BACKGROUND:Early-life respiratory infections are associated with subsequent asthma development; however, whether respiratory viruses contribute to asthma onset or merely unmask pre-existing susceptibility remains unclear. The COVID-19 pandemic's non-pharmaceutical interventions (NPIs) suppressed respiratory viruses, followed by their resurgence, offering a natural experiment. We examined whether these population-level changes in respiratory virus activity were associated with changes in newly recorded pediatric asthma diagnoses. METHODS:We conducted a nationwide interrupted time-series study using Japan's National Database of Health Insurance Claims, covering approximately 99% of the population. Segmented negative binomial regression with two intervention points-NPI implementation (T1: March 2020) and COVID-19 reclassification (T2: May 2023)-was applied to monthly counts of newly recorded asthma diagnoses among children aged under 19 years (January 2018-March 2024), with atopic dermatitis as negative control. Age-stratified/sex-stratified analyses and exploratory ecological analyses of pathogen-specific associations were conducted. RESULTS:Among 10,508,387 new asthma diagnoses, incidence declined significantly following NPI implementation (incidence rate ratio [IRR] 0.511, 95% confidence interval [CI] 0.422-0.620) and rebounded following NPI relaxation (IRR 1.395, 95% CI:1.120-1.737). Atopic dermatitis showed attenuated changes at both points. Rate differences were greatest in infants (0-1 years) at T1 and school-aged children (5-9 years) at T2. Rhinovirus, respiratory syncytial virus, influenza, and Mycoplasma pneumoniae, but not SARS-CoV-2, correlated with asthma diagnoses in ecological analyses. CONCLUSIONS:Newly recorded pediatric asthma diagnoses showed bidirectional changes that paralleled respiratory virus suppression and resurgence, compatible with a possible contributory role of respiratory infections, particularly among infants and school-aged children.
BACKGROUND:Banana allergy varies geographically, but molecular sensitization patterns and fruit co-reactivity remain incompletely defined. METHODS:We analyzed adults with IgE-mediated banana allergy from Thailand (n = 169) and Austria (n = 70) using banana extract-specific IgE (ImmunoCAP), ALEX (a multiplex allergen-specific IgE macroarray), and complementary line blotting. Country-stratified multivariable models assessed associations of sensitization patterns with systemic reactions and reaction severity. RESULTS:Systemic reactions predominated in Thailand (156/169, 92.3%), whereas isolated oral allergy syndrome (OAS) was more common in Austria (31/70, 44.3%). Banana extract-specific IgE was positive at ≥0.35 kUA/L in 115/168 (68.5%) Thai and 48/68 (70.6%) Austrian sera. Among samples with undetectable banana extract-sIgE (<0.10 kUA/L), molecular testing identified IgE reactivity to banana allergens or cross-reactive components in 16/18 (88.9%) Thai and 6/6 (100%) Austrian sera. ALEX-based profiling showed more heterogeneous sensitization patterns in Austria, with more frequent reactivity to nsLTPs, profilins, and latex allergens, whereas isolated ALEX reactivity to the TLP surrogate Act d 2 was common in Thailand but rare in Austria (55.6% vs 6.2%). Line blotting showed markedly more frequent IgE reactivity to TLP from banana (Mus a 4) in Thai than Austrian participants (90.5% vs 45.7%). In country-stratified analyses, TLP sensitization was independently associated with systemic reactions and greater severity in Austria. Thai estimates were imprecise because TLP sensitization was near-ubiquitous and non-systemic reactions were uncommon. CONCLUSIONS:Thai adults showed a TLP-dominant sensitization pattern, whereas Austrian profiles were more heterogeneous. TLP sensitization was associated with systemic reactions and greater severity in Austria.
