Doffman SR, Dosanjh DPS, Sadiq MW
… +17 more, Matsunaga Y, Cooper JD, Edwards G, Asimus S, Abuqayyas L, Zhou XH, Scott IC, Cardner M, Parnes JR, Kovacina K, White N, Cushion MG, Belvisi MG, Saralaya D, Brown T, Beier J, Molfino NA
BACKGROUND: AZD8630/AMG 104 is an inhaled anti-thymic stromal lymphopoietin (TSLP) antibody fragment in development for the treatment of patients with moderate-to-severe asthma. OBJECTIVE: We sought to evaluate the safet...BACKGROUND: AZD8630/AMG 104 is an inhaled anti-thymic stromal lymphopoietin (TSLP) antibody fragment in development for the treatment of patients with moderate-to-severe asthma. OBJECTIVE: We sought to evaluate the safety, tolerability, immunogenicity, pharmacokinetics, pharmacodynamics, and target engagement of AZD8630/AMG 104 in healthy adults and adults with moderate-to-severe asthma. METHODS: This was a first-in-human, 2-part, phase 1 study of AZD8630/AMG 104. Part A was a single-blind study in healthy adults evaluating single and multiple ascending doses (0.2-16 mg) inhaled once daily for up to 14 days; part B was a double-blind, randomized, placebo-controlled study in adults with moderate-to-severe asthma and elevated fractional exhaled nitric oxide (Feno; ≥30 ppb) randomized to AZD8630/AMG 104 (0.4, 2, and 8 mg) or placebo once daily for 28 days. The primary objective was safety and tolerability. Secondary and exploratory objectives included pharmacokinetics, immunogenicity, pharmacodynamics (change from baseline in Feno), and target engagement. RESULTS: In total, 181 participants (part A, n = 104; part B, n = 77) were randomized. AZD8630/AMG 104 showed an acceptable safety profile, with low incidence of treatment-induced antidrug antibodies (part A, n = 1; part B, n = 2), and dose-dependent pharmacokinetics. In part B, there was a statistically significant reduction in Feno in AZD8630/AMG 104 8 mg recipients versus placebo (day 28, 23%; P = .037). AZD8630/AMG 104 dosing led to a dose-dependent decrease of free TSLP levels and increased TSLP-AZD8630/AMG 104 levels in serum in all participants. CONCLUSION: AZD8630/AMG 104 was well tolerated, with pharmacokinetics suitable for once-daily dosing. Results demonstrate proof of mechanism: clinically meaningful reductions in Feno levels and evidence of target engagement. Further development of AZD8630/AMG 104 in adults with moderate-to-severe asthma is warranted.
BACKGROUND: Early-onset atopic dermatitis (AD) is a known precursor to respiratory atopic diseases, but identifying which children will develop persistent moderate-to-severe asthma and allergic rhinitis at school age rem...BACKGROUND: Early-onset atopic dermatitis (AD) is a known precursor to respiratory atopic diseases, but identifying which children will develop persistent moderate-to-severe asthma and allergic rhinitis at school age remains difficult. OBJECTIVE: We sought to develop and validate machine learning models that predict individualized risk for moderate-to-severe persistent asthma and allergic rhinitis in children diagnosed with AD before age 3. METHODS: We conducted a retrospective birth cohort study using longitudinal electronic health record data from Kaiser Permanente Southern California. Two prediction models were developed for each outcome (asthma and rhinitis) among children aged 5-11: a comprehensive electronic health records model using detailed, structured clinical variables; and a simplified clinical model that was based on fewer, routinely available clinical features. Model performance was evaluated by area under the curve (AUC), sensitivity, positive predictive value (PPV), and calibration across risk strata. RESULTS: Among 10,688 eligible children, asthma models demonstrated strong discrimination (AUC = 0.893 comprehensive; AUC = 0.892 simplified). At 95% specificity, the comprehensive model achieved 40.4% sensitivity and 39.3% PPV; the simplified model reached 36.2% sensitivity and 33.8% PPV. Rhinitis models showed moderate performance (AUC = 0.793 and AUC = 0.773); at 90% specificity, the comprehensive model achieved 35.5% sensitivity and 72.7% PPV, while the simplified model reached 34.0% sensitivity and 69.2% PPV. Calibration was acceptable, with strong agreement in the highest-risk groups. CONCLUSION: Machine-learning models using early-life clinical data can accurately stratify risk for moderate-to-severe persistent asthma and allergic rhinitis by school age, supporting proactive, individualized care.
