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Background: In the United States, Black and Latino children with asthma are more likely than White children with asthma to require emergency department visits or hospitalizations because of an asthma exacerbation. Although many cite patient-level socioeconomic status and access to health care as primary drivers of disparities, there is an emerging focus on a major root cause of disparities—systemic racism. Current conceptual models of asthma disparities depict the historical and current effects of systemic racism as the foundation for unequal exposures to social determinants of health, environmental exposures, epigenetic factors, and differential healthcare access and quality. These ultimately lead to biologic changes over the life course resulting in asthma morbidity and mortality. Methods: At the 2022 American Thoracic Society International Conference, a diverse panel of experts was assembled to identify gaps and opportunities to address systemic racism in childhood asthma research. Panelists found that to examine and address the impacts of systemic racism on children with asthma, researchers and medical systems that support biomedical research will need to 1) address the current gaps in our understanding of how to conceptualize and characterize the impacts of systemic racism on child health, 2) design research studies that leverage diverse disciplines and engage the communities affected by systemic racism in identifying and designing studies to evaluate interventions that address the racialized system that contributes to disparities in asthma health outcomes, and 3) address funding mechanisms and institutional research practices that will be needed to promote antiracism practices in research and its dissemination. Results: A thorough literature review and expert opinion discussion demonstrated that there are few studies in childhood asthma that identify systemic racism as a root cause of many of the disparities seen in children with asthma. Community engagement and participation in research studies is essential to design interventions to address the racialized system in which patients and families live. Dissemination and implementation studies with an equity lens will provide the multilevel evaluations required to understand the impacts of interventions to address systemic racism and the downstream impacts. To address the impacts of systemic racism and childhood asthma, there needs to be increased training for research teams, funding for studies addressing research that evaluates the impacts of racism, funding for diverse and multidisciplinary research teams including community members, and institutional and financial support of advocating for policy changes based on study findings. Conclusions: Innovative study design, new tools to identify the impacts of systemic racism, community engagement, and improved infrastructure and funding are all needed to support research that will address impacts of systemic racism on childhood asthma outcomes. [ABSTRACT FROM AUTHOR]

Rationale: The benefits of improved air quality on asthma remain understudied. Objectives: Our aim was to investigate associations of changes in ambient air pollution with incident asthma from school age until young adulthood in an area with mostly low air pollution levels. Methods: Participants in the BAMSE (Swedish abbreviation for Children, Allergy, Environment, Stockholm, Epidemiology) birth cohort from Stockholm without asthma before the 8-year follow-up were included (N = 2,371). We estimated the association of change in individual-level air pollutant exposure (particulate matter with an aerodynamic diameter ≤ 2.5 μm [PM2.5] and ≤ 10 μm [PM10], black carbon [BC], and nitrogen oxides [NOx]) from the first year of life to the 8-year follow-up with asthma incidence from the 8-year until the 24-year follow-up. Multipollutant trajectories were identified using the group-based multivariate trajectory model. We also used parametric G-computation to quantify the asthma incidence under different hypothetical interventions regarding air pollution levels. Results: Air pollution levels at residency decreased during the period, with median reductions of 5.6% for PM2.5, 3.1% for PM10, 5.9% for BC, and 26.8% for NOx. A total of 395 incident asthma cases were identified from the 8-year until the 24-year follow-up. The odds ratio for asthma was 0.89 (95% confidence interval [CI], 0.80–0.99) for each interquartile range reduction in PM2.5 (equal to 8.1% reduction). Associations appeared less clear for PM10, BC, and NOx. Five multipollutant trajectories were identified; the largest reduction trajectory displayed the lowest odds of asthma (odds ratio, 0.55; 95% CI, 0.31–0.98) compared with the lowest reduction trajectory. If the PM2.5 exposure had not declined up to the 8-year follow-up, the hypothetical asthma incidence was estimated to have been 10.9% higher (95% CI, 0.8–20.8%). Conclusions: A decrease in PM2.5 levels during childhood was associated with a lower risk of incident asthma from school age to young adulthood in an area with relatively low air pollution levels, suggesting broad respiratory health benefits from improved air quality. [ABSTRACT FROM AUTHOR]

Rationale: There is no consensus on criteria to include in an asthma remission definition in real life. Factors associated with achieving remission after biologic initiation remain poorly understood. Objectives: To quantify the proportion of adults with severe asthma achieving multidomain-defined remission after biologic initiation and identify prebiologic characteristics associated with achieving remission that may be used to predict it. Methods: This was a longitudinal cohort study using data from 23 countries from the International Severe Asthma Registry. Four asthma outcome domains were assessed in the 1 year before and after biologic initiation. A priori–defined remission cutoffs were: 0 exacerbations/yr, no long-term oral corticosteroid (LTOCS), partly/well-controlled asthma, and percent predicted FEV1 ⩾ 80%. Remission was defined using two (exacerbations + LTOCS), three (+control or +lung function), and four of these domains. The association between prebiologic characteristics and postbiologic remission was assessed by multivariable analysis. Measurements and Main Results: A total of 50.2%, 33.5%, 25.8%, and 20.3% of patients met criteria for two-, three- (+control), three- (+lung function), and four-domain remission, respectively. The odds of achieving four-domain remission decreased by 15% for every additional 10 years of asthma duration (odds ratio, 0.85; 95% confidence interval, 0.73–1.00). The odds of remission increased in those with fewer exacerbations per year, lower LTOCS daily dose, better control, and better lung function before biologic initiation. Conclusions: One in five patients achieved four-domain remission within 1 year of biologic initiation. Patients with less severe impairment and shorter asthma duration at initiation had a greater chance of achieving remission after biologic treatment, indicating that biologic treatment should not be delayed if remission is the goal. [ABSTRACT FROM AUTHOR]

Rationale: In asthma, sputum group 2 innate lymphoid cells (ILC2s) are activated within 7 hours after allergen challenge. Neuroimmune interactions mediate rapid host responses at mucosal interfaces. In murine models of asthma, lung ILC2s colocalize to sensory neuronal termini expressing the neuropeptide neuromedin U (NMU), which stimulates type 2 (T2) cytokine secretion by ILC2s, with additive effects to alarmins in vitro. Objectives: To investigate the effect of the NMU/NMUR1 (NMU receptor 1) axis on early activation of ILC2s in asthma. Methods: Subjects with mild asthma (n = 8) were enrolled in a diluent-controlled allergen inhalation challenge study. Sputum ILC2 expression of NMUR1 and T2 cytokines was enumerated by flow cytometry, and airway NMU levels were assessed by ELISA. This was compared with samples from subjects with moderate to severe asthma (n = 9). Flow sort–purified and ex vivo–expanded ILC2s were used for functional assays and transcriptomic analyses. Measurements and Main Results: Significant increases in sputum ILC2s expressing NMUR1 were detected 7 hours after allergen versus diluent challenge whereby the majority of NMUR1+ ILC2s expressed IL-5/IL-13. Sputum NMUR1+ ILC2 counts were significantly greater in mild versus moderate to severe asthma, and NMUR1+ ILC2s correlated inversely with the dose of inhaled corticosteroid in the latter group. Coculturing with alarmins upregulated NMUR1 in ILC2s, which was attenuated by dexamethasone. NMU-stimulated T2 cytokine expression by ILC2s, maximal at 6 hours, was abrogated by dexamethasone or specific signaling inhibitors for mitogen-activated protein kinase 1/2 and phosphoinositol 3-kinase but not the IL-33 signaling moiety MyD88 in vitro. Conclusions: The NMU/NMUR1 axis stimulates rapid effects on ILC2s and may be an important early activator of these cells in eosinophilic inflammatory responses in asthma. [ABSTRACT FROM AUTHOR]

Rationale: Nitric oxide (NO) is increased in the airways and serum of patients with allergic asthma, suggesting an important role in asthma. NO production has been widely attributed to the canonical inducible NO synthase. Much effort has been made to inhibit this enzyme, with two outcomes: no asthma improvement and partial NO reduction, suggesting the involvement of an inducible NO synthase–independent source. Objectives: Neutrophils produce NO under inflammatory conditions, and their role in asthma has been overlooked. The present study analyzes their possible role as sources of NO. Methods: Our hypothesis was tested in 99 allergic patients with intermittent bronchial asthma and 26 healthy donors. NO production by blood and sputum neutrophils in response to allergens, anti-IgE, and anti-IgE receptor antibodies was assessed by Griess reagent, flow cytometry, and confocal microscopy. The formation of extracellular traps (ETs) as a possible consequence of NO production was quantified by Western blot and confocal microscopy, and reactive oxygen species were assessed with luminol-enhanced chemiluminescence. Measurements and Main Results: Among blood and sputum granulocytes from patients with allergic asthma, only neutrophils produce NO by an IgE-dependent mechanism. This production is independent of NO synthase, but dependent on a reaction between L-arginine and reactive oxygen species from NOX2 (NADPH oxidase). NO and ETosis are induced in parallel, and NO amplifies ET formation, which is a key mediator in asthma. Conclusions: Our findings reveal a novel role of neutrophils as the unique allergen/IgE–dependent NO source in allergic asthma, enhancing ET formation. These results suggest that NO produced by neutrophils needs further consideration in the treatment of allergic asthma. [ABSTRACT FROM AUTHOR]

