man is an experimental method of exploring inflammation in the lung whereby interference in these pathways can help to assess pharmacologic interventions in COPD. BI 1026706, a potent B1R antagonist, was hypothesized to reduce the inflammatory activity after segmental lipopolysaccharide (LPS) challenge in humans due to decreased pulmonary cell influx. METHODS: In a monocentric, randomized, double-blind, placebo-controlled, parallel-group, phase I trial, 57 healthy, smoking subjects were treated for 28 days with either oral BI 1026706 100 mg bid or placebo. At day 21, turbo-inversion recovery magnitude magnetic resonance imaging (TIRM MRI) was performed. On the last day of treatment, pre-challenge bronchoalveolar lavage fluid (BAL) and biopsies were sampled, followed by segmental LPS challenge (40 endotoxin units/kg body weight) and saline control instillation in different lung lobes. Twenty-four hours later, TIRM MRI was performed, then BAL and biopsies were collected from the challenged segments. In BAL samples, cells were differentiated for neutrophil numbers as the primary endpoint. Other endpoints included assessment of safety, biomarkers in BAL (e.g. interleukin-8 [IL-8], albumin and total protein), B1R expression in lung biopsies and TIRM score by MRI as a measure for the extent of pulmonary oedema. RESULTS: After LPS, but not after saline, high numbers of inflammatory cells, predominantly neutrophils were observed in the airways. IL-8, albumin and total protein were also increased in BAL samples after LPS challenge as compared with saline control. There were no significant differences in cells or other biomarkers from BAL in volunteers treated with BI 1026706 compared with those treated with placebo. Unexpectedly, neutrophil numbers in BAL were 30% higher and MRI-derived extent of oedema was significantly higher with BI 1026706 treatment compared with placebo, 24 h after LPS challenge. Adverse events were mainly mild to moderate and not different between treatment groups. CONCLUSIONS: Treatment with BI 1026706 for four weeks was safe and well-tolerated in healthy smoking subjects. BI 1026706 100 mg bid did not provide evidence for anti-inflammatory effects in the human bronchial LPS challenge model. TRIAL REGISTRATION: The study was registered on January 14, 2016 at ClinicalTrials.gov (NCT02657408).

Pharmacokinetics of Nasal Esketamine in Patients with Allergic Rhinitis with and Without Nasal Decongestant Pretreatment and in Healthy Subjects with and Without Nasal Corticosteroid Pretreatment.

BACKGROUND AND OBJECTIVES: Nasal esketamine is indicated for the treatment of adults with treatment-resistant depression and depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Primary objectives of this study were to evaluate the effect of nasal decongestant pretreatment in patients with allergic rhinitis and the impact of daily nasal corticosteroid administration by healthy subjects on nasal esketamine pharmacokinetics. METHODS: Patients with allergic rhinitis self-administered 56 mg of nasal esketamine after pretreatment with nasal oxymetazoline (0.05%) at 1 h before esketamine and without oxymetazoline pretreatment. They were exposed to grass pollen in an allergen challenge chamber to induce allergic rhinitis symptoms at approximately 2 h before each esketamine administration until 1 h after. Healthy subjects self-administered esketamine (56 mg) before and after administration for 16 consecutive days of mometasone (200 µg), with the second esketamine dose administered 1 h after the last mometasone dose. The plasma pharmacokinetics of esketamine and noresketamine were assessed after each esketamine administration. The tolerability of esketamine, including effects on dissociative and potential psychotomimetic symptoms and level of sedation and suicidal ideation and behavior, was evaluated. RESULTS: The rate of esketamine absorption was slightly greater in patients exhibiting symptoms of allergic rhinitis (decrease in median tmax from 32 min to 22 min). Increases in esketamine Cmax and AUC were also small (mean, ≤ 21%). The pharmacokinetics of esketamine was not affected by oxymetazoline or mometasone pretreatment. Esketamine was well tolerated when it was administered with or without pretreatment of oxymetazoline or mometasone. CONCLUSIONS: Patients exhibiting symptoms of rhinitis may receive nasal esketamine spray without dose adjustment. In addition, esketamine may be administered 1 h after using a nasal decongestant or corticosteroid. TRIAL REGISTRATION: The study was registered in the Clinical Trials (NCT02154334) and EudraCT (2014-000534-38) registries.

