Bohnhoff J, Cutler A, Jacobs EA
… +2 more, Phipatanakul W, Jonk Y
J Allergy Clin Immunol
· 2026 May · PMID 42082023
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BACKGROUND: Receipt of asthma specialty care reduces asthma morbidity in children, but children living in rural, socioeconomically disadvantaged, and remote areas face potential barriers to accessing specialists. OBJECTI...BACKGROUND: Receipt of asthma specialty care reduces asthma morbidity in children, but children living in rural, socioeconomically disadvantaged, and remote areas face potential barriers to accessing specialists. OBJECTIVE: We sought to evaluate the associations of rurality, Child Opportunity Index (COI), and distance with pediatric asthma specialist utilization among children with an indication for specialist referral. METHODS: In this retrospective cohort study using 2015-2021 Maine Health Data Organization All-Payer Claims Data, we identified children (<18 years old) with asthma and one of the following indications for specialist referral: a complicating comorbidity, higher-level controller medications, 3 or more courses of systemic corticosteroids within a year, or a respiratory hospitalization. We performed multivariate logistic regressions to calculate the adjusted associations between utilization of pediatric asthma specialists (physicians or advanced practice providers specializing in allergy/immunology or pediatric pulmonology) in the year after indication and children's rurality, COI, and driving time to specialists. RESULTS: Among 12,014 children with indications for pediatric asthma specialist referral, 47% lived in micropolitan or rural areas, and 15% lived more than 1 hour from any specialist. A total of 2,296 children (19%) received care from specialists within a year of their indication. In adjusted analyses, children were significantly less likely to see specialists if they lived in small towns (adjusted odds ratio [aOR] 0.54, 95% CI 1.09-1.39) or isolated small rural areas (aOR 0.82, 95% CI 0.71-0.94), areas with a COI less than "very high" (for "very low," aOR 0.65, 95% CI 0.56-0.75), or farther from specialists (aOR 0.62 per hour, 95% CI 0.57-0.68). CONCLUSIONS: Children in rural areas, in areas of low socioeconomic opportunity, and far from specialists are at an increased risk of not receiving indicated asthma specialist care.
Nguyen TH, Alsulami S, Pham TT
… +3 more, Story D, Hauptman M, Phipatanakul W
J Allergy Clin Immunol
· 2026 Apr · PMID 42066916
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BACKGROUND: Asthma is one of the most common chronic conditions in the United States, disproportionately affecting racial and ethnic minority populations and low-income communities. Although both social and environmental...BACKGROUND: Asthma is one of the most common chronic conditions in the United States, disproportionately affecting racial and ethnic minority populations and low-income communities. Although both social and environmental factors are known contributors to asthma prevalence, the extent to which they interact to shape geographic disparities remains insufficiently understood. OBJECTIVE: This study aimed to explore how these factors vary across regions with differing asthma prevalence and thereby identify patterns that may inform targeted public health responses. METHODS: We used the US Centers for Disease Control and Prevention's 2022 Environmental Justice Index, which includes standardized social and environmental measures at the census tract level. K-means clustering identified geographic clusters with varying asthma prevalence based on asthma rates and related health outcomes. A random forest model was trained to predict asthma rates by using social and environmental variables, and feature importance was analyzed. RESULTS: We identified 9 clusters, with 3 showing the highest asthma prevalence. High-prevalence areas had greater social vulnerability, including higher poverty rate, minority population rate, limited English proficiency, unemployment, and housing cost burden. They also experienced greater environmental exposures, such as elevated level of fine particulate matter with an aerodynamic diameter of 2.5 μm or less, ozone, diesel pollution, more land near hazardous waste sites, more chemical facilities, and older housing. The random forest model predicted asthma rates with strong predictive performance (R = 0.81). Socioeconomic variables consistently ranked as stronger predictors than environmental exposures. CONCLUSIONS: Geographic areas with high asthma prevalence are shaped by overlapping social and environmental vulnerabilities. Socioeconomic disparities emerged as particularly influential. These findings support integrated, data-driven public health strategies to address asthma inequities.