Akin C, Sabato V, Gotlib J
… +35 more, Panse J, Álvarez-Twose I, Radia DH, Livideanu CB, Jurcic J, Elberink HO, Van Daele P, Cerquozzi S, Dybedal I, Reiter A, Pongdee T, Barete S, Ustun C, Schafhausen P, Vadas P, Bose P, DeAngelo DJ, Rein L, Vachhani P, Triggiani M, Bonadonna P, Hartmann K, Broesby-Olsen S, Mattsson M, George TI, Shomali W, Giannetti M, Siebenhaar F, Lin HM, Bidollari I, Lampson B, Hong J, Doyle A, Tashi T, Castells M
BACKGROUND: Indolent systemic mastocytosis (ISM), a clonal mast cell disease primarily driven by the KIT D816V mutation, can cause long-term debilitating symptoms and poor quality of life. Most patients rely on symptom-d...BACKGROUND: Indolent systemic mastocytosis (ISM), a clonal mast cell disease primarily driven by the KIT D816V mutation, can cause long-term debilitating symptoms and poor quality of life. Most patients rely on symptom-directed best supportive care (BSC) medications, which do not treat the underlying driver of ISM. Avapritinib, an oral, potent, selective KIT D816V inhibitor, is approved in adults with ISM. OBJECTIVE: We sought to understand the long-term efficacy and safety of avapritinib in ISM. METHODS: The PIONEER trial (NCT03731260) enrolled adults with moderate to severe ISM symptoms. Patients initiated avapritinib 25 mg once daily (QD; recommended dose) plus BSC in part 1, 2, or 3; open-label part 3 is ongoing with up to 5 years of follow-up. As per investigator discretion and disease burden, a dose increase up to avapritinib 50 mg QD was permitted in part 3. RESULTS: As of February 21, 2025, 226 patients initiated avapritinib at 25 mg QD. The median (range) treatment duration was 40.0 (0.7-67.2) months. Patients receiving avapritinib experienced durable and clinically meaningful symptom improvement (mean change, -19.39 [n = 127] in the Indolent Systemic Mastocytosis Symptom Assessment Form total symptom score) through approximately 3 years. Avapritinib continued to be well tolerated for a longer term with a safety profile comparable with the previously reported placebo-controlled portion. Most treatment-related adverse events (TRAEs) were grades 1 to 2, with limited grade 3 or higher reported. Edema events were the most frequent TRAEs (mostly grade 1). Serious TRAEs occurred in 3 patients (1%), and 7 patients (3%) discontinued treatment because of TRAEs. CONCLUSIONS: Long-term follow-up (median, ∼3 years) demonstrates that avapritinib is effective and well tolerated. Avapritinib shows a favorable benefit-risk profile as a chronic ISM treatment.
Edwards ESJ, Gugasyan R, Varese N
… +15 more, Sun S, Canning JE, Blight EG, Aui PM, Boo I, Turville S, Aggarwal A, Ojaimi S, Bosco JJ, Stojanovic S, Hogarth PM, Drummer HE, Bornheimer SJ, O'Hehir RE, van Zelm MC
Dupilumab is highly effective for moderate-to-severe atopic dermatitis (AD). Increasing reports of cutaneous T-cell lymphoma (CTCL) diagnosed during or after dupilumab therapy have raised concern, although a causal relat...Dupilumab is highly effective for moderate-to-severe atopic dermatitis (AD). Increasing reports of cutaneous T-cell lymphoma (CTCL) diagnosed during or after dupilumab therapy have raised concern, although a causal relationship remains unproven. Interpretation of the available evidence is limited by its retrospective, observational nature, diagnostic overlap between AD and early CTCL, and detection and surveillance bias. These clinical consensus recommendations, developed through expert consensus among European CTCL specialists, primarily address dupilumab receipt in patients initially diagnosed with AD in whom CTCL is suspected, while briefly considering selective IL-13 inhibitors for which evidence remains limited. Clinical, epidemiologic, and mechanistic evidence is synthesized to develop practice-oriented recommendations. Dupilumab remains an appropriate treatment for moderate-to-severe AD but should be avoided if mycosis fungoides or Sézary syndrome is suspected or confirmed. In atypical or treatment-refractory disease, particularly adult-onset AD without atopic history, clinicians should maintain a high index of suspicion for CTCL, with a low threshold for skin biopsy, clinicopathologic correlation, and T-cell clonality assessment. Lack of response, disease worsening, or emerging atypical features during therapy should prompt reassessment. These recommendations reflect expert consensus that is based on available evidence and highlight the need for prospective studies to better define risk profiles and guide patient selection.
