Journal of Allergy and Clinical Immunology最新文献

Background: Rhinoconjunctivitis phenotypes are conventionally described based on 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: To identify phenotypes of rhinoconjunctivitis based on 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 visits 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: two had high symptoms (22.5%) but differed in seasonal pattern, one had medium symptoms (13.6%), one had medium nasal congestion only (20.4%) and one had low symptoms (43.6%). The latter was further split into two 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 measures of atopy and type 2 inflammation. Factors beyond allergy need to be investigated to better understand the pathobiology of rhinoconjunctivitis.

Background: Patients with atopic dermatitis (AD) often have elevated type 2 inflammatory serum biomarkers.

Objective: The aim was to report changes in thymus and activation-regulated chemokine (TARC)/CC chemokine ligand 17 (CCL17), total IgE, lactate dehydrogenase (LDH), and eosinophils in pediatric patients treated with dupilumab or placebo.

Methods: Biomarker data were analyzed from 3 randomized, double-blind, placebo-controlled, phase 3 studies of patients with moderate-to-severe AD. Patients ages 6 months to 5 years were randomly assigned to weight-dependent dupilumab 200/300 mg every 4 weeks (q4w) or placebo; ages 6 to 11 years, to dupilumab 100/200 mg every 2 weeks (q2w), dupilumab 300 mg q4w, or placebo; ages 12 to 17 years, to dupilumab 200/300 mg q2w, dupilumab 300 mg q4w, or placebo. In the youngest 2 groups, topical corticosteroids were also applied. Median percent changes from baseline to week 16 were reported using last observation carried forward analysis, censoring after rescue treatment.

Results: Pediatric patients who received dupilumab versus placebo achieved significantly greater median percent reductions at week 16 in TARC/CCL17 (-83.3% to -72.4% vs -14.9% to -1.8%), total IgE (-71.2% to -58.4% vs -21.0% to +28.1%), and LDH (-26.2% to -9.8% vs -1.5% to +1.5%). All comparisons were significantly different (P < .0001) between each dupilumab dosing group and respective placebo groups. In contrast, absolute changes in eosinophils were small in all groups.

Conclusions: Dupilumab treatment for pediatric patients with moderate-to-severe AD significantly reduced levels of TARC/CCL17, total IgE, and LDH to levels comparable with those of healthy controls, reflecting a reduction in systemic type 2 and general inflammation.

Asthma has been increasingly recognized as a heterogeneous disease; however, many patients with asthma have allergic asthma (AA). Inhaled corticosteroids and other inhalers have been integral in treating many symptoms of asthma, but these medications do not completely address the disease's underlying mechanism. Pediatric asthma imposes a substantial burden on patients and the health care system. Omalizumab is consistently recognized as an important consideration for add-on therapy in pediatric patients with AA in published guidelines from multiple international societies such as the Global Initiative for Asthma. Since our last report in 2017, the amount of information available regarding the safety and effectiveness of omalizumab in pediatric patients with AA has continued to accumulate and is supported by several observational and real-world data studies. A number of studies including real-world effectiveness studies, post hoc analyses of clinical trial data, and systematic literature reviews and meta-analyses have since expanded the published data on the efficacy and safety of omalizumab in pediatric patients. In this article, we present an updated review of this literature focused on omalizumab therapy in children with AA.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory condition characterized by type 2 (T2) immune responses with significant impacts on quality of life and health care costs. Local IgE production in nasal polyp tissue plays a key role in the T2 inflammatory cascade. Omalizumab, an anti-IgE monoclonal antibody, is an effective treatment for some patients with CRSwNP regardless of the patient's allergic status. Clinical trials, including the pivotal POLYP 1 and POLYP 2 studies, demonstrated omalizumab's efficacy in reducing nasal polyp size, improving symptom scores, and enhancing quality of life, particularly in patients with comorbid asthma and aspirin-exacerbated respiratory disease. As we summarize in this review, omalizumab's effect appears to involve the reduction in local IgE and T2 inflammation; however, this remains poorly understood. Notably, omalizumab's effectiveness appears to be partially sustained after long-term therapy, though symptoms and inflammation begin to return at discontinuation. Ongoing research is needed to determine the optimal duration of therapy and potential for biologics to modify the disease course. Additionally, further studies are needed to identify biomarkers to predict treatment response and to compare omalizumab with other biologics such as dupilumab in head-to-head trials. Omalizumab is one of the key T2-targeted therapeutic options for CRSwNP, with sustained effectiveness and strong safety profile.

Omalizumab was recently approved by the US Food and Drug Administration for treatment of any single food allergy or multiple food allergies in children aged 1 year and older and adults. There is currently no formal guidance regarding recommended best practices for omalizumab use in food allergy, including patient selection, anticipated goals and outcomes of therapy, procedure for monitoring patients who elect to start omalizumab therapy, and ways in which omalizumab can be incorporated into the landscape of food allergy management and daily clinical practice. This work group report was developed by the food allergy therapies subcommittee of the Adverse Reactions to Foods Committee within the American Academy of Allergy, Asthma & Immunology. Consensus, evidence-based guidance regarding experts' recommendations for using omalizumab to treat children and adults with food allergy was developed by using modified Delphi methodology. In iterative fashion, a total of 8 statements regarding how to use omalizumab to treat patients with food allergy were developed by 16 clinical experts. This guidance provides the clinician with a suggested approach to patient selection, initiation of therapy, monitoring of efficacy, and long-term follow-up care. The role of preference-sensitive care is emphasized, with most statements offering care recommendations relevant to the culture and values of a particular practice setting.

