Clinical remission in asthma has gained prominence as both a therapeutic goal and a research endpoint, although its operational definitions have varied. To harmonize Japanese practice with emerging global frameworks, the Japanese Society of Allergology (JSA) conducted a two-round modified Delphi survey to establish a consensus definition for inclusion in the 2024 Asthma Prevention and Management Guidelines (JGL 2024).

In Round 1 (January 2024), 81 JGL 2024 guideline committee members representing adult and pediatric specialties were invited. Seventy-four percent agreed that clinical remission should be defined, and 50 % supported including both on- and off-treatment remission. Four core components emerged: absence of exacerbations, well-controlled symptoms, no continuous oral corticosteroid use, and optimization of pulmonary function.

Round 2 refined operational thresholds for symptom control, adopting ACT ≥23 (C-ACT ≥23 for children) and ACQ ≤0.75, consistent with JGL's long-standing goal of achieving a truly symptom-free state without reliever use. Pulmonary function was defined as “optimization,” encompassing normalization where achievable and stabilization when normalization is unlikely (e.g., airway remodeling), which received strong agreement.

Collaboration between adult and pediatric experts affirmed clinical remission as a milestone toward off-treatment remission and potential cure, broadening its applicability across severities and age groups. This review further summarizes evidence supporting remission as an outcome of biologic therapy, its key predictors (e.g., smoking, obesity, disease duration), pediatric perspectives, and future directions. JGL 2024 formally adopts these criteria, providing a rigorous and pragmatic framework to advance patient-centered asthma care and reframe management toward disease modification and eventual cure.

Severe asthma is associated with persistent symptoms, frequent exacerbations, oral corticosteroid dependence, and reduced lung function. The emergence of biologic therapies targeting type 2 (T2) cytokines, including IL-5, IL-4, IL-13, thymic stromal lymphopoietin, and circulating IgE, has changed disease management and led to substantial improvement. This approach has also introduced the concept of clinical remission (defined as controlled symptoms, no maintenance corticosteroid use, no exacerbations, and optimized/stabilized lung function) as a potential treatment target.

Although some guidelines propose remission criteria, no universally accepted definition exists, and reported prevalence varies depending on definitions, and therapies, and patient groups. Clinical remission has been achieved in approximately one-third of patients receiving T2-targeted biologics. Factors associated with achieving clinical remission include less severe disease (less symptoms, fewer exacerbations, and better lung function), fewer comorbidities (e.g. obesity, anxiety/depression), greater T2-disease activity (the presence of nasal polyps and higher T2 biomarkers), and early treatment response. Azithromycin therapy can also contribute to achieving remission in both T2-high and T2-low moderate to severe asthma phenotypes.

Future perspectives on asthma remission include integrating a treatable traits approach, establishing and validating the definition of complete remission, and assessing the long-term benefits of achieving remission. Complete remission may encompass clinical remission, inflammatory remission (normalization of T2 biomarkers), and structural/functional remission (resolution of bronchial hyperresponsiveness, mucus plugging, and airway remodeling). Standardizing remission criteria will enable the identification of predictive factors and facilitate personalized, treat-to-target strategies. Early induction of clinical remission may be a promising strategy for optimizing outcomes in severe asthma.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis for which achieving remission is the primary therapeutic goal. Historically, remission in EGPA was defined by the absence of active vasculitis, typically a Birmingham Vasculitis Activity Score (BVAS) of 0. However, this definition is insufficient as it overlooks the significant morbidity associated with long-term glucocorticoid (GC) therapy. Recent evidence highlights that even low-dose GCs carry substantial risks, challenging the traditional acceptance of remission on GC. This review summarizes the evolution of the remission concept in EGPA, highlighting the paradigm shift seen in recent pivotal clinical trials for biologics, which have incorporated stringent GC dose thresholds (e.g., prednisone ≤4 mg/day) into their primary endpoints. This reflects a growing consensus that minimizing GC exposure is a crucial component of a successful treatment outcome. Further, this review explores potential future components for remission criteria, such as organ-specific activity measures and patient-reported outcomes.