Background: The anti-IgE monoclonal antibody omalizumab is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during 1 year of omalizumab treatment. Methods: One-year open-label Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 patients with severe (Global Initiative for Asthma step 4/5) uncontrolled atopic asthma (at least two severe exacerbations in the previous year) taking high-dose inhaled corticosteroids and long-acting β-agonists with or without maintenance oral corticosteroids. It had two phases: 0–16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE); and 16–52 weeks, to assess late responses based on ⩾50% reduction in exacerbations or mOCS dose. All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. Measurements and Main Results: A total of 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ⩾50% and 57% (37 of 65) taking mOCSs had reduced their dose by ⩾50%. The primary outcomes 2,3-dinor-11-β-PGF2α, GETE score, and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five volatile organic compounds and five plasma lipid biomarkers strongly predicted the ⩾50% reduction in exacerbations (receiver operating characteristic areas under the curve of 0.780 and 0.922, respectively) and early responses (areas under the curve of 0.835 and 0.949, respectively). In an independent cohort, gas chromatography/mass spectrometry biomarkers differentiated between severe and mild asthma. Conclusions: This is the first discovery of omics biomarkers that predict improvement in asthma with biologic agent treatment. Prospective validation and development for clinical use is justified. [ABSTRACT FROM AUTHOR]

Rationale: Asthma poses a significant burden for U.S. patients and health systems, yet inpatient care quality is understudied. National chronic obstructive lung disease (COPD) readmission policies may affect inpatient asthma care through hospital responses to these policies because of imprecise diagnosis and identification of patients with COPD and asthma. Objectives: Evaluate inpatient care quality for patients hospitalized with asthma and potential collateral effects of the Medicare COPD Hospital Readmissions Reduction Program (HRRP). Methods: This was a retrospective cohort study of patients aged 18–54 years hospitalized for asthma across 924 U.S. hospitals (Premier Healthcare Database). Results: Care quality for patients with asthma was evaluated before HRRP implementation (n = 20,820; January 2010–September 2014) and after HRRP implementation (n = 26,885; October 2014–December 2018) using adherence to inpatient care guidelines (recommended, nonrecommended, and "ideal care" [all recommended with no nonrecommended care]). Between 2010 and 2018, at least 80% of patients received recommended care annually. Recommended care decreased similarly (rate of 0.02%/mo) after versus before HRRP (P = 0.8). Nonrecommended care decreased more rapidly after HRRP (rate of 0.29%/mo) versus before HRRP (rate of 0.17%/mo; P < 0.001), with changes driven largely by decreased antibiotic prescribing. Ideal care increased more rapidly after HRRP (rate of 0.25%/mo) versus before HRRP (rate of 0.17%/mo; P = 0.02), with changes driven largely by nonrecommended care improvements. Conclusions: Post-HRRP trends suggest asthma care improved with increased rates of guideline concordance in nonrecommended and ideal care. Although federal policies (e.g., HRRP) may have had positive collateral effects, such as with asthma care, parallel care efforts, including antibiotic stewardship, likely contributed to these improvements. [ABSTRACT FROM AUTHOR]

Rationale: Exposure to particulate matter is associated with various adverse health outcomes. Ultrafine particles (UFPs; diameter <0.1 μm) are a unique public health challenge because of their size. However, limited studies have examined their impacts on human health, especially across seasons and demographic characteristics. Objectives: To evaluate the effect of UFP exposure on the risk of visiting the emergency department (ED) for a chronic lower respiratory disease (CLRD) in New York State in 2013–2018. Methods: We used a case-crossover design and conditional logistic regression to estimate how UFP exposure led to CLRD-related ED visits. GEOS-Chem Advanced Particle Microphysics, a state-of-the-art chemical transport model with a size-resolved particle microphysics model, generated air pollution simulation data. We then matched UFP exposure estimates to geocoded health records for asthma, bronchiectasis, chronic bronchitis, emphysema, unspecified bronchitis, and other chronic airway obstructions in New York State from 2013 through 2018. In addition, we assessed interactions with age, ethnicity, race, sex, meteorological factors, and season. Results: Each 1-(interquartile range [IQR]) increase in UFP exposure led to a 0.37% increased risk of a respiratory-related ED visit on lag 0–0, or the day of the ED visits, (95% confidence interval [CI], 0.23–0.52%) and a 1.81% increase on lag 0–6, or 6 days before the ED visit, (95% CI, 1.58–2.03%). The highest risk was in the emphysema subtype (lag 0–5, 4.18%; 95% CI, 0.16–8.37%), followed by asthma (lag 0–6, 2.00%), chronic bronchitis (lag 0–6, 1.78%), other chronic airway obstructions (lag 0–6, 1.60%), and unspecified bronchitis (lag 0–6, 1.49%). We also found significant interactions between UFP health impacts and season (Fall, 3.29%), temperature (<90th percentile, 2.27%), relative humidity (>90th percentile, 4.63%), age (children aged <18 yr, 3.19%), and sex (men, 2.06%) on lag 0–6. Conclusions: In this study, UFP exposure increased CLRD-related ED visits across all seasons and demographic characteristics, yet these associations varied according to various factors, which requires more research. [ABSTRACT FROM AUTHOR]

Although substantial progress has been made in our understanding of asthma pathogenesis and phenotypes over the nearly 60-year history of the Aspen Lung Conferences on asthma, many ongoing challenges exist in our understanding of the clinical and molecular heterogeneity of the disease and an individual patient's response to therapy. This report summarizes the proceedings of the 2023 Aspen Lung Conference, which was organized to review the clinical and molecular heterogeneity of asthma and to better understand the impact of genetic, environmental, cellular, and molecular influences on disease susceptibility, heterogeneity, and severity. The goals of the conference were to review new information about asthma phenotypes, cellular processes, and cellular signatures underlying disease heterogeneity and treatment response. The report concludes with ongoing gaps in our understanding of asthma pathobiology and provides some recommendations for future research to better understand the clinical and basic mechanisms underlying disease heterogeneity in asthma and to advance the development of new treatments for this growing public health problem. [ABSTRACT FROM AUTHOR]

Rationale: The share of Black or Latinx residents in a census tract remains associated with asthma-related emergency department (ED) visit rates after controlling for socioeconomic factors. The extent to which evident disparities relate to the within-city heterogeneity of long-term air pollution exposure remains unclear. Objectives: To investigate the role of intraurban spatial variability of air pollution in asthma acute care use disparity. Methods: An administrative database was used to define census tract population-based incidence rates of asthma-related ED visits. We estimate the associations between census tract incidence rates and 1) average fine and coarse particulate matter, nitrogen dioxide (NO2), and sulfur dioxide (SO2), and 2) racial and ethnic composition using generalized linear models controlling for socioeconomic and housing covariates. We also examine for the attenuation of incidence risk ratios (IRRs) associated with race/ethnicity when controlling for air pollution exposure. Measurements and Main Results: Fine and coarse particulate matter and SO2 are all associated with census tract–level incidence rates of asthma-related ED visits, and multipollutant models show evidence of independent risk associated with coarse particulate matter and SO2. The association between census tract incidence rate and Black resident share (IRR, 1.51 [credible interval (CI), 1.48–1.54]) is attenuated by 24% when accounting for air pollution (IRR, 1.39 [CI, 1.35–1.42]), and the association with Latinx resident share (IRR, 1.11 [CI, 1.09–1.13]) is attenuated by 32% (IRR, 1.08 [CI, 1.06–1.10]). Conclusions: Neighborhood-level rates of asthma acute care use are associated with local air pollution. Controlling for air pollution attenuates associations with census tract racial/ethnic composition, suggesting that intracity variability in air pollution could contribute to neighborhood-to-neighborhood asthma morbidity disparities. [ABSTRACT FROM AUTHOR]