BACKGROUND: Central compartment atopic disease (CCAD) is an early stage of type 2 chronic rhinosinusitis characterized by type 2 inflammation and frequent olfactory dysfunction, primarily due to olfactory cleft (OC) obst...BACKGROUND: Central compartment atopic disease (CCAD) is an early stage of type 2 chronic rhinosinusitis characterized by type 2 inflammation and frequent olfactory dysfunction, primarily due to olfactory cleft (OC) obstruction. OBJECTIVE: A novel OC computed tomographic scoring system was developed to evaluate multisectional obstruction patterns in CCAD, identify key regions of OC obstruction, and examine their associations with olfactory function and eosinophilic inflammation. METHODS: A prospective cross-sectional study enrolled 257 adults with primary bilateral chronic rhinosinusitis. Participants were divided into a development cohort (n = 177) and a validation cohort (n = 80), with 75 allergic rhinitis patients as controls. A Multisection Olfactory Cleft Opacity Staging System (MOCOS) was developed to assess apical and middle-lower opacification by evaluating 6 coronal sections. Peripheral blood was analyzed for inflammatory endotypes. Risk factors were identified for CCAD and the relative importance of variables associated with olfactory dysfunction analyzed. RESULTS: Scores fell into 3 distinct zones according to OC subtype: a disease signature zone, which is predictive of CCAD diagnosis; an olfactory functional zone, which correlates with smell loss severity; and an eosinophilic inflammation zone, which is linked to systemic type 2 inflammation. Opacification progression from the disese signature zone to the olfactory function zone drives both the onset and progressive worsening of the olfactory dysfunction. CONCLUSIONS: MOCOS permitted us to identify a trizone OC model in CCAD, revealing a biphasic opacification progression that drives olfactory dysfunction onset and progression, thereby refining disease classification and elucidating its underlying pathogenesis to inform targeted therapy.
BACKGROUND: Hereditary angioedema (HAE) is a rare congenital disorder characterized by recurrent episodes of subcutaneous and submucosal swelling, which can progress to life-threatening laryngeal obstruction. The most co...BACKGROUND: Hereditary angioedema (HAE) is a rare congenital disorder characterized by recurrent episodes of subcutaneous and submucosal swelling, which can progress to life-threatening laryngeal obstruction. The most common form of HAE results from mutations in the SERPING1 gene, which encodes C1-esterase inhibitor. HAE belongs to the broader category of serpinopathy, in which misfolded serine protease inhibitors polymerize and are retained within the endoplasmic reticulum, leading to both loss-of-function and toxic gain-of-function effects. OBJECTIVE: We sought to develop a stable patient-derived cell line that accurately represents the molecular and cellular processes underlying HAE and serves as a replicable platform for drug discovery and therapy. METHODS: Two patients with HAE were recruited; PBMCs were obtained to generate patient-specific induced pluripotent stem cell (iPSC) lines. The HAE-iPSC cell lines were verified for their pluripotency and differentiated into hepatocytes for further physiopathological studies. RESULTS: The generated iPSC lines were genetically identical to those of the donors, expressed canonical pluripotency markers, and demonstrated trilineage differentiation potential through embryoid body formation and expression of germ layer markers. Importantly, immunohistochemical analysis revealed intracellular retention and aggregation of C1-esterase inhibitor protein. We also demonstrated that the dominant-negative effect of the mutant C1-esterase inhibitor could be ameliorated by androgen treatment, a well-established agent in long-term prophylactic therapy for HAE. CONCLUSIONS: This is the first development of patient-derived iPSC models of HAE. These models not only exhibit key molecular features of HAE but also provide a versatile platform for mechanistic studies and preclinical drug testing.