Airway mucus plugs are the main pathological and computed tomography (CT) findings that affect clinical outcomes in patients with asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap. Despite the introduction of biologics targeting type 2 inflammation, mucus plug removal remains challenging and understanding its pathogenesis is critical for improved management. In eosinophilic airways, elevated MUC5AC and eosinophil-derived molecules (galectin-10 and extracellular traps) cause highly viscoelastic plugs detectable as high-density regions on ultra-high-resolution CT. In neutrophilic airways, where phylum Proteobacteria and genus Haemophilus are predominant, excessive neutrophil elastase impairs mucociliary clearance, induces neutrophil extracellular traps (NETs), and promotes mucus overproduction. Since mucus plugs could be reservoirs for bacterial colonization, an altered airway microbiome and airway inflammation may be associated with mucus plugging. Phylum Firmicutes and genus Streptococcus are positively and genus Fusobacterium is negatively associated with mucus plugging in severe eosinophilic inflammation. Anaerobic commensals produce short-chain fatty acids, which suppress eosinophilic inflammation. In moderate eosinophilic inflammation, anaerobic commensals may be replaced by pathogenic bacteria of the phylum Proteobacteria and genus Haemophilus, which triggers severe neutrophilic inflammation and exacerbates mucus plugging. Finally, in eosinophilic inflammation, mucus plugs containing aggregated eosinophils may induce mechanical dilation of the airways. In contrast, the presence of mucus plugs in a neutrophilic milieu may reflect severe inflammation characterized by excessive neutrophil extracellular traps and degenerative tissue remodeling, which is consistent with the pathological features of bronchiectasis. This review provides clues regarding how inflammation and microbiome alterations interact with mucus plugging in chronic airway disease.

The epidermal immune microenvironment is a multifaceted system in which the interplay between the skin microbiome and antimicrobial peptides plays a pivotal role in sustaining skin homeostasis and preventing dysbiosis. Disruption of these interactions can lead to inflammatory skin conditions such as atopic dermatitis. This review aims to explore the complex mechanisms by which antimicrobial peptides and the skin microbiome communicate within the epidermal immune microenvironment, emphasizing causal dynamics and the dual role of antimicrobial peptides. This analysis opens new avenues for targeted interventions, including antimicrobial peptide modulation and microbiome-based therapies, to restore skin health and mitigate inflammatory skin disorders.

Background: Chitinase-3-like protein 1 (YKL-40) has been reported as a biomarker of neutrophilic airway inflammation in obstructive airway disorders. However, the pathophysiological features of YKL-40 remain unclear. The aim of the study is to evaluate the associations between YKL-40 and clinical features in patients with asthma, chronic obstructive pulmonary disease (COPD), or asthma-COPD overlap (ACO).

Methods: Serum and sputum YKL-40 levels were measured in 46 asthmatics, 35 COPD, and 32 ACO patients.

Results: Serum YKL-40 levels were elevated in the COPD and ACO patients, and sputum YKL-40 levels were higher in the COPD patients compared to the asthmatics. Both serum and sputum YKL-40 levels positively correlated with sputum neutrophils. Only serum YKL-40 levels negatively correlated with FEV₁ (%predicted), FEV₁/FVC, and annual decline in FEV₁. In 15 patients whose paired serum samples were obtained within 6 months, changes in serum YKL-40 levels showed a significant positive correlation with those in FEV₁. Furthermore, patients who had experienced exacerbations either in the past year or the following year showed significantly greater serum, but not sputum, YKL-40 levels. Sputum YKL-40 levels showed significant correlations with scores on the COPD assessment test and modified Medical Research Council dyspnea scale.

Conclusions: Serum and sputum YKL-40 may reflect distinct clinical features in obstructive airway disorders. Serum YKL-40 may provide beneficial information on predicting obstructive neutrophilic inflammation and exacerbations, whilst sputum YKL-40 may offer valuable insights for evaluating ongoing symptoms. Concomitant measurement of YKL-40 in serum and sputum might be more useful than individual measurement.

Background: The underlying pathophysiology of varying physical activity levels in patients with asthma remains unclear. In this study, we investigated the association between physical activity and air trapping, identified via chest computed tomography, in patients with asthma.

Methods: The following computed tomography analyses were used to evaluate air trapping in two cohorts (Cohort 1: 27 patients with asthma, 12 healthy individuals; Cohort 2: 90 patients with asthma, 43 healthy individuals): density analysis, focusing on air trapping characteristics during expiration, and parametric response mapping (PRM), which integrates inspiratory and expiratory computed tomography scans to categorize air trapping into small airway disease (PRM^SAD) and low-attenuation areas. Mucus plug scores were also measured.