Rationale: Chronic lung diseases (CLDs) have been variably associated with a risk for more severe manifestations and death with coronavirus disease (COVID-19). Objectives: To determine the risk overall and by type of CLD for severity of COVID-19 outcomes in a U.S. national cohort. Methods: Using data from the Veterans Health Administration, we determined the risk associated with CLDs, including chronic obstructive pulmonary disease (COPD) (mild or severe), asthma (mild, active, or severe), idiopathic pulmonary fibrosis (IPF), sarcoidosis, and other interstitial lung diseases (ILDs) for outcomes among veterans with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive tests between March 1, 2020 and April 30, 2021. We used multinomial regression to estimate risk of four mutually exclusive COVID-19 outcomes within 30 days: outpatient management, hospitalization, hospitalization with indicators of critical illness, or death. We calculated the overall proportion with each outcome, the absolute risk difference, and risk ratios for each outcome between those with and without CLD. We also describe clinical and laboratory abnormalities by CLD in those hospitalized. Results: We included 208,283 veterans with COVID-19; 35,587 (17%) had CLD. Compared with no CLD, veterans with CLD were older and had more comorbidities. Hospitalized veterans with CLD were more likely to have low temperature, mean arterial pressure, oxygen saturation, and leukopenia and thrombocytopenia and were more likely to receive oxygen, mechanical ventilation, and vasopressors. Veterans with CLD were significantly less likely to have mild COVID-19 (−4.5%; adjusted risk ratio [aRR], 0.94; 95% confidence interval [CI], 0.94–0.95), and more likely to have a moderate (+2.5%; aRR, 1.21; 95% CI, 1.18–1.24), critical (+1.4%; aRR, 1.38; 95% CI, 1.32–1.45), or fatal (+0.7%; aRR, 1.15; 95% CI, 1.10–1.20) outcome. IPF was most strongly associated with COVID-19 severity, especially mortality (+3.2%; aRR, 1.69; 95% CI, 1.46–1.96), followed by other ILDs and COPD, whereas asthma was less likely to be associated with severity of COVID-19. In veterans younger than age 65 years, worse COVID-19 outcomes were generally more likely with IPF, sarcoidosis, and other ILDs. Conclusions: Veterans who had CLD, particularly IPF, other ILDs, and COPD, had an increased probability of more severe 30-day outcomes with COVID-19. These results provide insight into the absolute and relative risk of different CLDs with severity of COVID-19 outcomes and can help inform considerations of healthcare utilization and prognosis. Observational clinical epidemiology study registered with (NCT04628039). [ABSTRACT FROM AUTHOR]

The article explores the intersection of pediatric asthma and sleep-disordered breathing (SDB), focusing on clinical characteristics and risk factors. Topics discussed include the prevalence of asthma and SDB, their bidirectional relationship, and the clinical features associated with their overlap in school-aged children from urban, low-income neighborhoods.

Airway remodeling is a cardinal feature of asthma, associated with increased airway smooth muscle (ASM) cell mass and upregulation of extracellular matrix deposition. Exaggerated ASM cell migration contributes to excessive ASM mass. Previously, we demonstrated the alleviating role of Kp (kisspeptin) receptor (KISS1R) activation by Kp-10 in mitogen (PDGF [platelet-derived growth factor])-induced human ASM cell proliferation in vitro and airway remodeling in vivo in a mouse model of asthma. Here, we examined the mechanisms by which KISS1R activation regulates mitogen-induced ASM cell migration. KISS1R activation using Kp-10 significantly inhibited PDGF-induced ASM cell migration, further confirmed using KISS1R shRNA. Furthermore, KISS1R activation modulated F/G actin dynamics and the expression of promigration proteins like CDC42 (cell division control protein 42) and cofilin. Mechanistically, we observed reduced ASM RhoA-GTPAse with KISS1R activation. The antimigratory effect of KISS1R was abolished by PKA (protein kinase A)-inhibitory peptide. Conversely, KISS1R activation significantly increased cAMP and phosphorylation of CREB (cAMP-response element binding protein) in PDGF-exposed ASM cells. Overall, these results highlight the alleviating properties of Kp-10 in the context of airway remodeling. [ABSTRACT FROM AUTHOR]

The authors discuss a study by Chacó and colleagues which identified a novel mechanism of immunoglobulin E (IgE)-dependent, inducible nitric oxide synthase (iNOS)-independent nitric oxide (NO) production by neutrophils, which regulates neutrophil extracellular trap (NET) formation by neutrophils derived from patients with intermittent bronchial allergic asthma. Topics include the level of NO in patients with allergic asthma and implications of the study for therapeutic interventions.

The article discusses how transition to nonhydrofluorocarbon (non-HFC) propellants will impact children in the U.S. and Europe disproportionately. Topics include how climate change is affecting children's health, regulatory and drug development challenges, and policy changes that should be considered by the U.S. Food and Drug Administration (FDA) during the transition period to non-HFC, or alternatives to HFC.

Rationale: Density thresholds in computed tomography (CT) lung scans quantify air trapping (AT) at the whole-lung level but are not informative for AT in specific bronchopulmonary segments. Objectives: To apply a segment-based measure of AT in asthma to investigate the clinical determinants of AT in asthma. Methods: In each of 19 bronchopulmonary segments in CT lung scans from 199 patients with asthma, AT was categorized as present if lung attenuation was less than −856 Hounsfield units at expiration in ⩾15% of the lung area. The resulting AT segment score (0–19) was related to patient outcomes. Measurements and Main Results: AT varied at the lung segment level and tended to persist at the patient and lung segment levels over 3 years. Patients with widespread AT (⩾10 segments) had more severe asthma (P < 0.05). The mean (±SD) AT segment score in patients with a body mass index ⩾30 kg/m2 was lower than in patients with a body mass index <30 kg/m2 (3.5 ± 4.6 vs. 5.5 ± 6.3; P = 0.008), and the frequency of AT in lower lobe segments in obese patients was less than in upper and middle lobe segments (35% vs. 46%; P = 0.001). The AT segment score in patients with sputum eosinophils ⩾2% was higher than in patients without sputum eosinophilia (7.0 ± 6.1 vs. 3.3 ± 4.9; P < 0.0001). Lung segments with AT more frequently had airway mucus plugging than lung segments without AT (48% vs. 18%; P ⩽ 0.0001). Conclusions: In patients with asthma, air trapping is more severe in those with airway eosinophilia and mucus plugging, whereas those who are obese have less severe trapping because their lower lobe segments are spared. [ABSTRACT FROM AUTHOR]

The article discusses the potential therapeutic impact of the GPR84 antagonist GLPG1205 in experimental severe asthma. It emphasizes GPR84's role in lung inflammation and metabolism, as well as the compound's effect on reducing airway inflammation and hyperresponsiveness, particularly in neutrophilic inflammation and steroid-insensitive features.

Rationale: The strongest genetic risk factor for childhood-onset asthma, the 17q21 locus, is associated with increased viral susceptibility and disease-promoting processes. Objectives: To identify biological targets underlying the escalated viral susceptibility associated with the clinical phenotype mediated by the 17q21 locus. Methods: Genome-wide transcriptome analysis of nasal brush samples from 261 children (78 healthy, 79 with wheezing at preschool age, 104 asthmatic) within the ALLIANCE (All-Age-Asthma) cohort, with a median age of 10.0 (range, 1.0–20.0) years, was conducted to explore the impact of their 17q21 genotype (SNP rs72163891). Concurrently, nasal secretions from the same patients and visits were collected, and high-sensitivity mesoscale technology was employed to measure IFN protein levels. Measurements and Main Results: This study revealed that the 17q21 risk allele induces a genotype- and asthma/wheeze phenotype–dependent enhancement of mucosal GSDMB expression as the only relevant 17q21-encoded gene in children with preschool wheeze. Increased GSDMB expression correlated with the activation of a type-1 proinflammatory, cell-lytic immune, and natural killer signature, encompassing key genes linked to an IFN type-2-signature (IFNG, CXCL9, CXCL10, KLRC1, CD8A, GZMA). Conversely, there was a reduction in IFN type 1 and type 3 expression signatures at the mRNA and protein levels. Conclusions: This study demonstrates a novel disease-driving mechanism induced by the 17q21 risk allele. Increased mucosal GSDMB expression is associated with a cell-lytic immune response coupled with compromised airway immunocompetence. These findings suggest that GSDMB-related airway cell death and perturbations in the mucosal IFN signature account for the increased vulnerability of 17q21 risk allele carriers to respiratory viral infections during early life, opening new options for future biological interventions. The All-Age-Asthma (ALLIANCE) cohort is registered at www.clinicaltrials.gov (pediatric arm, NCT 02496468). [ABSTRACT FROM AUTHOR]