Ultrastructural analysis of the intracellular surfactant in lungs of healthy and ovalbumin sensitized and challenged Brown Norway rats.

Introduction: In human and experimentally induced asthma, a dysfunction of the intra-alveolar-surface active agent (surfactant) has been demonstrated. Type II alveolar epithelial cells (AEII) synthesize, secrete and recycle surfactant. Prior to secretion, intracellular surfactant is stored in specific secretory organelles of AEII. The lamellar bodies (Lb) represent its ultrastructural correlate. The aim of this study was to investigate whether disturbances of the intra-alveolar surfactant are accompanied by alterations in the intracellular surfactant.Material and Methods: Brown-Norway rats were sensitized twice with ovalbumin (OVA) and heat killed Bordetella pertussis bacilli. During airway challenge, an aerosol of 5% ovalbumin/saline solution (0.25 l/min) was nebulized. 24 h after airway challenge, lungs were fixed by vascular perfusion. AEII and their Lb were characterized stereologically by light and electron microscopy.Results: In both groups, AEII were structurally intact. The number of AEII per lung and their number-weighted mean volume did not differ (controls: 49 × 106, 393 µm3; asthmatics: 44 × 106, 390 µm3). A mean of 90 Lb in AEII of asthmatics and of 93 Lb in AEII of controls were evaluated. The Lb mean total volume was 59 µm in asthmatics and 68 µm in controls. Values of both parameters did not reach significance. Also, the size distribution and mean volume of Lb was not influenced by asthma induction, because the volume weighted mean volume of Lb (2.18 µm in asthmatics compared to 1.87 µm in controls) and the numerical weighted mean volume (0.96 µm in asthmatics and 0.75 µm in controls) were comparable in both groups.Conclusion: The obtained results suggest that asthma-induced surfactant dysfunction is not related to disturbances in the intracellular surfactant´s ultrastructural correlates.

Occupational exposure to veterinary antibiotics: Pharmacokinetics of enrofloxacin in humans after dermal, inhalation and oral uptake - A clinical study.

Occupational exposure to veterinary antibiotics in hen houses at poultry feeding farms was demonstrated by biomonitoring campaigns in the past. The objective of this study was to investigate pharmacokinetics of three uptake routes: dermal, oral and inhaled. In an open-label cross-over study, six healthy volunteers were exposed to single occupational relevant doses of enrofloxacin. Plasma and urine samples were analysed for enrofloxacin and ciprofloxacin. Physiologically based pharmacokinetic (PBPK) modelling based on bioanalysis data showed underestimation for the elimination rate in comparison to experimental data pointing towards a lack of sufficient ADME information and limitations of available physico-chemical properties of the parent drug. The data obtained in this study indicate that oral uptake with its various sources, e.g. airborne enrofloxacin, direct hand-mouth contact, is the major source for occupational exposure to enrofloxacin in hen houses. Dermal exposure was considered negligible.

International consensus statement on allergy and rhinology: Allergic rhinitis - 2023.

BACKGROUND: In the 5 years that have passed since the publication of the 2018 International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (ICAR-Allergic Rhinitis 2018), the literature has expanded substantially. The ICAR-Allergic Rhinitis 2023 update presents 144 individual topics on allergic rhinitis (AR), expanded by over 40 topics from the 2018 document. Originally presented topics from 2018 have also been reviewed and updated. The executive summary highlights key evidence-based findings and recommendation from the full document. METHODS: ICAR-Allergic Rhinitis 2023 employed established evidence-based review with recommendation (EBRR) methodology to individually evaluate each topic. Stepwise iterative peer review and consensus was performed for each topic. The final document was then collated and includes the results of this work. RESULTS: ICAR-Allergic Rhinitis 2023 includes 10 major content areas and 144 individual topics related to AR. For a substantial proportion of topics included, an aggregate grade of evidence is presented, which is determined by collating the levels of evidence for each available study identified in the literature. For topics in which a diagnostic or therapeutic intervention is considered, a recommendation summary is presented, which considers the aggregate grade of evidence, benefit, harm, and cost. CONCLUSION: The ICAR-Allergic Rhinitis 2023 update provides a comprehensive evaluation of AR and the currently available evidence. It is this evidence that contributes to our current knowledge base and recommendations for patient evaluation and treatment.