BACKGROUND: Wheezing and asthma exacerbations are leading causes of pediatric hospital admissions. Predicting which children will experience persistent exacerbations remains challenging. Prior research has identified imm...BACKGROUND: Wheezing and asthma exacerbations are leading causes of pediatric hospital admissions. Predicting which children will experience persistent exacerbations remains challenging. Prior research has identified immune endotypes in the nasal epithelium of children with acute asthma and wheezing, characterized by varying balances of interferons and inflammatory markers. Notably, children exhibiting low interferon responses coupled with high inflammation are at an increased risk for recurrent respiratory exacerbations. OBJECTIVE: This study aimed to determine if blood-based gene network biomarkers can detect immune endotypes in children presenting with acute wheeze and asthma, potentially serving as predictive tools for future exacerbations. METHODS: We conducted gene expression analysis using microarrays of peripheral blood mononuclear cell samples from pediatric patients who presented to hospital for acute wheeze and asthma. Personal network inference was used to discern gene expression patterns, facilitating the classification of patients' disease into distinct immune endotypes. RESULTS: Three immune endotypes were identified. One endotype, characterized by low interferon responses and elevated expression of both innate and adaptive immune pathways, was significantly associated with an increased risk of subsequent hospital respiratory presentations and a persistent pattern of respiratory exacerbations over time. CONCLUSION: Peripheral blood mononuclear cell-based personal gene network biomarkers can effectively identify immune endotypes correlating with clinical outcomes in pediatric asthma. The high-risk endotype represents a potential treatable trait in acute wheezing episodes. Therapeutic strategies aimed at enhancing interferon responses and/or reducing inflammation may benefit this subgroup.
Kidoguchi M, Iwasaki N, Poposki JA
… +20 more, Ogasawara N, Oka A, Klingler AI, Suh L, Agrwal A, Bai J, Stevens WW, Peters AT, Grammer LC, Welch KC, Smith SS, Johnson M, Radwan A, Conley DB, Schleimer RP, Kern RC, Tan BK, Okano M, Fujieda S, Kato A
J Allergy Clin Immunol
· 2026 Jul · PMID 41956382
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BACKGROUND: Chronic rhinosinusitis with nasal polyps is characterized by type 2 (T2) inflammation with elevated IL-5 and IL-13. Although group 2 innate lymphoid cells (ILC2s) drive T2 inflammation, their subset diversity...BACKGROUND: Chronic rhinosinusitis with nasal polyps is characterized by type 2 (T2) inflammation with elevated IL-5 and IL-13. Although group 2 innate lymphoid cells (ILC2s) drive T2 inflammation, their subset diversity and clinical relevance in nasal polyps (NPs) remain unclear. OBJECTIVE: We investigated cellular sources of T2 cytokines, subset heterogeneity of ILC2s, and the relationship between ILC2 subsets and clinical severity in chronic rhinosinusitis with NPs. METHODS: ILC2s and CD4 T cells were isolated from NP tissue and analyzed for cytokine production. ILC2s from 6 NP and 4 peripheral blood samples underwent single-cell RNA sequencing. Differential gene expression, subset heterogeneity, and pseudotime trajectory analyses were performed. Flow cytometry validated ILC2 subsets and associations with clinical parameters. RESULTS: Under ex vivo conditions, NP-derived ILC2s produced higher IL-5 and IL-13 levels than T2 cells. NP-derived ILC2s showed downregulation of early developmental and trafficking genes (CD48, S1PR1) and upregulation of T2-associated cytokines (IL5, IL13), chemokines (XCL1, CXCL8), remodeling factors (AREG, TNFSF14), and METRNL. Four ILC2 subsets reflecting activation states were identified: migratory (tissue-homing with less activation), transitional (intermediate activation), inflammatory (high activation and T2 cytokines), and exhausted-like (expression of inhibitory receptors [eg, TIGIT]). The combined number of T2 cytokine-enriched subsets (transitional, inflammatory, and exhausted-like ILC2s) correlated with Lund-Mackay computed tomography scores. Inflammatory and exhausted-like ILC2s were associated with clinical symptom severity. CONCLUSION: ILC2s are one of the important effector populations driving local T2 inflammation in NPs and include 4 subsets with specific clinical associations. Subset-level ILC2 profiling may clarify chronic rhinosinusitis with NP pathophysiology and inform clinical stratification.