Rationale: Over 20,000 children are hospitalized in the United States for asthma every year. Although initial treatment guidelines are well established, there is a lack of high-quality evidence regarding the optimal respiratory support devices for these patients. Objectives: The objective of this study was to evaluate institutional and temporal variability in the use of respiratory support modalities for pediatric critical asthma. Methods: We conducted a retrospective cohort study using data from the Virtual Pediatrics Systems database. Our study population included children older than 2 years old admitted to a VPS contributing pediatric intensive care unit from January 2012 to December 2021 with a primary diagnosis of asthma or status asthmaticus. We evaluated the percentage of encounters using a high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), noninvasive bilevel positive pressure ventilation (NIV), and invasive mechanical ventilation (IMV) for all institutions, then divided institutions into quintiles based on the volume of patients. We created logistic regression models to determine the influence of institutional volume and year of admission on respiratory support modality use. We also conducted time-series analyses using Kendall's tau. Results: Our population included 77,115 patient encounters from 163 separate institutions. Institutional use of respiratory modalities had significant variation in HFNC (28.3%, interquartile range [IQR], 11.0–49.0%; P < 0.01), CPAP (1.4%; IQR, 0.3–4.3%; P < 0.01), NIV (8.6%; IQR, 3.5–16.1%; P < 0.01), and IMV (5.1%; IQR, 3.1–8.2%; P < 0.01). Increased institutional patient volume was associated with significantly increased use of NIV (odds ratio [OR], 1.33; 1.29–1.36; P < 0.01) and CPAP (OR, 1.20; 1.15–1.25; P < 0.01), and significantly decreased use of HFNC (OR, 0.80; 0.79–0.81; P < 0.01) and IMV (OR, 0.82; 0.79–0.86; P < 0.01). Time was also associated with a significant increase in the use of HFNC (11.0–52.3%; P < 0.01), CPAP (1.6–5.4%; P < 0.01), and NIV (3.7–21.2%; P < 0.01), whereas there was no significant change in IMV use (6.1–4.0%; P = 0.11). Conclusions: Higher-volume centers are using noninvasive positive pressure ventilation more frequently for pediatric critical asthma and lower frequencies of HFNC and IMV. Treatment with HFNC, CPAP, and NIV for this population is increasing in the last decade. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) is not just a three-dimensional scaffold that provides stable support for all cells in the lungs, but also an important component of chronic fibrotic airway, vascular, and interstitial diseases. It is a bioactive entity that is dynamically modulated during tissue homeostasis and disease, that controls structural and immune cell functions and drug responses, and that can release fragments that have biological activity and that can be used to monitor disease activity. There is a growing recognition of the importance of considering ECM changes in chronic airway, vascular, and interstitial diseases, including 1) compositional changes, 2) structural and organizational changes, and 3) mechanical changes and how these affect disease pathogenesis. As altered ECM biology is an important component of many lung diseases, disease models must incorporate this factor to fully recapitulate disease-driver pathways and to study potential novel therapeutic interventions. Although novel models are evolving that capture some or all of the elements of the altered ECM microenvironment in lung diseases, opportunities exist to more fully understand cell–ECM interactions that will help devise future therapeutic targets to restore function in chronic lung diseases. In this perspective article, we review evolving knowledge about the ECM's role in homeostasis and disease in the lung. [ABSTRACT FROM AUTHOR]

Rationale: The prevalence and diagnostic utility of bronchodilator responsiveness (BDR) in a real-life setting is unclear. Objective: To explore this uncertainty in patients aged ⩾12 years with physician-assigned diagnoses of asthma, asthma and chronic obstructive pulmonary disease (COPD), or COPD in NOVELTY, a prospective cohort study in primary and secondary care in 18 countries. Methods: The proportion of patients with a positive BDR test in each diagnostic category was calculated using 2005 (ΔFEV1 or ΔFVC ⩾12% and ⩾200 ml) and 2021 (ΔFEV1 or ΔFVC >10% predicted) European Respiratory Society/American Thoracic Society criteria. Measurements and Main Results: We studied 3,519 patients with a physician-assigned diagnosis of asthma, 833 with a diagnosis of asthma + COPD, and 2,436 with a diagnosis of COPD. The prevalence of BDR was 19.7% (asthma), 29.6% (asthma + COPD), and 24.7% (COPD) using 2005 criteria and 18.1%, 23.3%, and 18.0%, respectively, using 2021 criteria. Using 2021 criteria in patients diagnosed with asthma, BDR was associated with higher fractional exhaled nitric oxide; lower lung function; higher symptom burden; more frequent hospital admissions; and greater use of triple therapy, oral corticosteroids, or biologics. In patients diagnosed with COPD, BDR (2021) was associated with lower lung function and higher symptom burden. Conclusions: BDR prevalence in patients with chronic airway diseases receiving treatment ranges from 18% to 30%, being modestly lower with the 2021 than with the 2005 European Respiratory Society/American Thoracic Society criteria, and it is associated with lower lung function and greater symptom burden. These observations question the validity of BDR as a key diagnostic tool for asthma managed in clinical practice or as a standard inclusion criterion for clinical trials of asthma and instead suggest that BDR be considered a treatable trait for chronic airway disease. [ABSTRACT FROM AUTHOR]

The article focuses on the regulatory compliance and ethical approval processes of the International Severe Asthma Registry (ISAR), ensuring adherence to data transfer laws, ethical standards, and international regulations. Topics include obtaining regulatory agreements, ethical approval from the ADEPT committee, and compliance with ENCEPP guidelines, ensuring proper governance and characterization of patients with severe asthma in ISAR.

The article focuses on investigating the relationship between larger mediastinal lymph nodes (MLNs) and lung function in persistent asthma, utilizing computed tomography (CT) to quantify MLNs and retrospectively analyzing data from 150 patients with moderate to severe asthma. It study aims to elucidate the clinical associations of larger MLNs in persistent asthma.

Rationale: Previous studies investigating the impact of comorbidities on the effectiveness of biologic agents have been relatively small and of short duration and have not compared classes of biologic agents. Objectives: To determine the association between type 2-related comorbidities and biologic agent effectiveness in adults with severe asthma (SA). Methods: This cohort study used International Severe Asthma Registry data from 21 countries (2017-2022) to quantify changes in four outcomes before and after biologic therapy-annual asthma exacerbation rate, FEV1% predicted, asthma control, and long-term oral corticosteroid daily dose-in patients with or without allergic rhinitis, chronic rhinosinusitis (CRS) with or without nasal polyps (NPs), NPs, or eczema/atopic dermatitis. Measurements and Main Results: Of 1,765 patients, 1,257, 421, and 87 initiated anti-IL-5/5 receptor, anti-IgE, and anti-IL-4/13 therapies, respectively. In general, pre- versus post-biologic therapy improvements were noted in all four asthma outcomes assessed, irrespective of comorbidity status. However, patients with comorbid CRS with or without NPs experienced 23% fewer exacerbations per year (95% CI, 10-35%; P < 0.001) and had 59% higher odds of better post-biologic therapy asthma control (95% CI, 26-102%; P < 0.001) than those without CRS with or without NPs. Similar estimates were noted for those with comorbid NPs: 22% fewer exacerbations and 56% higher odds of better post-biologic therapy control. Patients with SA and CRS with or without NPs had an additional FEV1% predicted improvement of 3.2% (95% CI, 1.0-5.3; P = 0.004), a trend that was also noted in those with comorbid NPs. The presence of allergic rhinitis or atopic dermatitis was not associated with post-biologic therapy effect for any outcome assessed. Conclusions: These findings highlight the importance of systematic comorbidity evaluation. The presence of CRS with or without NPs or NPs alone may be considered a predictor of the effectiveness of biologic agents in patients with SA. [ABSTRACT FROM AUTHOR]

Rationale: The role and timing of vitamin D supplementation in the prevention of asthma has not been fully elucidated. Objective: To describe the association between prenatal and postnatal vitamin D with offspring asthma outcomes in participants of the Vitamin D Antenatal Asthma Reduction Trial. Methods: We classified 748 mother--offspring pairs into four groups based on the mother's randomization to receive high-dose versus low-dose (4,400 IU vs. 400 IU) vitamin D supplementation during pregnancy and the offspring parent-reported high-dose versus low-dose (>400 IU vs.,400 IU) vitamin D supplementation as estimated by intake of vitamin D drops or infant formula. We used logistic regression to test the association of the four vitamin D exposure groups--"mother-low/infant-low (reference)," "mother-high/infant-high," "mother-high/infant-low," and "mother-low/infant-high"--with offspring asthma and/or recurrent wheeze at age 3 years, active asthma at age 6 years, and atopic asthma at age 6 years. Results: The risk of asthma and/or recurrent wheeze at 3 years was lowest in the mother-high/infant-low group (adjusted odds ratio vs. mother-low/infant-low, 0.39; 95% confidence interval, 0.16--0.88, P = 0.03). When stratifying by history of exclusive breastfeeding until age 4 months, the protective effect in the mother-high/infant-low group was seen only among exclusively breastfed infants (odds ratio vs. mother-low/infant-low, 0.19; 95% confidence interval, 0.04--0.68; P = 0.02). We did not observe any significant associations with active or atopic asthma at age 6 years. Conclusions: We observe that high-dose prenatal and low-dose postnatal vitamin D supplementation may be associated with reduced offspring asthma or recurrent wheeze by age 3 years, but this association may be confounded by the protective effect of breastfeeding. [ABSTRACT FROM AUTHOR]

