The development of targeted mAbs has transformed the treatment of moderate-to-severe asthma. The main clinical trial outcomes have focused on exacerbation reduction and lung function improvement. In the past few years, there have been many high-quality studies examining pathophysiologic effects of the biologic therapies, giving insight into their downstream impacts. Clinical remission is a growing area of interest, and many studies highlight the utility as well as the limitations of commonly available biomarkers to predict treatment response. This review synthesizes the results of recent clinical trials and related topics focusing on relevant updates to the literature since 2024, highlighting new indications for use, predictors of response, safety data, real-world comparative effectiveness, remission, and mechanistic advances.

Children born small for gestational age (SGA) face elevated risks of metabolic, cardiovascular, respiratory, and neurodevelopmental disorders, as well as premature mortality, yet the underlying mechanisms remain only partly understood. We analyze blood proteomic data from multiple birth cohorts to identify molecular pathways linked to SGA and to later-life lung function. We find that approximately one-third of SGA children exhibit a distinct molecular endotype marked by dysregulation of axon-guidance proteins in cord blood. In peripheral blood collected later in life, these proteins are inversely associated with contemporaneous spirometric restriction. Using GWAS data and an experimental sheep model, we obtain convergent evidence that axon-guidance genes are associated with spirometric indices (FEV1/FVC) at genome-wide significance and are broadly expressed during fetal development across multiple organs. These findings offer new insight into the developmental origins of chronic disease and highlight axon-guidance pathways as promising targets for investigating multiorgan morbidity.

Background: Childhood-onset asthma is highly heritable, with nearly 200 risk loci identified in genome-wide association studies. Aggregated polygenic risk scores (PRSs) can be used to quantify genetic predisposition to asthma, but their power to predict asthma severity in multiancestral groups has not been previously evaluated. Objective: Our aim was to examine the predictive power of biobank-derived asthma PRSs in 4 multiancestry asthma study cohorts of children living in US urban environments. Methods: We generated PRSs for asthma, derived from a large-scale genome-wide association meta-analysis, and assessed genetic predictions across different subphenotypes of asthma and tested for associations between genetic asthma risk and measures of asthma severity. Results: PRS prediction was significantly stronger for more symptomatic asthma phenotypes (P < .001), and scores were significantly higher in difficult-to-control versus easy-to-control asthma (P = .02). Genetic risk was also significantly associated with more frequent exacerbations (P = .03), higher blood eosinophil levels (P = .01), and lower lung function (P < .001). Conclusion: Cumulative genetic risk for asthma is associated with disease severity and exacerbation risk in children with asthma.

Background: The nasal allergen challenge (NAC) is a tool for evaluating upper airway allergic responses. In the CRITICAL study, NAC with cockroach allergen was used to confirm clinical reactivity in sensitized individuals from urban environments before enrollment onto a subcutaneous immunotherapy trial. Objective: Immunologic and transcriptomic predictors of NAC responsiveness were identified. Methods: NAC was performed in 103 participants. Clinical responses were assessed by the Total Nasal Symptom Score (TNSS) and sneeze score (TSNEEZ), which scale positively with symptom severity. Baseline immunologic markers—including skin prick test wheal size, cockroach-specific IgE, IgG, and IgG4, and T-cell responses were evaluated. Nasal lavage samples were analyzed for gene expression modules. Clinical trial registration: ClinicalTrials.gov NCT03541187. Results: Larger skin prick test wheal sizes were significantly associated with positive NAC outcomes (2.2 mm larger than negative NAC) and lower reactive doses (hazard ratio = 1.10). Cockroach (i6 extract)-specific IgE levels were inversely correlated with TNSS, while levels of IgE, IgG, and IgG4 specific to the extract used for therapy showed no association. Higher IL-10 T-cell responses were observed in those without reaction, while Bla g 5 and Bla g 9 dominance correlated negatively with TNSS and positively with TSNEEZ, respectively. Transcriptomic analysis revealed that higher expression of eosinophil- and neutrophil-associated modules and lower expression of type 1 interferon, macrophage, and epithelial barrier modules were linked to positive NAC responses. Conclusion: NAC responsiveness to cockroach extract is influenced by skin test reactivity, T- and B-cell regulation, and nasal gene expression. These findings highlight the role of both adaptive and innate immunity in allergic airway responses and suggest potential biomarkers for clinical reactivity.