BACKGROUND:Allergic rhinitis (AR) prevalence is increasing worldwide. However, while information on the economic burden of AR remains limited globally, nationwide data for Japan are similarly scarce. Therefore, we investigated healthcare utilization and prescription drug costs for seasonal AR using a nationwide claims database, primarily focusing on spring AR. METHODS:This observational study used the National Database of Health Insurance Claims (2018-2019). Patients with spring AR were defined as those with an AR-related diagnosis and prescriptions covering ≥14 days in each of the two spring pollen seasons (January-April) in 2018 and 2019 (pre-COVID-19 years with heavy pollen dispersal). Patients with summer (May-August) and autumn (September-December) AR were similarly identified, whereas patients with perennial-only AR were excluded. We calculated the number of patients, healthcare visits, drug costs, and the correlation between the number of spring AR patients and pollen counts. RESULTS:Spring AR involved 12.9 million patients (female-to-male ratio, 1.36), with annual prescription drug costs of 101.8 billion yen (7874 yen per patient), a mean of 3.05 visits per season, and 83% of patients visiting outpatient clinics without beds. Regional patient numbers were correlated with pollen counts (Spearman's r = 0.61). Summer and autumn AR involved 5.7 million and 6.1 million patients, with costs of 38.7 and 42.4 billion yen, respectively. CONCLUSIONS:Patients with seasonal AR identified using strict criteria totaled 24.7 million annually, with drug costs totaling 182.9 billion yen. These figures represent a conservative estimate of the minimum medical expenditure for seasonal AR in Japan.
BACKGROUND:Interleukin (IL)-13 promotes airway epithelial remodeling in asthma; however, the mechanisms by which IL-4/IL-13 blockade restores airway barrier function and how treatment timing alters epithelial cell states remain unclear. METHODS:Primary human bronchial epithelial cells were differentiated under air-liquid interface conditions and stimulated with IL-13. Dupilumab was added either concurrently or after 4 days. Airway barrier function was assessed using transepithelial electrical resistance (TEER), fluorescein isothiocyanate-dextran permeability, immunofluorescence, RT-qPCR, and ciliary beat frequency. Single-cell RNA sequencing with RNA velocity and cell type-stratified preranked gene set enrichment analyses were performed. RESULTS:IL-13 treatment triggered epithelial phenotypic remodeling, characterized by goblet cell expansion, and subsequently reduced ciliary activity, decreased TEER, and increased permeability. Early dupilumab treatment preserved TEER and attenuated permeability, whereas delayed dupilumab treatment resulted in partial TEER recovery with increased permeability. Single-cell analyses identified mucus-producing goblet and mucous ciliated states, and inflammatory parabasal clusters expressing alarmins and periostin. Delayed dupilumab treatment was associated with goblet cell subsets consistent with dedifferentiation-like transition toward a club cell-like state. TEER inversely correlated with MUC5AC expression, and asthmatic airway epithelium showed reduced TEER and disrupted occludin localization around goblet cells. Gene ontology analysis showed enrichment of cilium programs with early dupilumab treatment, whereas delayed dupilumab treatment favored mitochondrial respiration, ATP production, and protein homeostasis. CONCLUSIONS:Dupilumab ameliorates IL-13-induced airway barrier dysfunction in a timing-dependent manner. Single-cell analyses highlight epithelial plasticity and persistent inflammatory programs as key determinants of differential barrier recovery, providing mechanistic insights into variable clinical responses to dupilumab in asthma.