Rationale: Air pollution caused by wildfire smoke is linked to adverse health outcomes, especially for people living with asthma. Objectives: To evaluate whether government rebates for high-efficiency particulate air (HEPA) filters, which reduce concentrations of smoke particles indoors, are cost effective in managing asthma and preventing exacerbations in British Columbia (BC), Canada. Methods: We used a Markov model to analyze health states for asthma control, exacerbation severity, and death over a retrospective time horizon of 5 years (2018–2022). Concentrations of wildfire smoke–derived particulate matter with an aerodynamic diameter ⩽2.5 μm (PM2.5) from the Canadian Optimized Statistical Smoke Exposure Model and relevant literature informed the model. The base-case analysis assumed continuous use of a HEPA filter. Costs and quality-adjusted life-years (QALYs) resulting from varying rebates were computed for each Health Service Delivery Area (HSDA). Measurements and Main Results: In the base-case analysis, HEPA filter use resulted in increased costs of $83.34 (SE, $1.03) and increased QALYs of 0.0011 (SE, 0.0001) per person. The average incremental cost-effectiveness ratio among BC HSDAs was $74,652/QALY (SE, $3,517), with incremental cost-effectiveness ratios ranging from $40,509 to $89,206 per QALY in HSDAs. Across the province, the intervention was projected to prevent 4,418 exacerbations requiring systemic corticosteroids, 643 emergency department visits, and 425 hospitalizations during the 5-year time horizon. A full rebate was cost effective in 1 of the 16 HSDAs across BC. The probability of cost-effectiveness ranged from 0.1% to 74.8% across HSDAs. A $100 rebate was cost effective in most HSDAs. Conclusions: The cost-effectiveness of HEPA filters in managing wildfire smoke–related asthma issues in BC varies by region. Government rebates up to two-thirds of the filter cost are generally cost effective, with a full rebate being cost effective only in Kootenay Boundary. [ABSTRACT FROM AUTHOR]

Rationale: A significant proportion of individuals with chronic obstructive pulmonary disease (COPD) and asthma remain undiagnosed. Objectives: The objective of this study was to evaluate symptoms, quality of life, healthcare use, and work productivity in subjects with undiagnosed COPD or asthma compared with those previously diagnosed, as well as healthy control subjects. Methods: This multicenter population-based case-finding study randomly recruited adults with respiratory symptoms who had no previous history of diagnosed lung disease from 17 Canadian centers using random digit dialing. Participants who exceeded symptom thresholds on the Asthma Screening Questionnaire or the COPD Diagnostic Questionnaire underwent pre- and post-bronchodilator spirometry to determine if they met diagnostic criteria for COPD or asthma. Two control groups, a healthy group without respiratory symptoms and a symptomatic group with previously diagnosed COPD or asthma, were similarly recruited. Measurements and Main Results: A total of 26,905 symptomatic individuals were interviewed, and 4,272 subjects were eligible. Of these, 2,857 completed pre- and post-bronchodilator spirometry, and 595 (21%) met diagnostic criteria for COPD or asthma. Individuals with undiagnosed COPD or asthma reported greater impact of symptoms on health status and daily activities, worse disease-specific and general quality of life, greater healthcare use, and poorer work productivity than healthy control subjects. Individuals with undiagnosed asthma had symptoms, quality of life, and healthcare use burden similar to those of individuals with previously diagnosed asthma, whereas subjects with undiagnosed COPD were less disabled than those with previously diagnosed COPD. Conclusions: Undiagnosed COPD or asthma imposes important, unmeasured burdens on the healthcare system and is associated with poor health status and negative effects on work productivity. [ABSTRACT FROM AUTHOR]

The article focuses on examining the effect of biologic therapy on changes in body composition, including BMI, fat mass index (FMI), and fat-free mass index (FFMI), in patients with severe asthma, with an emphasis on understanding the impact of biologics on body composition beyond changes.

Asthma pathobiology includes oxidative stress that modifies cell membranes and extracellular phospholipids. Oxidized phosphatidylcholines (OxPCs) in lung lavage from allergenchallenged human participants correlate with airway hyperresponsiveness and induce bronchial narrowing in murine thin-cut lung slices. OxPCs activate many signaling pathways, but mechanisms for these responses are unclear. We hypothesize that OxPCs stimulate intracellular free Ca21 flux to trigger airway smooth muscle contraction. Intracellular Ca21 flux was assessed in Fura-2-loaded, cultured human airway smooth muscle cells. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) induced an approximately threefold increase in 20 kD myosin light chain phosphorylation. This correlated with a rapid peak in intracellular cytoplasmic Ca21 concentration ([Ca21]i) (143nM) and a sustained plateau that included slow oscillations in [Ca21]i. Sustained [Ca21]i elevation was ablated in Ca21-free buffer and by TRPA1 inhibition. Conversely, OxPAPC-induced peak [Ca21]i was unaffected in Ca21-free buffer, by TRPA1 inhibition, or by inositol 1,4,5-triphosphate receptor inhibition. Peak [Ca21]i was ablated by pharmacologic inhibition of ryanodine receptor (RyR) Ca21 release from the sarcoplasmic reticulum. Inhibiting the upstream RyR activator cyclic adenosine diphosphate ribose with 8-bromo-cyclic adenosine diphosphate ribose was sufficient to abolish OxPAPC-induced cytoplasmic Ca21 flux. OxPAPC induced -15% bronchial narrowing in thin-cut lung slices that could be prevented by pharmacologic inhibition of either TRPA1 or RyR, which similarly inhibited OxPC-induced myosin light chain phosphorylation in cultured human airway smooth muscle cells. In summary, OxPC mediates airway narrowing by triggering TRPA1 and RyR-mediated mobilization of intracellular and extracellular Ca21 in airway smooth muscle. These data suggest that OxPC in the airways of allergen-challenged subjects and subjects with asthma may contribute to airway hyperresponsiveness. [ABSTRACT FROM AUTHOR]

The article offers information on the use of noninvasive respiratory support (NRS) in pediatric critical asthma, including high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), and noninvasive ventilation (NIV). Topics include the challenges of determining the optimal role of each NRS modality due to limited high-quality data, the variation in NRS use among institutions, and the association between NRS use and outcomes such as PICU length of stay and intubation rates.

Rationale: Intimate partner violence and child maltreatment have been separately associated with asthma in adults. No study has concurrently examined of adulthood adverse events (including, but not limited to, intimate partner violence) and child maltreatment on asthma in adults. Objectives: To concurrently examine of adulthood adverse events and child maltreatment on asthma in adults. Methods: This was a cross-sectional study of adulthood adverse events and child maltreatment on current asthma in 87,891 adults 40-69 years old who participated in the UK Biobank. Adulthood adverse events were assessed using questions adapted from a national crime survey. Child maltreatment was ascertained using the Childhood Trauma Screener questionnaire. Current asthma was defined as physician-diagnosed asthma and current wheeze and was further classified as noneosinophilic or eosinophilic according to eosinophil count (<300 vs. ≥300 cells per microliter). Results: In a multivariable analysis, participants who reported two or more types of adulthood adverse events had 1.19-1.45 times significantly higher odds of asthma than those who did not, whereas participants who reported two or more types of child maltreatment had 1.25-1.59 significantly higher odds of asthma than those who reported no child maltreatment. After stratification by sex, similar results were obtained for child maltreatment in women and men, whereas adulthood adverse events were only significantly associated with asthma in women. Similar findings were observed in analyses that were restricted to never-smokers and former smokers with <10 pack-years of smoking and in analyses of noneosinophilic and eosinophilic asthma. Conclusions: In a cohort of British adults, child maltreatment was associated with current asthma in men and women, whereas adulthood adverse events were associated with current asthma in women only. This was independent of cigarette smoking or eosinophil count. [ABSTRACT FROM AUTHOR]