BACKGROUND:Wheezing lower respiratory tract illnesses are a major health concern in preschool children. We report the results of the ORBEX trial which evaluated the safety and efficacy of the bacterial lysate, OM-85, in the primary prevention of wheezing lower respiratory tract illness. METHODS:ORBEX is a parallel-arm, double-blind, placebo-controlled trial for the primary prevention of wheezing lower respiratory tract illness in young children at increased risk for asthma due to atopic dermatitis, parental asthma, or asthma in a blood sibling aged 4 years or older. Children aged 6-18 months were centrally randomly assigned (1:1) at 11 academic clinical sites with experience in recruiting young children in the USA to receive OM-85 3·5 mg or placebo orally for 10 days each month for 24 months and then followed for an additional 36 months to evaluate outcomes while they were off the study drug. Identical openable capsules were used for active drug and placebo, and staff, investigators, and participants were masked to treatment assignment. Participants received usual treatment for wheezing illness as per US guidelines. Randomisation was stratified by sex, age group, family history of asthma, and clinical site. The primary outcome was the time to first wheezing lower respiratory tract illness during the 36-month observation period off the study drug analysed in the intention-to-treat population, which included all randomly assigned participants. The trial is registered with clinicaltrials.gov, NCT02148796, and is completed. FINDINGS:Between Jan 3, 2017, and Nov 30, 2020, 984 children were screened for eligibility, 162 were excluded, and 822 were randomly assigned (411 to the OM-85 intervention group and 411 to the placebo group). 492 participants were male (59·9%) and 330 (40·1%) were female and the mean age of participants was 11·8 months (SD 3·8). 681 children completed the 24-month treatment period, and 596 children completed the 36-month observation period. 132 children experienced at least one wheezing lower respiratory tract illness during the observation period; 71 (21%) of 342 in the OM-85 group and 61 (18%) of 339 in the placebo group. There was no significant difference between OM-85 and placebo with respect to the time to first wheezing lower respiratory tract illness (log-rank test p value 0·35; hazard ratio 1·16 [95% CI 0·82-1·64]). The most frequent adverse events, fevers, coughs, and colds, did not differ between groups. INTERPRETATION:Oral administration of OM-85 in early life did not decrease the incidence of wheezing lower respiratory tract illness in this high-risk population. Bacterial lysates are not efficacious for the primary prevention of asthma-like symptoms during the preschool years. FUNDING:National Heart, Lung, and Blood Institute and OM Pharma with supplemental funding and provision of study drug and placebo from OM Pharma.

Respiratory syncytial virus (RSV) infects nearly all children by age 2 to 3 years, and early-life infection-defined using active and passive surveillance with quantitative polymerase chain reaction- and serology-identified infection-has been implicated as a causal factor in childhood asthma. As such, identifying infants that are likely to be infected with RSV during this critical susceptibility window has important implications for identifying individuals at risk for chronic respiratory sequelae. However, determining the age of RSV infection in large populations is challenging because many infections are asymptomatic, making accurate detection dependent on intensive and costly surveillance. To address this, we developed a probability model for age of first RSV infection. It uses an infant's birthdate, demographic covariates, and publicly available RSV circulation data to determine the probability they were first infected at any age from birth to one year. Our model is interpretable, accounts for nearly 37% of the variance in age at first infection, and generalizes across four independent datasets collected from participants in the United States, where we use it to accurately predict age of first infection in two independent cohorts. Our work facilitates reliable estimation of the age of infant RSV infection during the first year of life without the need for active surveillance.

BACKGROUND:Depemokimab, the first ultra-long-acting biologic with enhanced IL-5 binding affinity, high inhibition potency, and extended half-life, enables twice-yearly dosing in patients with asthma. In phase III SWIFT-1/-2 trials, depemokimab significantly reduced the annualized exacerbation rate by 54% versus placebo with sustained suppression of inflammation assessed by blood eosinophil count in type 2 asthma. OBJECTIVE:To evaluate the onset and duration of depemokimab efficacy across each 26-week dosing period in the pooled SWIFT-1/-2 population and identify patient characteristics associated with enhanced clinical response. METHODS:Patients with type 2 asthma, independent of Asthma Control Questionnaire-5 (ACQ-5) status, were randomized 2:1 to receive depemokimab 100 mg subcutaneously or placebo every 26 weeks for 52 weeks. Prespecified end points included time to first exacerbation, St George's Respiratory Questionnaire total score, ACQ-5 score, Asthma Nighttime Symptom Diary weekly score, Asthma Daytime Symptom Diary weekly score, and rescue medication use over time. We conducted post hoc subgroup analyses by baseline characteristics. RESULTS:Depemokimab reduced the probability of first exacerbation over 52 weeks versus placebo by 46% (hazard ratio = 0.54; 95% CI, 0.43-0.69), with effects from week 4 sustained across both dosing periods. Annualized exacerbation rate reductions were most pronounced in patients with asthma disease duration less than 10 years, comorbid chronic rhinosinusitis with nasal polyps, and medium-dose inhaled corticosteroids (ICS) at baseline. Across each dosing period, depemokimab also improved St George's Respiratory Questionnaire, ACQ-5, Asthma Nighttime Symptom Diary, and Asthma Daytime Symptom Diary scores, particularly in patients with baseline ACQ-5 scores of 1.5 or greater, with sustained improvements in rescue medication. CONCLUSION:Early and sustained efficacy with depemokimab was observed across 26-week dosing periods in type 2 asthma, with enhanced benefits in patients with shorter disease duration who had not progressed to high-dose ICS.