BACKGROUND:Chronic spontaneous urticaria (CSU) is a chronic skin disorder primarily driven by mast cell activation and basophil involvement. CSU is often associated with autoimmune mechanisms, positioning Bruton's tyrosine kinase (BTK) inhibition as an attractive therapeutic strategy. TAS5315 is a once-daily oral inhibitor of BTK with activity against Tec tyrosine-protein kinase and IL-2-inducible T-cell kinase (ITK). This study evaluated the efficacy and safety of TAS5315 in patients with CSU inadequately responding to non-sedating second-generation H1 receptor antagonists (ns-antihistamines). METHODS:This Phase 2a, randomized, double-blind, parallel-group, multicenter study randomized patients (1:1:1:1:1:1) with CSU to TAS5315 4 mg, 2 mg, 1 mg, 0.5 mg, 0.25 mg, or placebo for 12 weeks. The primary endpoint was the change from baseline in Weekly Urticaria Activity Score (UAS7) at Week 12. RESULTS:Of 126 patients enrolled, all received study treatment (n = 21 per dose group). The primary endpoint, mean changes from baseline in UAS7 at Week 12 were -17.15, -16.01, -15.19, -11.63, -17.84, and -9.06 for the TAS5315 4 mg, 2 mg, 1 mg, 0.5 mg, 0.25 mg, and placebo groups, respectively. Similar improvements were observed with TAS5315 versus placebo for other efficacy endpoints. Adverse events (AEs) were reported in over half of patients in each treatment group, and most were mild in severity. The most frequently reported AE with TAS5315 was petechiae. CONCLUSIONS:Once-daily TAS5315 was well tolerated and showed promising efficacy, making it a potential treatment option for CSU patients with inadequate response to ns-antihistamines.
BACKGROUND:Obstructive lung diseases, such as asthma and COPD, are characterized by chronic or variable airflow limitations and similar symptoms, hindering differential diagnosis. We therefore sought to investigate the clustering of clinical features, based on multiple computed tomography (CT) findings, in patients with physician-assigned diagnoses of asthma and/or COPD. METHODS:We used data for Japanese patients enrolled in the NOVELTY study, and a subset of patients with CT scans available within 1 year prior to the baseline visit (NOVELTY-CT substudy). We applied hierarchical cluster analysis (Ward's method with the Gower distance) for four CT features: emphysema, mucus plugs, increased bronchial wall thickness, and fibrosis. RESULTS:Data were collected for 228 patients, of whom 121 (53.1%), 46 (20.2%), and 61 (26.8%) were diagnosed with asthma, asthma + COPD, and COPD, respectively. Cluster analysis using data from 184 patients yielded four clusters: (C1) pauci-specific findings (74 patients); (C2) predominant-emphysema with bronchial features (9 patients); (C3) emphysema with mucus plugs (95 patients); and (C4) emphysema with fibrosis (6 patients). Baseline characteristics varied across the clusters, particularly the physician's diagnosis, age, respiratory function, disease severity, and patient-reported outcomes for symptom burden and quality of life/well-being. CONCLUSIONS:Patients with obstructive lung diseases were classified into four different clusters using CT findings. The classification was achieved by using objective CT features, which may support more tailored management.
BACKGROUND:While clinical remission occurs in some patients receiving biologics for severe asthma after one year of treatment, sustaining remission and frequency of relapse are unclear. This study evaluated sustained clinical remission, relapse, and its predictors over two to four years among people with severe asthma receiving mepolizumab. METHODS:Data from 208 patients (median age 59.6 years [52.0, 68.9], 41.3% male) in the Australian Mepolizumab Registry, a real-world prospective severe asthma registry, were analysed. Clinical remission was defined as: mean Asthma Control Questionnaire-5 score ≤1.0, no exacerbations, and no oral corticosteroid use over a 12-month period. Remission and relapse were assessed from 12 to 48 months at 12-month intervals. RESULTS:Of 184 with data available at 24 months, 29.9% (n = 55) achieved remission. 20.1% (35 of 174 with data from baseline to 24 months) sustained remission showing certain degree of stability since treatment initiation, while 9.2% (16/174) relapsed during treatment. Older age, severe disease, obesity, and depression significantly reduced the odds of achieving remission at 24 months. When assessed longitudinally (n = 47 with data from baseline to 48 months), remission increased from 36.1% at 12 months to 48.9% at 48 months. However, 17% relapsed over four years. Patterns of persistent non-remission, stable, delayed and unstable remission were also observed. CONCLUSIONS:Although remission rates may be overestimated in a cohort skewed toward treatment-responsive patients, clinical remission is achievable and sustained in a subgroup of patients with asthma, while remaining transient in some patients who risk relapsing and transitioning between disease states during continued mepolizumab treatment.