Background: Wheezing in childhood is prevalent, with over one-half of all children experiencing at least 1 episode by age 6. The pathophysiology of wheeze, especially why some children develop asthma while others do not, remains unclear.

Objectives: This study addresses the knowledge gap by investigating the transition from preschool wheeze to asthma using multiomic profiling.

Methods: Unsupervised, group-agnostic integrative multiomic factor analysis was performed using host/bacterial (meta)transcriptomic and bacterial shotgun metagenomic datasets from bronchial brush samples paired with metabolomic/lipidomic data from bronchoalveolar lavage samples acquired from children 1-17 years old.

Results: Two multiomic factors were identified: one characterizing preschool-aged recurrent wheeze and another capturing an inferred trajectory from health to wheeze and school-aged asthma. Recurrent wheeze was driven by type 1-immune signatures, coupled with upregulation of immune-related and neutrophil-associated lipids and metabolites. Comparatively, progression toward asthma from ages 1 to 18 was dominated by changes related to airway epithelial cell gene expression, type 2-immune responses, and constituents of the airway microbiome, such as increased Haemophilus influenzae.

Conclusions: These factors highlighted distinctions between an inflammation-related phenotype in preschool wheeze, and the predominance of airway epithelial-related changes linked with the inferred trajectory toward asthma. These findings provide insights into the differential mechanisms driving the progression from wheeze to asthma and may inform targeted therapeutic strategies.

Background: The rate of diagnosis of mast cell activation syndrome (MCAS) has increased since the disorder's original description as a mastocytosis-like phenotype. While a set of consortium MCAS criteria is well described and widely accepted, this increase occurs in the setting of a broader set of proposed alternative MCAS criteria.

Objective: Effective diagnostic criteria must minimize the range of unrelated diagnoses that can be erroneously classified as the condition of interest. We sought to determine if the symptoms associated with alternative MCAS criteria result in less concise or consistent diagnostic alternatives, reducing diagnostic specificity.

Methods: We used multiple large language models, including ChatGPT, Claude, and Gemini, to bootstrap the probabilities of diagnoses that are compatible with consortium or alternative MCAS criteria. We utilized diversity and network analyses to quantify diagnostic precision and specificity compared to control diagnostic criteria including systemic lupus erythematosus, Kawasaki disease, and migraines.

Results: Compared to consortium MCAS criteria, alternative MCAS criteria are associated with more variable (Shannon diversity 5.8 vs 4.6, respectively; P = .004) and less precise (mean Bray-Curtis similarity 0.07 vs 0.19, respectively; P = .004) diagnoses. The diagnosis networks derived from consortium and alternative MCAS criteria had lower between-network similarity compared to the similarity between diagnosis networks derived from 2 distinct systemic lupus erythematosus criteria (cosine similarity 0.55 vs 0.86, respectively; P = .0022).

Conclusion: Alternative MCAS criteria are associated with a distinct set of diagnoses compared to consortium MCAS criteria and have lower diagnostic consistency. This lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses.

Background: Myhre syndrome is an exceedingly rare yet increasingly diagnosed genetic disorder arising from germline variants in the SMAD4 gene. Its core manifestation is the progression of stiffness and fibrosis across multiple organs. Individuals with Myhre syndrome exhibit a propensity for upper respiratory tract remodeling and infections. The molecular and cellular mechanisms underlying this phenotype remain unclear.

Objective: We sought to investigate how SMAD4 pathogenic variants associated with Myhre syndrome affect SMAD4 protein levels, activation, and physiological functions in patient-derived nasal epithelial cells.

Methods: Clinical observations were conducted on a cohort of 47 patients recruited at Massachusetts General Hospital from 2016 to 2023. Nasal epithelial basal cells were isolated and cultured from inferior turbinate brushings of healthy subjects (n = 8) and patients with Myhre syndrome (n = 3; SMAD4-Ile500Val, Arg496Cys, and Ile500Thr). Transcriptomic analysis and functional assays were performed to assess SMAD4 levels, transcriptional activity, and epithelial cell host defense functions, including cell proliferation, mucociliary differentiation, and bacterial elimination.

Results: Clinical observations revealed a prevalent history of otitis media and sinusitis among most individuals with Myhre syndrome. Analyses of nasal epithelial cells indicated that SMAD4 mutations do not alter SMAD4 protein stability or upstream regulatory SMAD phosphorylation but enhance signaling transcriptional activity, supporting a gain-of-function mechanism, likely attributable to increased protein-protein interaction of the SMAD complex. Consequently, Myhre syndrome nasal basal cells exhibit reduced potential in cell proliferation and mucociliary differentiation. Furthermore, Myhre syndrome nasal epithelia are impaired in bacterial killing.

Conclusions: Compromised innate immunity originating from epithelial cells in Myhre syndrome may contribute to increased susceptibility to upper respiratory tract infections.