Rationale: Little is known about the long-term impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on children with asthma. Objectives: To determine whether SARS-CoV-2 infection affects symptom control and lung function in children with asthma. Methods: Using data from clinical registries and the electronic health record, we conducted a prospective case-control study of children with asthma aged 6-21 years who had (cases) or did not have (control subjects) SARS-CoV-2 infection, comparing baseline and follow-up asthma symptom control and spirometry within an ~ 18-month time frame and, for cases, within 18 months of acute coronavirus disease (COVID-19). Results: A total of 171 cases had baseline and follow-up asthma symptom data, and 114 cases had baseline and follow-up spirometry measurements. There were no significant differences in asthma symptom control (P = 0.50), forced expiratory volume in 1 second (P = 0.47), forced vital capacity (P = 0.43), forced expiratory volume in 1 second/forced vital capacity (P = 0.43), or forced expiratory flow, midexpiratory phase (P = 0.62), after SARS-CoV-2 infection. Compared with control subjects (113 with symptom data and 237 with spirometry data), there were no significant differences in follow-up asthma symptom control or lung function. A similar proportion of cases and control subjects had poorer asthma symptom control (17.5% vs. 9.7%; P = 0.07) or worse lung function (29.0% vs. 32.5%; P = 0.50) at follow-up. Patients whose asthma control worsened after COVID-19 had a shorter time to follow-up (3.5 [1.5-7.5] vs. 6.1 [3.1-9.8] mo; P = 0.007) and were more likely to have presented with an asthma exacerbation during COVID-19 (46% vs. 26%; P = 0.04) than those without worse control. Conclusions: We found no significant differences in asthma symptom control or lung function in youth with asthma up to 18 months after acute COVID-19, suggesting that COVID-19 does not affect long-term asthma severity or control in the pediatric population. [ABSTRACT FROM AUTHOR]

Prostaglandin E2 imparts diverse physiological effects on multiple airway cells through its actions on four distinct E-type prostanoid (EP) receptor subtypes (EP1-EP4). Gs-coupled EP2 and EP4 receptors are expressed on airway smooth muscle (ASM), yet their capacity to regulate the ASM contractile state remains subject to debate. We used EP2 and EP4 subtype-specific agonists (ONO-259 and ONO-329, respectively) in cell- and tissue-based models of human ASM contraction--magnetic twisting cytometry (MTC), and precision-cut lung slices (PCLSs), respectively--to study the EP2 and EP4 regulation of ASM contraction and signaling under conditions of histamine or methacholine (MCh) stimulation. ONO-329 was superior (<0.05) to ONO-259 in relaxing MCh-contracted PCLSs (log half maximal effective concentration [logEC50]: 4.9 x 10-7 vs. 2.2 x 10-6; maximal bronchodilation ± SE, 35 ± 2% vs. 15 ± 2%). However, ONO-259 and ONO-329 were similarly efficacious in relaxing histamine-contracted PCLSs. Similar differential effects were observed in MTC studies. Signaling analyses revealed only modest differences in ONO-329- and ONO-259-induced phosphorylation of the protein kinase A substrates VASP and HSP20, with concomitant stimulation with MCh or histamine. Conversely, ONO-259 failed to inhibit MCh-induced phosphorylation of the regulatory myosin light chain (pMLC20) and the F-actin/G-actin ratio (F/G-actin ratio) while effectively inhibiting their induction by histamine. ONO-329 was effective in reversing induced pMLC20 and the F/G-actin ratio with both MCh and histamine. Thus, the contractile-agonist-dependent differential effects are not explained by changes in the global levels of phosphorylated protein kinase A substrates but are reflected in the regulation of pMLC20 (cross-bridge cycling) and F/G-actin ratio (actin cytoskeleton integrity, force transmission), implicating a role for compartmentalized signaling involving muscarinic, histamine, and EP receptor subtypes. [ABSTRACT FROM AUTHOR]

Rationale: Club cell secretory protein (CC16) is an antiinflammatory protein highly expressed in the airways. CC16 deficiency has been associated with lung function deficits, but its role in asthma has not been established conclusively. Objectives: To determine 1) the longitudinal association of circulating CC16 with the presence of active asthma from early childhood through adult life and 2) whether CC16 in early childhood predicts the clinical course of childhood asthma into adult life. Methods: We assessed the association of circulating CC16 and asthma in three population-based birth cohorts: the Tucson Children's Respiratory Study (years 6-36; total participants, 814; total observations, 3,042), the Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey (years 8-24; total participants, 2,547; total observations, 3,438), and the UK Manchester Asthma and Allergy Study (years 5-18; total participants, 745; total observations, 1,626). Among 233 children who had asthma at the first survey in any of the cohorts, baseline CC16 was also tested for association with persistence of symptoms. Measurements and Main Results: After adjusting for covariates, CC16 deficits were associated with increased risk for the presence of asthma in all cohorts (meta-analyzed adjusted odds ratio per 1-SD CC16 decrease, 1.20; 95% confidence interval [CI], 1.12-1.28; P,0.0001). The association was particularly strong for asthma with frequent symptoms (meta-analyzed adjusted relative risk ratio, 1.40; 95% CI, 1.24-1.57; P,0.0001), was confirmed for both atopic and nonatopic asthma, and was independent of lung function impairment. After adjustment for known predictors of persistent asthma, children with asthma in the lowest CC16 tertile had a nearly fourfold increased risk for having frequent symptoms persisting into adult life compared with children with asthma in the other two CC16 tertiles (metaanalyzed adjusted odds ratio, 3.72; 95% CI, 1.78-7.76; P,0.0001). Conclusions: Circulating CC16 deficits are associated with the presence of asthma with frequent symptoms from childhood through midadult life and predict the persistence of asthma symptoms into adulthood. These findings support a possible protective role of CC16 in asthma and its potential use for risk stratification. [ABSTRACT FROM AUTHOR]

Rationale: Fungal exposure has been associated with predisposing and protective effects on the development of childhood asthma. Objectives: To study whether early-life house dust mycobiota composition is associated with the development of asthma. Methods: Mycobiota were determined by amplicon sequencing from 382 dust samples collected from living room floors 2 months after birth in homes of the LUKAS cohort. Asthma status by 10.5 years of age was defined from questionnaires and assigned as ever asthma (n = 68) or current asthma (n = 27). Inhalant atopy was clinically determined at the same age. b-composition was analyzed using PERMANOVA-S, and asthma and atopy analyses were performed using discrete time hazard models and logistic regression, respectively. Results: The house dust mycobiota composition based on Bray-Curtis distance was different in the homes of children who later did or did not develop asthma. The first and the fourth axes scores of principal coordinates analysis based on Bray-Curtis were associated with ever asthma. Of the genera with the strongest correlation with these axes, the relative abundance of Boeremia, Cladosporium, Microdochium, Mycosphaerella, and Pyrenochaetopsis showed protective associations with asthma. None of these associations remained significant after mutual adjustment among the five genera or when mutually adjusted for other microbial cell wall markers and previously identified asthma-protective bacterial indices. Neither fungal a-diversity nor load was associated with asthma in the whole population, but higher fungal richness was a risk factor among children on farms. Higher fungal loads (measured via quantitative polymerase chain reaction) in house dust were associated with the risk of inhalant atopy. Conclusions: The results of our analyses from this wellcharacterized birth cohort suggest that the early-life house dust mycobiota in Finnish homes, characterized via DNA amplicon sequencing, do not have strong predisposing or protective effects on asthma development. [ABSTRACT FROM AUTHOR]

Epithelial–mesenchymal transition (EMT) contributes to airway remodeling, a predominant feature of asthma. DOCK2 (dedicator of cytokinesis 2) is an innate immune signaling molecule involved in vascular remodeling. However, it is unknown if DOCK2 plays a role in airway remodeling during asthma development. In this study, we found that DOCK2 is highly induced in both normal human bronchial epithelial cells treated with house dust mite (HDM) extract and human asthmatic airway epithelium. DOCK2 is also upregulated by TGF-b1 (transforming growth factor b1) during EMT of human bronchial epithelial cells. Importantly, knockdown of DOCK2 inhibits, and overexpression of DOCK2 promotes, TGFb1–induced EMT. Consistently, DOCK2 deficiency suppresses the EMT of airway epithelium, attenuates the subepithelial fibrosis, and improves pulmonary function in HDM-induced asthmatic lungs. These data suggest that DOCK2 plays an important role in EMT and asthma development. Mechanistically, DOCK2 interacts with transcription factor FoxM1 (forkhead box M1), which enhances FoxM1 binding to mesenchymal marker gene promoters and further promotes mesenchymal marker gene transcription and expression, leading to EMT. Taken together, our study identifies DOCK2 as a novel regulator for airway EMT in an HDM-induced asthma model, thus providing a potential therapeutic target for treatment of asthma. [ABSTRACT FROM AUTHOR]

The article focuses on the impact of comorbidities on the response to biologic treatments in severe asthma, drawing from data from the International Severe Asthma Registry. It highlights the differential effects of comorbidities such as chronic rhinosinusitis with nasal polyps (CRS 6 NP) and nasal polyps (NP) on exacerbation rates, asthma control, and lung function in patients undergoing biologic therapies.