Results: Patients with asthma exhibited significantly reduced activity levels compared with healthy participants at intensities of ≥2, ≥3, and ≥4 metabolic equivalents (METs) in both cohorts. Among patients with asthma, air trapping was significantly associated with decreased physical activity of ≥4 METs, corresponding to moderate-to-vigorous exercise intensity. Among the air-trapping components, increased PRM^SAD significantly contributed to reduced physical activity at ≥4 METs. Regarding the relationship between PRM^SAD and physical activity for each lung lobe, elevated PRM^SAD in the left upper lobe played a significant role in decreasing physical activity. The presence of mucus plugs was associated with elevated PRM^SAD.

Conclusions: The uneven distribution of air trapping in the lungs of patients with asthma, particularly in the upper lobe, was linked to reduced moderate-to-vigorous-intensity physical activity and was partially attributable to small airway obstruction caused by mucus plugs.

Background: Sublingual immunotherapy (SLIT) involves the induction of allergen-specific regulatory T (Treg) cells in the oral mucosa-draining submandibular lymph nodes (LNs). However, their subsequent maintenance remains unclear, including the involvement of the gut microbiota. We aimed to investigate where and how SLIT-induced Treg cells are maintained to ensure tolerance to allergens.

Methods: We used a mouse model of prophylactic SLIT with ovalbumin as the allergen. SLIT-induced tolerance was assessed by suppressing delayed-type hypersensitivity (DTH) responses. The distribution of SLIT-induced Treg cells was determined based on their ability to suppress the DTH response upon adoptive transfer. The involvement of LNs and gut microbiota was assessed by the surgical removal of LNs and antibiotic depletion of the gut microbiota, respectively.

Results: Suppression of DTH by SLIT was impaired by surgical removal of submandibular LNs prior to SLIT. Functional SLIT-induced Treg cells were detected in submandibular LNs and gut-draining mesenteric LNs, however, not in skin-draining LNs or the spleen. Intriguingly, the surgical removal of mesenteric LNs alone after SLIT was sufficient to abolish the suppressive effect of SLIT. Gut microbiota depletion by antibiotic treatment after SLIT also abolished the suppressive effect of SLIT and impaired the maintenance of functional SLIT-induced Treg cells in mesenteric LNs.

Conclusions: Functional SLIT-induced Treg cells were maintained in mesenteric LNs in a gut microbiota-dependent manner. Thus, this study revealed a previously unrecognized role of the gut microbiota in SLIT and provided a rationale for targeting the gut environment to improve the efficacy and prolong the maintenance of SLIT.

Background: Recent findings suggest skin microbiota is closely linked to the aggravation of atopic dermatitis (AD) and skin barrier dysfunction.

Methods: This prospective cross-sectional study included 52 children: 35 with AD flare (F) and non-flare (NF), and 17 without AD (non-AD). Microbes in the skin samples from the three groups were analyzed using 16S rRNA amplicon sequencing. We estimated the anti-virulence of Kocuria rhizophila in the skin microbiome of children. The effects of K. rhizophila were evaluated in human skin cell models with AD-like damage caused by Staphylococcus aureus secretory toxins, including protein A (PA), lipoteichoic acid, and protease V8.

Results: Taxonomic classification revealed significant phylum-level differences among the three groups. Alpha-diversity indices tended to decrease in the AD-F group compared with the non-AD group but were higher in the AD-NF group. The AD group had a high relative abundance of S. aureus, but S. aureus was almost absent in the non-AD group and exhibited a marked decrease in the AD-NF group; K. rhizophila was negatively correlated with AD severity. Heat-killed K. rhizophila (HKKR) treatment upregulated gene expression of the tight junction protein zonula occludens-1 and critical components of the cornified cell envelope, involucrin and filaggrin, while downregulating the expression of the pro-inflammatory cytokines interleukin (IL)-1b and IL-6. Transcriptomic analysis revealed that HKKR treatment was associated with skin barrier functions, cell–cell junctions, and immune responses.

Conclusions: K. rhizophila may be associated with the mitigation of skin barrier dysfunction and inflammation in S. aureus infection, highlighting its potential for AD treatment.

Background: Heterogeneity of asthma requires a personalized therapeutic approach. However, objective measurements, such as spirometry and fraction of exhaled nitric oxide (FeNO) for implementing treatable traits approach, are limited in low- and middle-income countries and non-specialist settings. To implement precision medicine even with minimal resources, we developed an algorithm using unsupervised machine learning techniques that estimates key treatable traits (airflow limitation, type 2 [T2] inflammation, and frequent exacerbations) based on an asthma patient-reported outcome (PRO).