Freeman AF, Wang C, Urban A
… +46 more, Martin I, Dang L, Davis J, Bergerson JRE, Ali S, An ZA, Patel M, Williamson H, Marciano BE, Lafeer C, Roy S, Ulrick J, Heller T, Sharma D, Castelo-Soccio L, Cowen EW, Kong HH, Gupta S, Ghosh R, Seifert BA, Tokita MJ, Walkiewicz MA, Similuk M, Stoddard J, Rosenzweig SD, Matta JR, Gharib AM, Jahanmir G, Brenchley L, Shastri K, Moutsopoulos NM, Kitani T, Arnold DE, Dimitrova D, Gonzalez CE, Pai SY, Malech HL, Gallin JI, Fennelly K, Olivier KN, Mackie J, Tangye SG, Hsu AP, Milner JD, Heimall J, Holland SM
J Allergy Clin Immunol
· 2026 Apr · PMID 42061468
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BACKGROUND: Signal transducer and activator of transcription 3 hyper-IgE syndrome (STAT3-HIES) is a multisystem disorder with both immunologic and nonimmunologic manifestations. OBJECTIVE: We sought to characterize the s...BACKGROUND: Signal transducer and activator of transcription 3 hyper-IgE syndrome (STAT3-HIES) is a multisystem disorder with both immunologic and nonimmunologic manifestations. OBJECTIVE: We sought to characterize the spectrum of clinical manifestations, genetics, treatment approaches, and long-term outcomes of patients with STAT3-HIES. METHODS: Clinical features, laboratory findings, treatment, and survival were reviewed in the largest single-center STAT3-HIES cohort (n = 164) prospectively followed under a natural history protocol (NCT00006150). RESULTS: In addition to the classic skin, lung, dental, and musculoskeletal manifestations captured in the 1999 scoring system, we comprehensively characterized disease phenotypes across multiple organ systems, including previously underrecognized features. Lung disease remained the major morbidity with both infectious and parenchymal complications. During longitudinal follow-up, age-related vascular and skeletal degeneration emerged and significantly affected quality of life in patients 45 years and older. No genotype-phenotype correlations were identified. In terms of management, optimal supportive measures, including antimicrobials and immunoglobulin replacement therapy, tailored to disease features and individual risk factors, remained the primary approach. Dupilumab was used primarily for the eczematous dermatitis and demonstrated significant clinical benefit. In highly selected cases (n = 6), allogeneic hematopoietic stem cell transplantation was performed and showed reduction in infection burden. The median overall survival was 55 years-significantly shorter than that of the general United States population-and was not affected by sex, variant location, or proband status. CONCLUSIONS: STAT3-HIES is a multisystem disorder that requires multidisciplinary care. Early diagnosis and supportive measures have altered its natural history. Recognition and improved understanding of the nonimmunologic manifestations of this disorder will further improve patient outcomes.
J Allergy Clin Immunol
· 2026 Jul · PMID 42061467
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Over the past 2 decades, innate lymphoid cells (ILCs) have emerged as critical early responders in immune responses, orchestrating inflammation through cytokine production independent of antigen specificity. Early after...Over the past 2 decades, innate lymphoid cells (ILCs) have emerged as critical early responders in immune responses, orchestrating inflammation through cytokine production independent of antigen specificity. Early after their discovery, group 2 ILCs (ILC2s) were found to produce high levels of IL5 and IL13 upon stimulation by epithelial-derived alarmins IL33, IL25, and TSLP. Since then, a robust amount of literature has emerged that places ILC2s central to type 2 inflammatory diseases, including rhinosinusitis and asthma. Recent work continues to rapidly expand our knowledge of how ILC2s are modulated and contribute to immune disease and maintain homeostasis. This review will focus on recent updates to our understanding of ILC2s in the context of neural and endocrine modulation, memory/trained immunity, cellular fate/plasticity, and adaptive type 2 responses.