Asthma is a heterogeneous chronic airway disease with an unmet need for improved therapeutics in uncontrolled severe disease. The calcium-sensing receptor (CaSR) is a G protein–coupled receptor upregulated in asthma. The CaSR agonist, spermine, is also increased in asthmatic airways and contributes to bronchoconstriction. CaSR negative allosteric modulators (NAMs) oppose chronic airway inflammation, remodeling, and hyperresponsiveness in murine and guinea pig asthma models, but whether CaSR NAMs are effective acute bronchodilators compared with standard of care has not yet been established. Furthermore, the ability of different classes of NAMs to inhibit spermine-induced CaSR signaling or methacholine (MCh)-induced airway contraction has not been quantified. Here, we show CaSR NAMs differentially inhibit spermine-induced intracellular calcium mobilization and inositol monophosphate accumulation in HEK293 cells stably expressing the CaSR. NAMs reverse MCh-mediated airway contraction in mouse precision-cut lung slices with similar maximal relaxation compared with the standard treatment, salbutamol. Of note, the bronchodilator effects of CaSR NAMs are maintained under conditions of β2-adrenergic receptor desensitization when salbutamol efficacy is abolished. Furthermore, overnight treatment with some, but not all, CaSR NAMs prevents MCh-mediated bronchoconstriction. These findings further support the CaSR as a putative drug target and NAMs as alternative or adjunct bronchodilators in asthma. [ABSTRACT FROM AUTHOR]

Rhinoviruses (RVs) evoke as many as 85% of acute asthma exacerbations in children and 50% in adults and can induce airway hyperresponsiveness and decrease efficacy of current therapeutics to provide symptom relief. Using human precision-cut lung slices (hPCLSs), primary human air–liquid interface–differentiated airway epithelial cells (HAECs), and human airway smooth muscle (HASM) as preclinical experimental models, we demonstrated that RV-C15 attenuates agonist-induced bronchodilation. Specifically, airway relaxation to formoterol and cholera toxin, but not forskolin (Fsk), was attenuated following hPCLS exposure to RV-C15. In isolated HASM cells, exposure to conditioned media from RV-exposed HAECs decreased cellular relaxation in response to isoproterenol and prostaglandin E2, but not Fsk. Additionally, cAMP generation elicited by formoterol and isoproterenol, but not Fsk, was attenuated following HASM exposure to RV-C15–conditioned HAEC media. HASM exposure to RV-C15–conditioned HAEC media modulated expression of components of relaxation pathways, specifically GNAI1 and GRK2. Strikingly, similar to exposure to intact RV-C15, hPCLS exposed to UV-inactivated RV-C15 showed markedly attenuated airway relaxation in response to formoterol, suggesting that the mechanism(s) of RV-C15–mediated loss of bronchodilation is independent of virus replication pathways. Further studies are warranted to identify soluble factor(s) regulating the epithelial-driven smooth muscle loss of β2-adrenergic receptor function. [ABSTRACT FROM AUTHOR]

Rationale: There is a differential response to eosinophilic modulation between patients with asthma and those with chronic obstructive pulmonary disease (COPD). There is also evidence of different subtypes of eosinophils in murine models. However, no study has compared eosinophil subtypes in individuals with COPD and in those with asthma. Objectives: Study the differences in eosinophils subtypes based in the surface protein expression in COPD patients and asthmatic patients. Methods: We studied 10 stable subjects in each of four groups: subjects with COPD, subjects with asthma, smokers without COPD, and healthy volunteers. Subjects with COPD and those with asthma were matched by age, sex, and FEVi% predicted. The following variables were determined: anthropometries, smoking, exacerbation history, medication use, lung function, and comorbidities. Using flow cytometry and confocal microscopy from blood samples, we determined differences in eosinophil surface proteins and classified them as 1) resident eosinophils (Siglec-8+CD62L+IL-3R10) or 2) inflammatory eosinophils (iEos; Siglec-8+CD62LloIL-3Rhl). IL-5 receptor was also determined. Findings were validated in 59 patients with COPD and in 17 patients with asthma. Measurements and Main Results: Patients with asthma had a higher proportion of iEos (25 ±15%) compared with those with COPD (0.5 ± 1%), smokers without COPD (0.14 ± 0.24%), and healthy volunteers (0.67 ± 1.72%). In patients with asthma, the proportion of iEos was independent of total eosinophil number. iEos had more IL-5 receptors than resident eosinophils (777.02 ± 124.55 vs. 598.35 ±318.69; P<0.01). In patients with COPD, there was no relation between iEos number and inhaled corticosteroid use, disease severity, or exacerbations rate. The findings in patients with COPD and those with asthma were confirmed in validation cohorts. Conclusions: There are differences in the subtypes of circulating eosinophils between patients with asthma and those with COPD. This could have clinical implications in the interpretation of eosinophil significance and the approach to therapy in these patients. [ABSTRACT FROM AUTHOR]

Rationale: Children with preschool wheezing or school-age asthma are reported to have airway microbial imbalances. Objectives: To identify clusters in children with asthma or wheezing using oropharyngeal microbiota profiles. Methods: Oropharyngeal swabs from the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) pediatric asthma or wheezing cohort were characterized using 16S ribosomal RNA gene sequencing, and unsupervised hierarchical clustering was performed on the Bray-Curtis ß-diversity. Enrichment scores of the Molecular Signatures Database hallmark gene sets were computed from the blood transcriptome using gene set variation analysis. Children with severe asthma or severe wheezing were followed up for 12-18 months, with assessment of the frequency of exacerbations. Measurements and Main Results: Oropharyngeal samples from 241 children (age range, 1-17 years; 40% female) revealed four taxa-driven clusters dominated by Streptococcus, Veillonella, Rothia, and Haemophilus. The clusters showed significant differences in atopic dermatitis, grass pollen sensitization, FEVi% predicted after salbutamol, and annual asthma exacerbation frequency during follow-up. The Veillonella cluster was the most allergic and included the highest percentage of children with two or more exacerbations per year during follow-up. The oropharyngeal clusters were different in the enrichment scores of TGF-ß (transforming growth factor-ß) (highest in the Veillonella cluster) and Wnt/ß-catenin signaling (highest in the Haemophilus cluster) transcriptomic pathways in blood (all q values <0.05). Conclusions: Analysis of the oropharyngeal microb iota of children with asthma or wheezing identified four clusters with distinct clinical characteristics (phenotypes) that associate with risk for exacerbation and transcriptomic pathways involved in airway remodeling. This suggests that further exploration of the oropharyngeal microbiota may lead to novel pathophysiologic insights and potentially new treatment approaches. [ABSTRACT FROM AUTHOR]

Rationale: Tezepelumab reduced exacerbations in patients with severe, uncontrolled asthma across a range of baseline blood eosinophil counts and fractional exhaled nitric oxide levels, and irrespective of allergy status, in the phase 2b PATHWAY (Study to Evaluate the Efficacy and Safety of MEDI9929 [AMG 157] in Adult Subjects With Inadequately Controlled, Severe Asthma; NCT 02054130) and phase 3 NAVIGATOR (Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma; NCT 03347279) trials. Objectives: To examine the efficacy and safety of tezepelumab in additional clinically relevant subgroups using pooled data from PATHWAY and NAVIGATOR. Methods: PATHWAY and NAVIGATOR were randomized, double-blind, placebo-controlled trials with similar designs. This pooled analysis included patients with severe, uncontrolled asthma (PATHWAY, 18–75 years old; NAVIGATOR, 12–80 years old) who received tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. The annualized asthma exacerbation rate over 52 weeks and secondary outcomes were calculated in the overall population and in subgroups defined by inflammatory biomarker levels or clinical characteristics. Measurements and Main Results: Overall, 1,334 patients were included (tezepelumab, n = 665; placebo, n = 669). Tezepelumab reduced the annualized asthma exacerbation rate versus placebo by 60% (rate ratio, 0.40 [95% confidence interval, 0.34–0.48]) in the overall population, and clinically meaningful reductions in exacerbations were observed in tezepelumab-treated patients with type 2–high and type 2–low disease by multiple definitions. Tezepelumab reduced exacerbation-related hospitalization or emergency department visits and improved secondary outcomes compared with placebo overall and across subgroups. The incidence of adverse events was similar between treatment groups. Conclusions: Tezepelumab resulted in clinically meaningful reductions in exacerbations and improvements in other outcomes in patients with severe, uncontrolled asthma, across clinically relevant subgroups. [ABSTRACT FROM AUTHOR]