Methods: We applied hierarchical clustering and Uniform Manifold Approximation and Projection (UMAP) to Asthma Control Questionnaire (ACQ)-5 including five residual symptoms from two asthma cohorts (the discovery cohort with 1697 patients and validation cohort with 157 patients).

Results: We identified five symptom clusters, characterized by key treatable traits: Cluster 1, minimal asthma symptoms; Cluster 2, a little symptom, mild airflow limitation; Cluster 3, predominant shortness of breath and wheezes, airflow limitation; Cluster 4, predominant morning symptoms and nocturnal awakening, T2 inflammation; and Cluster 5, all symptoms severe, airflow limitation, T2 inflammation and frequent exacerbations. The UMAP projections of ACQ-5 (five-dimensional) to two-dimensions allowed to visualize datapoints and clusters, which visually revealed that patients with poorly-controlled asthma were divided into Clusters 3, 4 and 5. These results were externally validated in an independent cohort.

Conclusions: Based on asthma PRO data, the developed algorithm categorized asthma patients into five symptom-based subtypes that provide insights into key treatable traits. Our data-driven digital health approach will extend precision medicine of asthma to medical facilities even in resource-constrained settings.

Background: There have been few epidemiological surveys regarding adult anaphylaxis in Japan. The aim of the study is to investigate the current condition in the diagnosis and management of adult anaphylaxis in Japan.

Methods: An observational, descriptive, cross-sectional study was conducted among physicians who belong to the Japanese Society for Cutaneous Immunology and Allergy and the Japanese Allergology Society, via cloud-based software. A 24-item questionnaire focused on the implementation of diagnostics and management of anaphylaxis, especially in adults.

Results: There were 537 departments that treated anaphylaxis, including 243 pediatrics, 156 dermatology, 124 internal medicine, and 14 allergy departments. Of the group, 362 departments treated adult patients with anaphylaxis, with 149 dermatology being the most common, followed by114 internal medicine, 85 pediatrics and 14 allergy departments. Big prefectures such as Tokyo have the most facilities. However, in terms of population ratio, it became clear that there was not necessarily more coverage in large cities. For anaphylaxis due to foods, specific IgE measurements were the most frequently performed at more than 90 % of all four departments, whereas skin tests and challenge tests were performed less than the IgE measurements at 56.9 % and 35.1 %, respectively. As for the reasons for not performing them, a lack of manpower was mostly cited, followed by lack of preparation for anaphylaxis before testing, unfamiliarity with testing methods, and low or no medical fees.

Conclusions: The survey revealed the uneven geographical distribution of medical departments and the chief barriers for implementation of the examination in adult anaphylaxis.

Background: Eosinophilic otitis media (EOM) is characterized by eosinophilic infiltration of the middle ear; it is frequently associated with bronchial asthma and chronic rhinosinusitis with nasal polyposis. Although biologics have been used to treat EOM, their efficacy based on clinical characteristics remains unclear. In this study, we evaluated the effectiveness of biologics and analyzed the clinical factors that influenced outcomes.

Methods: We retrospectively studied 29 patients with EOM treated with either mepolizumab or dupilumab as an adjunct to standard therapy, which included intratympanic instillation of triamcinolone. Clinical efficacy was assessed by severity scores, temporal bone computed tomography scores, and pure-tone audiometry. The control group comprised 15 patients with EOM who did not receive biologics. We also analyzed the correlations between changes in severity score from baseline and clinical factors for each patient.

Results: Both biologics groups had significantly lower severity scores at 6 months, with sustained effects until 12 months. The patients with severe middle ear mucosal changes and high baseline severity scores experienced significant improvement with the use of dupilumab; mepolizumab was more effective in elderly patients. Temporal bone computed tomography scores improved in both biologics groups, indicating inflammation resolution in the whole temporal bone. No deterioration of bone-conduction hearing levels was observed in any group.

Conclusions: Mepolizumab and dupilumab showed efficacy for EOM, with therapeutic effects evident within 6 months. Dupilumab is preferable for patients with severe mucosal changes, whereas mepolizumab may benefit elderly patients. Further studies are needed to refine treatment strategies.

Background: The risk of asthma exacerbation is intrinsic to female patients. Enhanced type 2 immune responses are considered to be associated with sustained increased susceptibility to asthma exacerbation in female patients; however, the mechanisms mediating this relationship remain unclear.