Background Single-nucleotide polymorphisms (SNPs) in the chromosome 17q12-q21 region and, independently, early-life nasal microbiota dominated by Moraxella, Streptococcus, or Haemophilus (MSH) increase risk of chronic wheeze and asthma development. Objective We sought to determine whether 17q12-q21 risk SNPs and nasal microbiota interact to modulate childhood wheeze risk. Methods Nasal wash samples from 12-month-old infants in 2 birth cohorts, COAST (Childhood Origins of Asthma; n = 180) and URECA (Urban Environment and Childhood Asthma; n = 139), underwent 16S ribosomal RNA variable region 4 sequencing. Nasal microbiota dominated by MSH or Corynebacterium, Dolosigranulum, Staphylococcus, or Bacillus (CDSB) were assessed. Paired blood was genotyped for 9 17q12-q21 risk SNPs. Logistic regression tested interactions between 17q12-q21 SNPs and MSH or CDSB on wheeze risk in the first 3 years of life. A549 lung epithelial cells, CRISPR-edited to encode the rs7216389 risk genotype (rs7216389TT) were compared to the heterozygous (rs7216389CT) line using bulk RNA sequencing. Results SNPs, particularly those in the ORMDL3 (rs8076131; odds ratio [OR]: 1.72; 95% CI: 1.09-2.71; Pint = .031) and GSDMB (rs2305480; OR: 1.72; 95% CI: 1.09-2.71; Pint = 0.042; and rs7216389; OR: 1.73; 95% CI: 1.09-2.70; Pint = .047) genes, interact with MSH microbiota to increase early-life wheeze risk (false discovery rate Pint = .016 for all), while interactions with CDSB reduce risk. A549 airway epithelial cells homozygous for rs7216389TT exhibited decreased expression of genes involved in antimicrobial responses and neutrophil recruitment and evidence increased microbial adherence compared with the heterozygous cell line. Conclusion Airway microbiota interact with SNPs at the 17q12-q21 locus in genes involved in sphingolipid metabolism and intracellular antimicrobial responses, to modulate wheeze risk.

Background:In ∼10% of asthma patients, symptoms remain uncontrolled despite maximal treatment, representing an unmet clinical need. The causal variants, genes and pathways underlying genetic risk factors have not been fully elucidated, and it is unclear whether there are unique genetic risk factors for this asthma subtype. Methods:We used electronic healthcare records linked to UK Biobank to identify asthma patients with high treatment burden and/or worse outcomes. We performed a genome-wide association study (GWAS) with this case population and healthy controls. We sought replication for associated (p≤5×10-6) signals in four independent studies (12 152 cases and 32 316 controls). Replicated signals were fine-mapped and linked to genes and pathways. Results:In total, 7681 participants met our case definition and showed enrichment for adult-onset asthma, female gender and higher body mass index compared to asthma individuals not meeting case criteria. GWAS with 7681 cases and 38 405 controls revealed 21 reproducible association signals that had previously been associated with asthma, but had a larger effect size in our study. Variant-to-gene mapping highlighted 85 candidate genes, five of which were considered high confidence (BACH2, D2HGDH, IL1RL1, RPS26, SMAD3). Conclusion:We present the first use of electronic healthcare records in UK Biobank to identify a subtype of asthma enriched for patients with high treatment burden and/or worse outcomes. Our findings support the role of known asthma genes, highlighting genetic risk variants with stronger effect in these groups of patients. The prioritised genes provide potential therapeutic opportunities for this difficult-to-treat patient population.