McEvoy CT, Idrose NS, Dharmage SC
… +23 more, Bui DS, Simpson SJ, Patchen B, Marshall NE, Kelly RS, Lynch SV, McDonald CM, Sood BG, Pratt C, Vitalis D, Lu Q, Carroll KN, Duijts L, Forno E, Venter C, Prakash YS, Miller AN, DeMeo DL, Subbarao P, Britt RD, Sengupta S, McGrath-Morrow SA, Litonjua AA
J Allergy Clin Immunol
· 2026 Jul · PMID 42061466
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The National Heart, Lung, and Blood Institute-sponsored workshop, "Maternal and Perinatal Nutritional Programming of Lung Health and Disease in Childhood and Early Adulthood: Research Gaps and Opportunities," was convene...The National Heart, Lung, and Blood Institute-sponsored workshop, "Maternal and Perinatal Nutritional Programming of Lung Health and Disease in Childhood and Early Adulthood: Research Gaps and Opportunities," was convened (October 24-25, 2024) to explore how nutrition before, during, and after pregnancy influences lung development and respiratory health across the lifespan. The workshop focused on identifying critical knowledge gaps, mechanistic pathways, and intervention opportunities. Presentations spanned maternal dietary patterns, specific nutrient supplementation, gestational weight gain, and the role of maternal obesity in offspring wheeze and asthma. The role of early postnatal nutrition, particularly human milk for preterm infants at risk for bronchopulmonary dysplasia, was emphasized. Emerging areas included circadian rhythms and the maternal and infant microbiome, metabolome, and epigenome in mediating nutrition-related respiratory outcomes. Research needs included randomized trials of dietary interventions, mechanistic studies to elucidate biological pathways, and implementation strategies to integrate nutritional interventions into practice. Vulnerable populations were emphasized, including preterm infants and families experiencing food insecurity. Participants emphasized the need for a coordinated research agenda to inform future interventions that could improve outcomes across generations.
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a T2 disease characterized by heterogeneous mast cell hyperplasia. We previously used transcriptomics to identify discrete gene expression linked with intr...BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a T2 disease characterized by heterogeneous mast cell hyperplasia. We previously used transcriptomics to identify discrete gene expression linked with intraepithelial mast cells expressing tryptase alone (MCs), subepithelial mast cells coexpressing tryptase and chymase (MCs), and immature mast cells in CRSwNP. Although MCs were the only subset consistently observed in both CRSwNP and chronic rhinosinusitis without nasal polyps (CRSsNP), the degree to which they differ across disease states remains unexplored. OBJECTIVE: We sought to use transcriptomics and flow cytometry to compare MCs in CRSwNP with those in CRSsNP. METHODS: MCs were flow-sorted from CRSwNP and CRSsNP samples for RNA-sequencing analysis to identify differentially expressed genes and pathways across disease states. In silico observations were validated using flow cytometry on cryopreserved tissue samples from CRSwNP and CRSsNP and RNA sequencing of stimulated ex vivo-differentiated MCs. RESULTS: We found a significant increase in MC concentrations in CRSwNP donors, which were enriched for activation-associated pathways linked with differential expression of transcripts encoding proinflammatory mediators and cell receptors, including IL2RA. Validation studies highlighted significant cell surface expression of CD25 on MCs in CRSwNP. Ex vivo-stimulated primary MCs upregulated IL2RA in response to IL-33 stimulus. CONCLUSIONS: Our data show that MCs in CRSwNP exhibit an activated transcriptional phenotype with expression of transcripts encoding proinflammatory mediators and IL2RA. Moreover, the CD25 upregulation on MCs in CRSwNP suggests its potential to serve as an in vivo marker of activated MCs during allergic disease.