Luo Y, Eliasen AU, Fischer-Rasmussen K
… +15 more, Thorsen J, Brustad N, Jensen SK, Chen L, Sultan T, Thysen AH, Linneberg A, Werge T, Bybjerg-Grauholm J, Bækvad-Hansen M, Brix S, Stokholm J, Chawes B, Pedersen CT, Bønnelykke K
BACKGROUND: Neutrophils are key in eliminating bacterial and fungal pathogens, but they are less effective against viruses. Excessive neutrophil activity may indicate dysregulated immunity preceding childhood asthma and...BACKGROUND: Neutrophils are key in eliminating bacterial and fungal pathogens, but they are less effective against viruses. Excessive neutrophil activity may indicate dysregulated immunity preceding childhood asthma and viral respiratory illnesses. OBJECTIVE: We investigated if genetic predisposition to an excessive neutrophil activation is linked to childhood asthma and viral respiratory illnesses. METHODS: Polygenic risk scores (PRS), calculated as the weighted sum of genetic variants associated with blood neutrophil counts, were derived for children in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC) cohort and 2 registry-based cohorts hospitalized for asthma by age 6 years (iPSYCH and COPSAC). Mendelian randomization was used to test whether genetically predicted neutrophil counts causally influence childhood asthma risk. In COPSAC, blood cytokines were measured at 18 months on ex vivo stimulation with virus-mimicking ligands (R848 and poly (I:C)) and then combined into neutrophil PRS-associated immune signature scores representing genetically linked variation in innate immune responsiveness. Nasopharyngeal samples from children during acute illness were analyzed for pathogenic viruses and bacteria. RESULTS: The neutrophil PRS was associated with an increased risk of hospitalization for asthma (odds ratio = 1.09; 95% confidence interval, 1.05-1.13; P = 8.7e-6). Mendelian randomization suggested causality. In COPSAC, neutrophil PRS was associated with an increased type 17 immune response to viral stimulation, notably CXCL8, IL-6, and IL-18. The neutrophil PRS-associated cytokine signature scores were associated with increased risk of viral respiratory illnesses by age 3 and asthma by age 6. CONCLUSION: Genetic predisposition to elevated neutrophils may drive early-life antiviral immune dysregulation, increasing the risk of respiratory illness and childhood asthma. This supports neutrophil pathways as potential preventive or therapeutic targets.
Dahl A, Sajuthi S, Rappaport N
… +5 more, Galanter J, Gignoux C, Burchard E, Seibold M, Zaitlen N
J Allergy Clin Immunol
· 2026 Jul · PMID 41935671
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BACKGROUND: Asthma has heterogeneous risk factors, subtypes, and treatments. It is often unclear how to stratify this heterogeneity in scientific studies and clinical care. Genetics could explain root causes of this clin...BACKGROUND: Asthma has heterogeneous risk factors, subtypes, and treatments. It is often unclear how to stratify this heterogeneity in scientific studies and clinical care. Genetics could explain root causes of this clinical heterogeneity, called endotypes, but prior studies have used models that are not designed for complex diseases like asthma. OBJECTIVE: We aimed to find genetic effects that partly explain different asthma endotypes. METHODS: We used recent powerful and robust statistical models of context-specific genetic effects in complex traits. We identified genetic subtypes by clustering clinical asthma features in a case-control cohort, GALA II. We replicated the genetic endotypes in the UK Biobank with gene-context interaction tests. RESULTS: Asthma-associated single nucleotide polymorphisms, polygenic scores, and genome-wide heritability revealed subtype-specific genetic endotypes correlated with type 2 inflammation, allergy, and neuroticism. We validated the type 2 associations with molecular data including nasal RNA sequencing. In the UK Biobank, we replicated these endotypes and found they interact with several polygenic scores and drug-relevant genes. CONCLUSION: Our results show how context-specific genetic effects can unravel biomedically meaningful endotypes of complex disease and suggest novel precision treatment strategies.