BACKGROUND:DNA methylation accurately predicts chronological age, including gestational age (GA). Previous studies have used 5'-C-phosphate-G-3' sites (CpGs) on the EPIC or 450K arrays to generate epigenetic clocks for estimating GA. OBJECTIVE:Using the Asthma&Allergy array, we estimated GA and calculated GA acceleration (GAA) in cord blood DNA from 2451 ancestrally diverse participants from 7 birth cohorts investigating early life risk factors for asthma and allergic diseases and disease onset in childhood. METHODS:Two gestational epigenetic clocks were constructed: one used GA-associated CpGs in an epigenome-wide association study (EWAS) and a second used CpGs associated with GA in specific cell types. For both, we calculated GAA and tested for associations with 6 prenatal variables and 8 allergy-related childhood outcomes. We then conducted pathway analysis of expressed genes correlated with GAA and validated gene expression signatures in peripheral blood at age 2 years. RESULTS:Strong correlations between reported GA and estimated GA were observed using the EWAS and the cell-specific clocks (r = 0.90 and 0.83, respectively). Using the cell-specific clock, GAA was associated with 2 outcomes (higher birthweight, Padj = 1.69 × 10-5; less allergic asthma, Padj = .025), while the EWAS clock was associated with birthweight (Padj = 4.68 × 10-4). A significant sex-by-GAA interaction effect on birthweight, with a larger effect size in females, was observed with both clocks (EWAS, Pint = 5.77 × 10-3; cell-specific, Pint = .021). Cord blood RNA-sequencing analysis revealed upregulated IL6 and TNF and downregulated IL10 signaling pathways associated with GAA, and gene expression in blood at age 2 years further revealed associations with asthma at age 7 years. CONCLUSION:Positive correlations between GAA and inflammatory gene expression and the negative association with allergic asthma suggest that increased expression of inflammatory genes in cord blood and at age 2 years is protective against developing asthma. CpGs on the Asthma&Allergy array are accurate predictors of GA, capturing aging aspects specifically related to inflammatory programs.

RATIONALE:Depemokimab is the first ultra-long-acting biologic with high IL-5 binding affinity, high potency, and an extended half-life enabling twice-yearly dosing. OBJECTIVES:Investigate the efficacy and safety of switching to depemokimab in participants with severe asthma already managed with and responsive to short-acting biologic therapies targeting IL-5 or its receptor. METHODS:NIMBLE (NCT04718389) was a multicenter, randomized, double-blind, double-dummy, parallel-group, phase 3A noninferiority study. Participants were ≥12 years old with asthma and documented clinical benefit on mepolizumab 100 mg subcutaneously every 4 weeks or benralizumab 30 mg subcutaneously every 8 weeks for ≥12 months. Participants were randomized 1:1 to depemokimab 100 mg subcutaneously every 26 weeks or maintained on their prior biologic (mepolizumab or benralizumab). The primary endpoint was annualized rate of clinically significant exacerbations over 52 weeks, with predefined noninferiority margin set at 1.28. Safety endpoints included adverse events. MEASUREMENTS AND MAIN RESULTS:Annualized rates (95% confidence intervals [CIs]) of clinically significant exacerbations over 52 weeks were 0.57 (0.50 to 0.64) with depemokimab (n = 848) and 0.49 (0.43 to 0.55) with active comparator (n = 839); the rate ratio (95% CI) was 1.16 (0.98 to 1.38). Since the upper bound of the 95% CI exceeded 1.28, noninferiority was not met. Most participants in both treatment arms experienced no clinically significant exacerbations. Health-related quality of life, asthma control, and lung function outcomes were stable throughout the study. Adverse events were comparable between treatment groups. CONCLUSIONS:While statistical noninferiority was not met, exacerbation rates were low and symptom control/lung function were maintained in both groups. This first randomized, controlled switch trial in severe asthma suggests that participants with severe asthma on mepolizumab or benralizumab may safely switch to twice-yearly depemokimab.