BACKGROUND: Atopic dermatitis (AD) is a heterogeneous inflammatory skin disease with known ethnic disparities in clinical presentation and treatment response. However, molecular data, particularly for Hispanic patients,...BACKGROUND: Atopic dermatitis (AD) is a heterogeneous inflammatory skin disease with known ethnic disparities in clinical presentation and treatment response. However, molecular data, particularly for Hispanic patients, remain limited. OBJECTIVE: We sought to characterize the molecular phenotype of AD across Hispanic, Black, Asian, and White patients using tape strip transcriptomic and blood proteomic profiling. METHODS: We enrolled 47 patients with AD (9 Hispanic, 14 Black, 11 Asian, 13 White) and 40 control subjects. Tape strips and serum were collected for RNA sequencing and proteomic analysis, respectively. Differential expression, pathway enrichment, and gene-clinical correlations were analyzed across ethnicities. RESULTS: Across ethnicities, we identified shared immune activation in lesional and nonlesional skin in patients with AD, including upregulation of T1-related (eg, IL12B, TNF), T2-related (eg, CCL17, IL13), and T17-related (eg, CXCL1/2, IL6) pathways. However, gene-level drivers varied: T1-related markers (eg, CXCL10) were more elevated in White and Black patients, T17 axis skewing was most pronounced in Asian patients, and T22 and Janus kinase 3 signaling showed greater activation in White and Black patients. Hispanic patients demonstrated a mixed immune phenotype resembling AD in both White and Black patients. Barrier dysfunction, including filaggrin deficiency and lipid synthesis defects, was universal, with Asian patients exhibiting the most pronounced lipid-related gene downregulation. Proteomic data mirrored transcriptomic trends and highlighted broad systemic inflammation in Hispanic patients. White patients exhibited the strongest correlations between lesional gene expression and disease severity, though differences in clinical presentation and global scoring methods may influence these correlations across skin tones. CONCLUSIONS: This multi-omics, multiethnic analysis reveals both shared and ethnicity-specific molecular signatures in AD, with the first in-depth profiling, to our knowledge, of Hispanic patients. These findings may inform future precision-targeted therapies across diverse populations.
J Allergy Clin Immunol
· 2026 Apr · PMID 42034298
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This review article summarizes key advances from October 2022 to December 2025 on the link between environmental exposures and allergic diseases, with an emphasis on early-life exposures and mechanistic insights relevant...This review article summarizes key advances from October 2022 to December 2025 on the link between environmental exposures and allergic diseases, with an emphasis on early-life exposures and mechanistic insights relevant to disease prevention and therapy. Allergic diseases have genetic and environmental origins. As to the latter, predisposition to allergy is thought to arise as a result of increased exposure to harmful environmental factors that act as immune adjuvants for allergens, and reduced exposure to beneficial factors that induce allergen tolerance. Harmful factors include air pollutants (eg, road traffic-related particulate matter and gases, cigarette smoke, fire smoke), and various man-made chemicals and particles. Beneficial exposures include commensal microorganisms and nonmicrobial factors present in the farming environment. Allergic diseases frequently start in early childhood. Therefore, many recently published reports focus on environmental exposures occurring prenatally or during the first few months or years after birth-that is, time windows before allergic disease manifestation. This review article summarizes and comments on recent work on prenatal, childhood, adult, protective, and harmful exposures, highlighting relevant human cohort studies as well as mechanistic work in mouse models and in vitro culture systems. Studies published in the past 3 years describe novel biomarkers of environmental exposures, elucidate novel mechanisms by which exposures shape allergic diseases, and highlight novel targets for therapeutic intervention, setting a foundation for new approaches for early detection of allergic predisposition, allergy treatment, and prevention.