Asthma is a chronic inflammatory airway disease driven by various infiltrating immune cell types into the lung. Optical microscopy has been used to study immune infiltrates in asthmatic lungs. Confocal laser scanning microscopy (CLSM) identifies the phenotypes and locations of individual immune cells in lung tissue sections by employing high-magnification objectives and multiplex immunofluorescence staining. In contrast, light-sheet fluorescence microscopy (LSFM) can visualize the macroscopic and mesoscopic architecture of wholemount lung tissues in three dimensions (3D) by adopting an optical tissue-clearing method. Despite each microscopy method producing image data with unique resolution from a tissue sample, CLSM and LSFM have not been applied together because of different tissue-preparation procedures. Here, we introduce a new approach combining LSFMand CLSM into a sequential imaging pipeline. We built a new optical tissue clearing workflow in which the immersion clearing agent can be switched from an organic solvent to an aqueous sugar solution for sequential 3D LSFMand CLSMof mouse lungs. This sequential combination microscopy offered quantitative 3D spatial analyses of the distribution of immune infiltrates in the samemouse asthmatic lung tissue at the organ, tissue, and cell levels. These results show that ourmethod facilitates multiresolution 3D fluorescencemicroscopy as a new imaging approach providing comprehensive spatial information for a better understanding of inflammatory lung diseases. [ABSTRACT FROM AUTHOR]

Rationale: Indirect airway hyperresponsiveness (AHR) is a highly specific feature of asthma, but the underlying mechanisms responsible for driving indirect AHR remain incompletely understood. Objectives: To identify differences in gene expression in epithelial brushings obtained from individuals with asthma who were characterized for indirect AHR in the form of exercise-induced bronchoconstriction (EIB). Methods: RNA-sequencing analysis was performed on epithelial brushings obtained from individuals with asthma with EIB (n = 11) and without EIB (n = 9). Differentially expressed genes (DEGs) between the groups were correlated with measures of airway physiology, sputum inflammatory markers, and airway wall immunopathology. On the basis of these relationships, we examined the effects of primary airway epithelial cells (AECs) and specific epithelial cell–derived cytokines on both mast cells (MCs) and eosinophils (EOS). Measurements and Main Results: We identified 120 DEGs in individuals with and without EIB. Network analyses suggested critical roles for IL-33–, IL-18–, and IFN-γ–related signaling among these DEGs. IL1RL1 expression was positively correlated with the density of MCs in the epithelial compartment, and IL1RL1, IL18R1, and IFNG were positively correlated with the density of intraepithelial EOS. Subsequent ex vivo modeling demonstrated that AECs promote sustained type 2 (T2) inflammation in MCs and enhance IL-33–induced T2 gene expression. Furthermore, EOS increase the expression of IFNG and IL13 in response to both IL-18 and IL-33 as well as exposure to AECs. Conclusions: Circuits involving epithelial interactions with MCs and EOS are closely associated with indirect AHR. Ex vivo modeling indicates that epithelial-dependent regulation of these innate cells may be critical in indirect AHR and modulating T2 and non-T2 inflammation in asthma. [ABSTRACT FROM AUTHOR]

Rationale: Emerging research suggests that e-cigarette (EC) use may have detrimental health effects, increasing the burden on healthcare systems. Objectives: To determine whether young EC users had increased asthma, asthma attacks, and health services use (HSU). Methods: This cohort study used the linked Canadian Community Health Survey (cycles 2015–16 and 2017–18) and health administrative data (January 2015–March 2018). A propensity score method matched self-reported EC users to up to five control subjects. Matched multivariable logistic and negative binomial regressions were used to calculate odds ratios, rate ratios (RRs), and 95% confidence intervals (CIs) with EC use as the exposure and asthma, asthma attacks, and all-cause HSU as the outcomes. Results: Analyses included 2,700 matched Canadian Community Health Survey participants (15–30 yr), 505 (2.4% of 20,725 participants) EC users matched to 2,195 nonusers. After adjusting for confounders, EC users with asthma had over twofold higher odds of having an asthma attack in the last 12 months (odds ratio, 2.30; 95% CI, 1.29–4.12). Dual EC and conventional tobacco users had a twofold increased all-cause HSU rate compared with nonusers who never smoked tobacco (RR, 2.13; 95% CI, 1.53–2.98). This rate was greater than that for EC users who never smoked tobacco (RR, 1.73; 95% CI, 1.00–3.00) and non-EC users who regularly smoke tobacco (RR, 1.72; 95% CI, 1.29–2.29). Compared with male nonusers, female EC users had the highest increased all-cause HSU (RR, 1.94; 95% CI, 1.39–2.69) over male EC users and female nonusers (RR, 1.13; 95% CI, 0.86–1.48; RR, 1.41; 95% CI, 1.16–1.71, respectively). Conclusions: Current EC use is associated with significantly increased odds of having an asthma attack. Furthermore, concurrent EC use and conventional cigarette smoking are associated with a higher rate of all-cause HSU. The odds of asthma attack and all-cause HSU were highest among women. Thus, EC use may be an epidemiological biomarker for youth and young adults with increased health morbidity. [ABSTRACT FROM AUTHOR]

Epidemiological surveys indicate that intrauterine inflammation increases the risk of asthma in offspring. However, the underlying mechanisms remain largely unknown. Previous studies in BALB/c and C57BL/6 mice showed that prenatal exposure to endotoxins prevented allergic airway inflammation in offspring, which is inconsistent with most clinical observations. In this study, we found that prenatal LPS exposure increased airway resistance and total exfoliated cell counts, eosinophils, and IL-4 concentrations in BAL fluid of ovalbumin-sensitized Institute of Cancer Research (ICR) mice. Importantly, long noncoding RNA (lncRNA) NONMMUT033452.2 was upregulated in the lungs of LPS-exposed ICR offspring. Fluorescence in situ hybridization and cytoplasmic and nuclear fraction analyses revealed that this lncRNA was distributed in both the nuclei and cytoplasm of lung and airway epithelial cells, smooth muscle cells, and fibroblasts. Intranasal administration of NONMMUT033452.2 siRNA markedly alleviated allergic airway inflammation in ovalbumin-sensitized ICR mice. In vitro functional experiments demonstrated that overexpression of NONMMUT033452.2 inhibited the proliferation of lung and bronchiolar epithelial cells and promoted oxidative stress. RNA pull-down assays proved that NONMMUT033452.2 could directly bind Eef1D (eukaryotic translation elongation factor 1 delta). Overexpression of NONMMUT033452.2 induced the redistribution of Eef1D and substantially inhibited the expression of its downstream heat shock genes. NONMMUT033452.2 was also involved in the modulation of IL-1, IL-12, and some key molecules related to asthma, including Npr3 (natriuretic peptide receptor 3), Rac1 (Rac family small GTPase 1), and Nr4a3 (nuclear receptor subfamily 4, group A, member 3). Furthermore, the human lncRNA NONHSAT078603.2 was identified as a functional homolog of NONMMUT033452.2. These findings provide new insight into the pathogenic mechanism underlying asthma development. [ABSTRACT FROM AUTHOR]

TAS2Rs (bitter taste receptors) are GPCRs (G protein-coupled receptors) expressed on human airway smooth muscle (HASM) cells; when activated by receptor agonists they evoke marked airway relaxation. In both taste and HASM cells, TAS2Rs activate a canonical Gβγ-mediated stimulation of Ca2+ release from intracellular stores by activation of PLCβ (phospholipase Cβ). Alone, this [Ca2+]i signaling does not readily account for relaxation, particularly since bronchoconstrictive agonists acting at Gq-coupled receptors also increase [Ca2+]i. We established that TAS2R14 activation in HASM promotes relaxation through F-actin (filamentous actin) severing. This destabilization of actin was from agonist-promoted activation (dephosphorylation) of cofilin, which was pertussis toxin sensitive. Cofilin dephosphorylation was due to TAS2R-mediated deactivation of LIM domain kinase. The link between early receptor action and the distal cofilin dephosphorylation was found to be the polarity protein partitioning defective 3 (Par3), a known binding partner with PLCβ that inhibits LIM kinase. The physiologic relevance of this pathway was assessed using knock-downs of cofilin and Par3 in HASM cells and in human precision-cut lung slices. Relaxation by TAS2R14 agonists was ablated with knock-down of either protein as assessed by magnetic twisting cytometry in isolated cells or intact airways in the slices. Blocking [Ca2+]i release by TAS2R14 inhibited agonist-promoted cofilin dephosphorylation, confirming a role for [Ca2+]i in actin-modifying pathways. These results further elucidate the mechanistic basis of TAS2R-mediated HASM relaxation and point toward nodal points that may act as asthma or chronic obstructive pulmonary disease response modifiers or additional targets for novel bronchodilators. [ABSTRACT FROM AUTHOR]