BACKGROUND:Mugwort pollen allergy, largely driven by the major allergen Art v 1, is a major cause of seasonal allergic rhinitis and asthma. Although recombinant allergens enable standardized allergen-specific immunotherapy, clinical data on ultra-short regimens remain limited. We conducted the first-in-human evaluation of an ultra-short recombinant Art v 1 subcutaneous immunotherapy (SCIT) regimen in adults with mugwort-induced allergic rhinitis. METHODS:In this randomized, double-blind, placebo-controlled Phase I study conducted outside the pollen season, 30 adults were assigned (1:2:2) to placebo (n = 6) or recombinant Art v 1 formulated with the oil-based adjuvant and administered at cumulative doses of 22 μg (n = 12) or 44 μg (n = 12) over four weekly injections. Primary endpoints were safety and tolerability. Secondary exploratory endpoints included allergen-specific antibody responses, IgE-blocking activity, cytokine production by allergen-restimulated peripheral blood mononuclear cells, and skin prick test (SPT) reactivity. RESULTS:No deaths, serious adverse events, anaphylaxis, or treatment discontinuations occurred. Adverse events were predominantly mild or moderate and mainly consisted of local injection-site reactions. Both active groups showed marked induction of Art v 1-specific IgG4 and IgG1, increased IgE-blocking activity, and stable total IgE levels. Cytokine profiling demonstrated dose-dependent immune deviation, with increased IL-10 and IL-2 at 22 μg and induction of IFN-γ-associated responses at 44 μg, without activation of Th2-related cytokines. SPT reactivity was reduced in both active groups, with no change in placebo. CONCLUSIONS:An ultra-short recombinant Art v 1 SCIT regimen was safe and induced rapid, dose-dependent allergen-specific immune modulation, supporting further clinical development. CLINICALTRIALS:GOV: NCT07317960.
BACKGROUND:Eosinophilic chronic rhinosinusitis (ECRS) is characterized by nasal polyps, type 2 inflammation, and excessive fibrin deposition. Although local dysregulation of coagulation and fibrinolysis is implicated in ECRS pathogenesis, it remains unclear whether these abnormalities involve systemic hemostatic changes. METHODS:We enrolled 20 patients with ECRS, 20 with non-ECRS, and 20 controls (patients undergoing septoplasty without CRS). Peripheral blood was collected 1 month preoperatively to measure coagulation and fibrinolysis markers-including fibrin degradation products (FDP), D-dimer, and factor XIII activity-via standard clinical assays. Group differences were assessed using nonparametric tests, and categorical variables were compared using the χ2 or Fisher's exact tests. RESULTS:FDP levels were significantly higher in both the ECRS and non-ECRS groups than in the controls (control vs. non-ECRS, P = 0.011; control vs. ECRS, P = 0.045). D-dimer levels were significantly higher in the non-ECRS group than in the controls (P = 0.002). Factor XIII activity was significantly higher in the ECRS group than in the controls (P = 0.041). CONCLUSIONS:Chronic rhinosinusitis (CRS) may be associated with mild alterations in coagulation and fibrinolysis. In the original cohort, non-ECRS showed a pattern compatible with enhanced coagulation-fibrinolysis turnover, whereas ECRS showed elevated factor XIII activity with possible alterations in fibrin stabilization. Sensitivity analyses suggested that the factor XIII signal in ECRS was relatively robust, whereas the findings for FDP and D-dimer were more sensitive to control group composition. These findings support that CRS, particularly ECRS, is accompanied by subtle systemic hemostatic changes, although further validation required.