BACKGROUND: Eosinophilic and neutrophilic inflammation, along with tissue remodeling, are key pathogenic features in chronic rhinosinusitis with nasal polyps (CRSwNP). While ADAM8 (a disintegrin and metalloproteinase 8)...BACKGROUND: Eosinophilic and neutrophilic inflammation, along with tissue remodeling, are key pathogenic features in chronic rhinosinusitis with nasal polyps (CRSwNP). While ADAM8 (a disintegrin and metalloproteinase 8) is implicated in inflammation and remodeling in various contexts, its specific role in CRSwNP remains unclear. OBJECTIVE: We aimed to elucidate the role of ADAM8 and its underlying mechanisms in CRSwNP pathogenesis. METHODS: Bulk RNA sequencing, single-cell RNA sequencing reanalysis, and histologic analysis were performed on human nasal tissues. Eosinophil and neutrophil migration, transendothelial migration, and adhesion were assessed in vitro.ADAM8 was overexpressed in a human nasal epithelial cell (HNEC) line (HNEpC) via transfection. Primary HNECs were stimulated with CRSwNP-related factors. In vivo, a murine CRSwNP model was treated with an ADAM8 inhibitor. RESULTS: ADAM8 expression was significantly elevated in both eosinophilic and noneosinophilic CRSwNP and was abundantly expressed by multiple inflammatory cells and epithelial cells. This elevation strongly correlates with inflammatory cell infiltration, tissue remodeling, and disease severity. ADAM8 inhibition reduced the migration, transendothelial migration, and adhesion to endothelial cells of both eosinophils and neutrophils. ADAM8 overexpression in HNEpCs activated inflammation pathways and upregulated the expression of matrix metalloproteinases (MMPs), including MMP2, MMP10, and MMP24. IL-4, IL-13, TGF-β1, and hypoxia upregulated ADAM8 in HNECs. In the murine CRSwNP model, ADAM8 inhibition reduced nasal polyp formation, eosinophil and neutrophil infiltration, and tissue remodeling. CONCLUSION: ADAM8 functions as a critical mediator of inflammatory cell infiltration and tissue remodeling in CRSwNP. Targeting ADAM8 represents a promising therapeutic strategy potentially applicable across different CRSwNP subtypes.
Lim WK, Wipperman MF, Rothenberg ME
… +18 more, Collins MH, Hamon SC, Chehade M, Spergel JM, Gayvert KM, Ehmann PJ, Horowitz JE, Farrell AB, Dellon ES, Maloney J, Radin A, Louisias M, Wolfe K, Akinlade B, Ajithdoss DK, Herman G, Yancopoulos GD, Hamilton JD
BACKGROUND: Eosinophilic esophagitis (EoE) is a type 2 inflammatory disease of the esophagus, characterized by eosinophilic inflammation and an altered esophageal transcriptome. Dupilumab, a fully human mAb that blocks I...BACKGROUND: Eosinophilic esophagitis (EoE) is a type 2 inflammatory disease of the esophagus, characterized by eosinophilic inflammation and an altered esophageal transcriptome. Dupilumab, a fully human mAb that blocks IL-4 and IL-13 signaling, is approved for use in multiple type 2 inflammatory diseases, including EoE, where it produces histologic, symptomatic, and endoscopic improvements in pediatric, adolescent, and adult patients. OBJECTIVE: We sought to investigate the effect of dupilumab on the dysregulated esophageal transcriptome in pediatric, adolescent, and adult patients with EoE. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02379052, NCT03633617, and NCT04394351. METHODS: Changes in the esophageal transcriptome were analyzed from pretreatment and posttreatment esophageal biopsy specimens provided by pediatric, adolescent, and adult patients with EoE who participated in 1 of 3 placebo-controlled clinical trials of dupilumab. RESULTS: Dupilumab treatment resulted in marked normalization of the EoE disease transcriptome, including gene signatures associated with eosinophils as well as other aspects of type 2 inflammation and esophageal dysfunction including mast cells, fibrosis, barrier function, and other cell functions and pathways. Overall, gene ontology enrichment analysis identified 41 biological processes dysregulated in EoE that were normalized with dupilumab treatment, including processes likely to be eosinophil independent. Transcriptome changes were comparable and sustained through week 52 across pediatric, adolescent, and adult patients with EoE. CONCLUSIONS: IL-4 and IL-13 are the critical drivers of the molecular differences in the esophageal mucosa of patients with EoE compared with control subjects, consistent with the clinical benefit of dupilumab treatment.
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, R...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.