BACKGROUND: Evidence regarding the safety of asthma controller medications (particularly montelukast) for the fetus remains insufficient and controversial. OBJECTIVE: We sought to comprehensively evaluate the association...BACKGROUND: Evidence regarding the safety of asthma controller medications (particularly montelukast) for the fetus remains insufficient and controversial. OBJECTIVE: We sought to comprehensively evaluate the association between first-trimester use of 5 common asthma controller regimens and the risk of major congenital malformations in the offspring of women with asthma. METHODS: We conducted a population-based cohort study using data from the AMerican PREGNANcy Mother-Child CohorT (AM-PREGNANT) from 2003 to 2021, which primarily comprises individuals with private insurance coverage in the United States. Singleton live births to mothers with asthma were included. Exposure was based on first-trimester prescription fills for asthma controller medications. The outcomes included major congenital malformations overall, organ-specific malformations, and 2 specific defects. RESULTS: We identified 44,435 eligible pregnancies. Compared with the no asthma controller medication group, none of the 5 controller medication groups (montelukast monotherapy, inhaled corticosteroid [ICS] monotherapy, ICS + long-acting β-adrenergic agonist [LABA] combination, montelukast + ICS combination, montelukast + ICS + LABA combination) was associated with an increased risk of major congenital malformations. The montelukast + ICS combination group was associated with an increased risk of cleft palate and/or lip compared with the no asthma controller medication group, but the number of events was limited (<5). CONCLUSIONS: Among pregnant women with asthma, first-trimester exposure to any of the 5 common asthma controller regimens in this study was not associated with an increased risk of major congenital malformations. Further studies are needed to confirm the association between the montelukast + ICS combination regimen and the risk of cleft palate and/or lip.
BACKGROUND: Asthma is a common heritable respiratory disorder with a complex genetic basis. Although large-scale genome-wide association studies have identified many risk loci, the full spectrum of its polygenic architec...BACKGROUND: Asthma is a common heritable respiratory disorder with a complex genetic basis. Although large-scale genome-wide association studies have identified many risk loci, the full spectrum of its polygenic architecture remains to be defined. OBJECTIVE: We refined the genetic landscape of asthma in individuals of European ancestry and improve polygenic risk prediction through statistical and deep learning-based methods. METHODS: We conducted the largest genome-wide association study meta-analysis of asthma in individuals of European ancestry, combining data from the Global Biobank Meta-analysis Initiative (121,940 cases, 1,254,131 controls) and the Million Veteran Program (36,823 cases, 398,278 controls). To enhance discovery, we applied pleiotropy-informed multitrait analysis and conditional false discovery rate approaches, each incorporating eosinophil counts as a secondary trait. In parallel, we used a Transformer-based deep learning framework to further prioritize variants and improve polygenic risk prediction. RESULTS: The meta-analysis identified 69 independent genome-wide significant loci (P < 5 × 10) not previously reported in asthma. Multitrait analysis of genome-wide association studies, conditional false discovery rate, and deep learning approaches uncovered additional candidate loci. Functional annotation and expression quantitative trait locus mapping implicated novel genes in immune regulation, airway remodeling, and metabolic processes. Polygenic risk score models derived from deep learning-prioritized variants outperformed those based on conventional genome-wide association study and standard statistical approaches. CONCLUSIONS: Our study yields a comprehensive map of asthma-associated loci in European ancestry populations, improves genetic risk prediction, and informs future mechanistic studies.