BACKGROUND:During the Japanese cedar pollen (JCP) and cypress pollen seasons, skin symptoms are occasionally reported in individuals with seasonal allergic rhinitis (sAR). Although the seasonal worsening of atopic dermatitis is known, the clinical relevance of pollen season skin symptoms in the broader population with sAR remains unclear. This study examined skin symptoms during the pollen seasons and their association with severe sAR. METHODS:This cross-sectional study included 4119 patients with sAR during the JCP and Japanese cypress dispersal seasons, who were categorized based on skin symptom presence or absence. The primary outcome was severe sAR. Multivariable logistic regression analyses using inverse probability weighting were performed to evaluate the association between skin-related variables and severe sAR. Additional analyses were conducted, with adjustment for skin symptom scores. RESULTS:Skin symptoms were reported by 1993 (48.4%) patients, of whom 985 (49.4%) experienced seasonal worsening during the pollen seasons. Facial and extremity or trunk involvement was observed in 64.8% and 56.2%, respectively. In inverse probability weighting-adjusted analyses, skin symptom seasonal worsening (OR: 1.45, 95% CI: 1.14-1.86), facial involvement (OR: 1.47, 95% CI: 1.12-1.93), and moderate-to-most severe skin symptoms (OR: 1.35, 95% CI: 1.02-1.79) were associated with severe sAR. These associations were not materially altered after additional adjustment for skin symptom scores. CONCLUSIONS:Approximately one quarter of patients with sAR reported seasonal worsening of skin symptoms during the pollen seasons. These findings suggest that skin symptoms are associated with increased sAR severity and may reflect interactions between cutaneous and airway inflammation.
The global prevalence of childhood asthma has undergone profound shifts, marked by a late-20th-century plateau in Western nations and a rapidly emerging epidemic across many developing countries. Traditional risk factors, such as air pollution, allergen exposure, and viral infections-fail to fully explain these trends. Instead, many birth cohorts and migrant studies strongly implicate changing early-life environments. Grounded in the hygiene and biodiversity hypotheses, this review explores the critical environmental determinants of childhood asthma. We synthesize global epidemiological data highlighting stark urban-rural disparities, drawing on seminal studies of European farming cohorts, US Amish and Hutterite communities, and cross-border Chinese populations. These populations collectively demonstrate the protective effects of early-life microbial exposure. We detail the current understanding of how environmental microbes and their metabolites dictate the maturation of the infant immune system, fostering systemic tolerance and preventing allergic trajectories. Furthermore, we evaluate emerging prospective primary intervention trials, including the ORBEX, TIGER, and MARTHA studies, which leverage microbial strategies in an attempt to alter the natural history of asthma development. Ultimately, the loss of environmental microbial diversity could be a primary driver of the allergy epidemic. Elucidating the underlying biological mechanisms of immune-microbe crosstalk and advancing prospective intervention trials will be essential for developing effective primary prevention strategies against childhood asthma.
BACKGROUND:Atopic dermatitis (AD) is often associated with ocular surface disease (OSD). Dupilumab, an IL-4Rα inhibitor, is an effective treatment for AD but it sometimes induces dupilumab-associated OSD (DAOSD). DAOSD may associate with a paucity of conjunctival goblet cells or altered immune response; however, the mechanism remains undetermined. Therefore, we aimed to identify ophthalmological alterations and to explore the potential mechanisms of DAOSD in AD patients receiving dupilumab. METHODS:We conducted a prospective, single-arm, observational study with 50 moderate-to-severe AD patients receiving dupilumab for 24 weeks. We performed ophthalmological evaluations, conjunctival impression cytology analysis, and tear fluid profiling at baseline, weeks 4, 12, and 24. RESULTS:Clinical severity scores of AD indicated significant improvement with dupilumab. At baseline, 18% of patients already exhibited OSD. During the study period, DAOSD ever occurred in 46% of patients, and it was mild and controllable by topical anti-inflammatory drops. AD patients with reduced conjunctival goblet cells at baseline had significantly a lower level of BDNF and higher levels of VEGF-A, PDGF-BB, and MCP-1 in tears. Patients with DAOSD had higher residual AD severity at weeks 12 and 24. Elevated levels of IL-9, IL-16, and GM-CSF in tears were specific for new onset DAOSD, indicating a shift toward Th1/9 and innate immune activation. CONCLUSIONS:DAOSD is common but transient in AD patients receiving dupilumab. Its underlying mechanisms may involve pre-existing goblet cell deficiency, changes in tear composition, and an altered inflammatory profile. Timely ophthalmic intervention may mitigate the damage and symptoms associated with related complications.