Inhaled anti-TSLP antibody fragment, ecleralimab, blocks responses to allergen in mild asthma.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a key upstream regulator driving allergic inflammatory responses. We evaluated the efficacy and safety of ecleralimab, a potent inhaled neutralising antibody fragment against human TSLP, using allergen inhalation challenge (AIC) in subjects with mild atopic asthma. METHODS: This was a 12-week, randomised, double-blind, placebo-controlled, parallel-design, multicentre allergen bronchoprovocation study conducted at 10 centres across Canada and Germany. Subjects aged 18-60 years with stable mild atopic asthma were randomised (1:1) to receive 4 mg once-daily inhaled ecleralimab or placebo. Primary end-points were the allergen-induced change in forced expiratory volume in 1 s (FEV1) during the late asthmatic response (LAR) measured by area under the curve (AUC3-7h) and maximum percentage decrease (LAR%) on day 84, and the safety of ecleralimab. Allergen-induced early asthmatic response (EAR), sputum eosinophils and fractional exhaled nitric oxide (F ENO) were secondary and exploratory end-points. RESULTS: 28 subjects were randomised to ecleralimab (n=15) or placebo (n=13). On day 84, ecleralimab significantly attenuated LAR AUC3-7h by 64% (p=0.008), LAR% by 48% (p=0.029), and allergen-induced sputum eosinophils by 64% at 7 h (p=0.011) and by 52% at 24 h (p=0.047) post-challenge. Ecleralimab also numerically reduced EAR AUC0-2h (p=0.097) and EAR% (p=0.105). F ENO levels were significantly reduced from baseline throughout the study (p<0.05), except at 24 h post-allergen (day 43 and day 85). Overall, ecleralimab was safe and well tolerated. CONCLUSION: Ecleralimab significantly attenuated allergen-induced bronchoconstriction and airway inflammation, and was safe in subjects with mild atopic asthma.

Efficacy and Safety of a Drug-Free, Barrier-Forming Nasal Spray for Allergic Rhinitis: Randomized, Open-Label, Crossover Noninferiority Trial.

INTRODUCTION: Symptoms of allergic rhinitis can be reduced by nonpharmacological nasal sprays that create a barrier between allergens and the nasal mucosa. A new nasal spray (AM-301) containing the clay mineral bentonite was tested for its ability to reduce symptoms of grass pollen. METHODS: This open-label, crossover, noninferiority trial compared the efficacy and safety of AM-301 to that of hydroxypropyl methylcellulose (HPMC; Nasaleze® Allergy Blocker), an established barrier method. Adults with seasonal allergic rhinitis were exposed to Dactylis glomerata pollen, in a controlled setting, the Fraunhofer allergen challenge chamber, first without protection and then protected by HPMC or AM-301 (7 days apart). Efficacy was assessed from total nasal symptom score (TNSS), nasal secretion weight, and subjective rating. The primary endpoint was the difference, between AM-301 and HPMC, in least square mean change in TNSS over a 4-h exposure to allergen. RESULTS: The study enrolled 36 persons, and 35 completed all study visits. The mean TNSS was 5.91 (SD = 1.45) during unprotected exposure, 5.20 (SD = 1.70) during protection with HPMC, and 4.82 (SD = 1.74) during protection with AM-301. The difference in least square means between the two treatments was -0.39 (95% CI: -0.89 to 0.10), establishing the noninferiority of AM-301. No difference in mean weight of nasal secretions was observed between the treatments. Efficacy was rated as good or very good for AM-301 by 31% and for HPMC by 14% of subjects. Sixteen subjects reported adverse events with a relationship to AM-301 or HPMC; most adverse events were mild, and none was serious. DISCUSSION/CONCLUSION: AM-301 demonstrated noninferiority toward HPMC in the primary endpoint and was perceived better in subjective secondary endpoints. Both barrier-forming products had a persisting protective effect over 4 h and were safe.

Absolute thermometry using hyperpolarized 129 Xe free-induction decay and spin-echo chemical-shift imaging in rats.