BACKGROUND:Rhinoviruses (RV) are the most common respiratory viruses globally and a major cause of airway symptoms in children and individuals with asthma. Although more than 170 RV types exist across 3 species (RV-A, RV-B, RV-C), type-specific circulation patterns and age-related prevalence remain poorly defined. OBJECTIVE:We characterized long-term circulation patterns, age-specific prevalence, and host genetic associations of RV types using a large pediatric dataset. METHODS:We retrospectively analyzed 12,697 RV infections identified by PCR and partial sequencing from 11,960 nasal samples collected between 1997 and 2025 across 20 pediatric populations in Finland, Australia, and the United States, including 10 National Institutes of Health ECHO cohort sites. RV types were classified by species, and host CDHR3 rs6967330 genotype, which impacts RV-C receptor binding, was available for a subset. Temporal stability, phylogenetic clustering, and detection frequency by age were assessed by stream graph visualization, slope modeling, and Spearman correlation. RESULTS:RV type circulation was remarkably stable over 3 decades; 97% of types had slope estimates whose 95% confidence intervals included zero, indicating no significant temporal change. Commonly detected types did not consistently cluster phylogenetically, suggesting that capsid sequence similarity does not fully explain fitness. Certain types (eg, A36, A101, C15) were prevalent across all pediatric age groups, whereas others (eg, C2, C40, A78, A12) were more frequent in younger children. The CDHR3 rs6967330-A risk allele was associated with increased overall RV-C infection but it did not alter the distribution of common versus rare RV-C types. CONCLUSION:RV type prevalence and age-specific patterns have remained stable for decades, supporting targeted interventions focused on consistently circulating types and those most common in young children.

Striving for clinical remission in asthma is a new approach to treatment whose time has come. It is critical that a widely accepted definition of asthma clinical remission be developed that is agreed to be both practical and meaningful to clinicians, researchers, and patients. To advance this development process, National Jewish Health convened a panel of experts in the field for a 2-day virtual workshop to critically assess previously proposed definitions of remission in asthma and other immune-mediated diseases and the latest evidence from clinical studies of remission in patients with asthma treated with biologic therapies. After careful deliberation, we present the panel's definition of asthma clinical remission and identify unresolved issues that deserve further investigation and wider discussion among different stakeholder groups. This article is part of a supplement supported by an educational grant from AstraZeneca Pharmaceuticals. The content of this article was developed independently by National Jewish Health and the article authors.

BACKGROUND:Rhinoconjunctivitis phenotypes are conventionally described on the basis of symptom severity, duration and seasonality, and aeroallergen sensitization. It is not known whether these phenotypes fully reflect the patterns of symptoms seen at a population level. OBJECTIVE:We sought to identify phenotypes of rhinoconjunctivitis on the basis of symptom intensity and seasonality using an unbiased approach and to compare their characteristics. METHODS:A cohort of children with asthma in low-income urban environments was prospectively followed with a rhinoconjunctivitis activity questionnaire, and their upper and lower airway disease was managed for 12 months with every 2-month visit based on standardized algorithms. We identified individual rhinoconjunctivitis symptom trajectories and clusters of those trajectories and compared the clusters focusing on atopic characteristics. RESULTS:Data obtained from 619 children yielded 5 symptom clusters: 2 had high symptoms (22.5%) but differed in seasonal pattern, 1 had medium symptoms (13.6%), 1 had medium nasal congestion only (20.4%), and 1 had low symptoms (43.6%). The latter was further split into 2 subgroups if nasal corticosteroids were frequently prescribed (23.6%) or not (20.0%). Seasonal variation was absent in the low symptom clusters. The number of allergic sensitizations and family history of allergic airway disease were higher in the high symptom clusters, but allergic sensitization did not explain differences in seasonality. CONCLUSIONS:This study identified rhinoconjunctivitis phenotypes that have not been previously reported and were not differentiated by demographics or by measures of atopy and type 2 inflammation. Factors beyond allergy need to be investigated to better understand the pathobiology of rhinoconjunctivitis.

The relationship between infections, immune development, and preschool recurrent wheezing and asthma is complex and multifaceted. Respiratory syncytial virus (RSV) and rhinovirus (RV) are significant early-life triggers for wheezing, with differing immunologic and genetic associations. RV, especially RV-C, has been closely linked to asthma development, particularly allergic asthma. RSV wheezing illnesses can identify susceptible children and are linked to nonallergic asthma. Ongoing studies using broader RSV prevention (vaccines, mAbs) in full-term infants may further clarify these relationships. Both RSV and RV infections are associated with changes in bacterial abundance. The timing of these changes and the bacterial strains that are altered are likely important factors in asthma development that are continually being investigated. Beyond viral triggers, asthma and recurrent wheeze in preschoolers result from a complex interplay of microbial (urban vs rural living), environmental (eg, air pollution levels and diet) and host immune factors. Strategies focusing on microbiome modulation (eg, bacterial lysate ingestion), pollution reduction, increasing biodiversity, and nutritional support (eg, vitamin D) may offer promising paths for prevention and improved management.