BACKGROUND:Delgocitinib ointment is a non-steroidal Janus kinase inhibitor approved for atopic dermatitis (AD). To address limitations of topical corticosteroids (TCS)-such as reduced adherence and efficacy due to the complexity of anatomical location-based potency adjustments, and patient reluctance to use high-ranked TCS-this study investigated the potential of combining delgocitinib ointment with a medium-ranked TCS (Japanese guideline) to induce remission in pediatric AD patients. METHODS:Eligible Japanese AD patients aged 2 to under 16 years were randomized in a 1:1 ratio to receive either delgocitinib-TCS combination therapy or TCS monotherapy for 4 weeks in an open-label, parallel-group design. Assessments included Eczema Area and Severity Index (EASI), Numeric Rating Scale (NRS), Patient-Oriented Eczema Measure (POEM), and Validated Investigator's Global Assessment (vIGA) for efficacy, and adverse events (AEs) for safety. The study was registered with the Japan Registry of Clinical Trials (jRCTs031240119). RESULTS:Eighty-three and 84 pediatric AD patients received delgocitinib combination therapy and TCS monotherapy, respectively, and showed 71.74% and 60.03% reductions in EASI score after up to 4 weeks of treatment (primary endpoint). The delgocitinib combination group demonstrated a statistically significant 11.71% greater reduction compared to the TCS monotherapy group (p = 0.0383). The adverse drug reactions (ADRs) observed in the delgocitinib combination group were expected local events, and no notable safety concerns were identified with the addition of delgocitinib to TCS therapy. CONCLUSIONS:The combination of delgocitinib ointment and TCS is considered a promising novel therapeutic option for remission induction in pediatric patients with moderate to severe AD.
BACKGROUND:In eosinophilic chronic rhinosinusitis (ECRS), eosinophil extracellular traps (EETs) formed via extracellular trap-forming cell death contribute to abnormal mucus properties, including increased viscosity and hydrophobicity, which exacerbate disease progression. This study aimed to determine the modulatory effects of heparin-like compounds on the viscosity, hydrophilicity, and water content of EET-rich mucus in ECRS, and to assess their potential as adjunctive agents in enhancing mucolytic efficacy. METHODS:Mucus samples obtained from six patients with ECRS were treated with heparin-like compounds, including unfractionated heparin, mucopolysaccharide polysulfate (MPS), and dalteparin. Shear viscosity was measured using a rotational viscometer, hydrophobicity was assessed by contact-angle measurements, and water content was determined by thermogravimetric analysis based on time-dependent weight changes and final dry weight. The effects of these compounds on EETs were evaluated using peripheral blood-derived eosinophils in vitro. RESULTS:Treatment with heparin-like compounds, similar to unfractionated heparin, reduced the viscosity of ECRS mucus and EET aggregates while increasing both the water content and hydrophilicity. These compounds also promoted the relaxation of EET structures, and co-treatment with DNase further enhanced mucus dissolution. Increased turbidity upon mixing with histones indicated a direct interaction between heparin-like compounds and histones. CONCLUSIONS:These findings suggest that heparin-like compounds interact with EET-associated histones and alter the mucus polymer network, thereby improving the biophysical properties of pathological mucus by reducing its viscosity and enhancing its hydrophilicity.