PURPOSE: To implement and test variants of chemical shift imaging (CSI) acquiring both free induction decays (FIDs) showing all dissolved-phase compartments and spin echoes for specifically assessing 129 $$ {}^{129} $$ Xe in lipids in order to perform precise lipid-dissolved 129 $$ {}^{129} $$ Xe MR thermometry in a rat model of general hypothermia. METHODS: Imaging was performed at 2.89 T. T 2 $$ {T}_2 $$ of 129 $$ {}^{129} $$ Xe in lipids was determined in one rat by fitting exponentials to decaying signals of global spin-echo spectra. Four rats (conventional CSI) and six rats (turbo spectroscopic imaging) were scanned at three time points with core body temperature 37/34/37 ∘ $$ {}^{\circ } $$ C. Lorentzian functions were fit to spectra from regions of interest to determine the water-referenced chemical shift of lipid-dissolved 129 $$ {}^{129} $$ Xe in the abdomen. Absolute 129 $$ {}^{129} $$ Xe-derived temperature was compared to values from a rectal probe. RESULTS: Global T 2 $$ {T}_2 $$ of 129 $$ {}^{129} $$ Xe in lipids was determined as 251 . 3 ms ± 81 . 4 ms $$ 251.3\;\mathrm{ms}\pm 81.4\;\mathrm{ms} $$ . Friedman tests showed significant changes of chemical shift with time for both sequence variants and both FID and spin-echo acquisitions. Mean and SD of 129 $$ {}^{129} $$ Xe and rectal probe temperature differences were found to be - 0 . 1 5 ∘ C ± 0 . 9 3 ∘ C $$ -0.1{5}^{\circ}\mathrm{C}\pm 0.9{3}^{\circ}\mathrm{C} $$ (FID) and - 0 . 3 8 ∘ C ± 0 . 6 4 ∘ C $$ -0.3{8}^{\circ}\mathrm{C}\pm 0.6{4}^{\circ}\mathrm{C} $$ (spin echo) for conventional CSI as well as 0 . 0 3 ∘ C ± 0 . 7 7 ∘ C $$ 0.0{3}^{\circ}\mathrm{C}\pm 0.7{7}^{\circ}\mathrm{C} $$ (FID) and - 0 . 0 6 ∘ C ± 0 . 7 6 ∘ C $$ -0.0{6}^{\circ}\mathrm{C}\pm 0.7{6}^{\circ}\mathrm{C} $$ (spin echo) for turbo spectroscopic imaging. CONCLUSION: 129 $$ {}^{129} $$ Xe MRI using conventional CSI and turbo spectroscopic imaging of lipid-dissolved 129 $$ {}^{129} $$ Xe enables precise temperature measurements in the rat's abdomen using both FID and spin-echo acquisitions with acquisition of spin echoes enabling most precise temperature measurements.

"Rogue" neutrophil-subset [DEspR+CD11b+/CD66b+] immunotype is an actionable therapeutic target for neutrophilic inflammation-mediated tissue injury - studies in human, macaque and rat LPS-inflammation models.

Background and objective: The correlation (Rs > 0.7) of neutrophils expressing the dual endothelin1/signal peptide receptor (DEspR+CD11b+/CD66b+) with severity of hypoxemia (SF-ratio) and multi-organ failure (SOFA-score) in patients with acute respiratory distress syndrome (ARDS) suggest the hypothesis that the DEspR+ neutrophil-subset is an actionable therapeutic target in ARDS. To test this hypothesis, we conducted in vivo studies to validate DEspR+ neutrophil-subset as therapeutic target and test efficacy of DEspR-inhibition in acute neutrophilic hyperinflammation models. Methods: We performed tests in lipopolysaccharide (LPS)-induced acute neutrophilic inflammation in three species - human, rhesus macaque, rat - with increasing dose-dependent severity. We measured DEspR+CD66b+ neutrophils in bronchoalveolar lavage fluid (BALF) in healthy volunteers (HVs) 24-hours after segmental LPS-challenge by ChipCytometry, and DEspR+CD11b+ neutrophils in whole blood and BALF in an LPS-induced transient acute lung injury (ALI) model in macaques. We determined anti-DEspR antibody efficacy in vivo in LPS-ALI macaque model and in high-mortality LPS-induced encephalopathy in hypertensive rats. Results: ChipCytometry detected increased BALF total neutrophil and DEspR+CD66b+ neutrophil counts after segmental LPS-challenge compared to baseline (P =0.034), as well as increased peripheral neutrophil counts and neutrophil-lymphocyte ratio (NLR) compared to pre-LPS level (P <0.05). In the LPS-ALI macaque model, flow cytometry detected increased DEspR+ and DEspR[-] neutrophils in BALF, which was associated with moderate-severe hypoxemia. After determining pharmacokinetics of single-dose anti-DEspR[hu6g8] antibody, one-time pre-LPS anti-DEspR treatment reduced hypoxemia (P =0.03) and neutrophil influx into BALF (P =0.0001) in LPS-ALI vs vehicle mock-treated LPS-ALI macaques. Ex vivo live cell imaging of macaque neutrophils detected greater "intrinsic adhesion to hard-surface" in DEspR+ vs DEspR[-] neutrophils (P <0.001). Anti-DEspR[hu6g8] antibody abrogated intrinsic high adhesion in DEspR+ neutrophils, but not in DEspR[-] neutrophils (P <0.001). In the LPS-encephalopathy rat model, anti-DEspR[10a3] antibody treatment increased median survival (P =0.0007) and exhibited brain target engagement and bioeffects. Conclusion: Detection of increased DEspR+ neutrophil-subset in human BALF after segmental LPS-challenge supports the correlation of circulating DEspR+ neutrophil counts with severity measure (SOFA-score) in ARDS. Efficacy and safety of targeted inhibition of DEspR+CD11b+ neutrophil-subset in LPS-induced transient-ALI and high-mortality encephalopathy models identify a potential therapeutic target for neutrophil-mediated secondary tissue injury.

PREFUL MRI Depicts Dual Bronchodilator Changes in COPD: A Retrospective Analysis of a Randomized Controlled Trial.

Purpose: To assess whether dynamic ventilation and perfusion (Q) biomarkers derived by phase-resolved functional lung (PREFUL) MRI can measure treatment response to 14-day therapy with indacaterol-glycopyrronium (IND-GLY) and correlate to clinical outcomes including lung function, symptoms, and cardiac function in patients with chronic obstructive pulmonary disease (COPD), as determined by spirometry, body plethysmography, cardiac MRI, and dyspnea score measurements. Materials and Methods: The cardiac left ventricular function in COPD (CLAIM) study enrolled patients aged 40 years or older with COPD, stable cardiovascular function, and hyperinflation (residual volume > 135% predicted). Dynamic MRI data of these patients were retrospectively analyzed using the PREFUL technique to assess the effect of 14-day IND-GLY treatment versus placebo on regional measurements of ventilation dynamics. After manual segmentation of the lung parenchyma, flow-volume loops of each voxel were correlated to an individualized reference flow-volume loop, creating a two-dimensional flow-volume loop correlation map (FVL-CM) as a measure of ventilation dynamics. Ventilation-perfusion match (VQM) was evaluated in combination with perfusion and regional ventilation (VQMRVent) and with perfusion and the FVL-CM measurement (VQMCM). For image and statistical analysis, the lung parenchyma was segmented as a region of interest by manually delineating the lung boundary and excluding the large (central) vessels for each section. Differences in ventilation, perfusion, and VQM between IND-GLY and placebo were compared using analysis of variance, with study treatment, patient, and period included as factors. Results: Fifty patients (mean age, 64.3 years ± 7.65 [SD]; 35 men) were included in this analysis. IND-GLY significantly increased mean correlation as measured with FVL-CM versus that of placebo (least squares [LS] means treatment difference: 0.05 [95% CI: 0.03, 0.07]; P < .0001). Compared with placebo, IND-GLY increased mean Q (LS means treatment difference: 9.27 mL/min/100 mL [95% CI: 0.05, 18.49]; P = .049) and improved both VQMCM and VQMRVent (LS means treatment difference: 0.06 [95% CI: 0.03, 0.08]; P < .0001 and 0.05 [95% CI: 0.02, 0.08]; P = .001, respectively). Conclusion: Regional ventilation dynamics and VQM measured by PREFUL MRI show treatment response in COPD. Supplemental material is available for this article. Clinical trial registration no. NTR6831Keywords: MRI, COPD, Perfusion, Ventilation, Lung, PulmonaryPublished under a CC BY 4.0 license.