Methods: Using a Dermatophagoides farinae-induced asthma mouse model, asthma-related features were evaluated. We focused on memory T cells and aimed to determine the cell types responsible for female-predominant long-term asthma exacerbations using a functional S1P₁ receptor antagonist and parabiotic mouse model.

Results: Compared to male mice, female mice demonstrated aggravated asthma exacerbation 3 months after allergen re-exposure. Higher levels of Th2 cytokines and IL-33 were observed in the lungs of female mice than in those of male mice. Moreover, enhanced Il33 mRNA synthesis in female mice was attributable to LNGFR ⁺ airway epithelial cells. Increased IL-33 production or the female hormonal environment may have led to increased number of ST2⁺CD4⁺ memory T cells. Both 17β-estradiol and progesterone were associated with the expansion of these cells; however, only 17β-estradiol maintained elevated numbers of ST2⁺CD4⁺ memory T cells over time. The suppressed migration of ST2⁺CD4⁺ circulating memory T cells into the lungs attenuated asthmatic inflammation in female mice to levels comparable to those observed in male mice. In contrast, ST2⁺CD4⁺ tissue-resident memory T cells are attributable asthmatic inflammation in male mice.

Conclusions: Our findings suggest that the contribution of memory T cells to asthmatic inflammation varies depending on sex, and female predominance is attributable to an increased number of ST2⁺CD4⁺ circulating memory T cells.

Background: Despite advances in pharmacologic therapy, a subset of patients with bronchial asthma (BA) experience persistent symptoms. Multiple chemical sensitivity (MCS), a non-allergic condition triggered by low-level chemical exposures, may be responsible for asthma-like symptoms. Although epidemiological studies have reported a high co-prevalence of MCS and BA, clinical comparisons among patients with BA between those with and without MCS are limited. We aimed to characterize the clinical and symptomatic profiles of patients with BA and comorbid MCS.

Methods: This cross-sectional study included 100 patients with BA treated at Sagamihara Hospital. MCS-related symptoms were evaluated using the Quick Environmental Exposure and Sensitivity Inventory (QEESI). Clinical data including serum total Immunoglobulin E (IgE) levels, eosinophil counts, pulmonary function, hospitalization frequency, comorbidities, and medications were collected by attending physicians. Fifteen patients who exceeded the QEESI MCS cut-off value (BA-MCS group) were compared with 30 age- and sex-matched controls without MCS (BA-control group).

Results: Compared to BA-controls, the BA-MCS group had strong symptoms in multiple organs other than the respiratory system (p = 0.000), exhibited significantly higher percentage forced expiratory volume (%FEV₁) (p = 0.047), lower serum IgE levels (p = 0.028), more frequent hospitalizations (p = 0.002), and higher incidence of atopic dermatitis history (p = 0.001).

Conclusions: The BA-MCS group had a distinct phenotype characterized by preserved lung function, low IgE levels, systemic symptoms, and high disease burden. For these patients, a multidisciplinary approach addressing BA and MCS may be more effective than intensifying asthma pharmacotherapy alone.

Background: Dupilumab is approved in Japan for the treatment of atopic dermatitis in patients aged 6 months to 18 years. However, long-term data are lacking in this patient population. Here we report the final analysis of a long-term open-label extension (OLE) of a phase 3 study that assessed dupilumab in Japanese patients aged ≥6 months to <18 years with moderate-to-severe atopic dermatitis inadequately controlled with existing therapies.

Methods: Study participants were randomly assigned to dupilumab or placebo with concomitant topical corticosteroids for 16 weeks, then to open-label dupilumab until approval or for 3 years, whichever came first.

Results: Of the 62 participants randomized, 60 entered the OLE and continued to receive dupilumab (n = 28) or initiated dupilumab (n = 32). Improvements in clinical severity scores seen with dupilumab at Week 16 persisted up to Week 116, as confirmed by several efficacy endpoints (proportion of patients who achieved ≥75 % or ≥90 % improvement in Eczema Area and Severity Index [EASI] score, and Investigator's Global Assessment score of 0/1, and percent change in EASI scores from baseline). During the dupilumab exposure period, 93.5 % of patients experienced a treatment-emergent adverse event (TEAE). No adverse events leading to death, or TEAEs leading to study treatment discontinuation were observed during the OLE period. One (3.1 %) treatment-emergent positive anti-drug antibody response was observed during the OLE period in the placebo/dupilumab group.

Conclusions: This analysis supports the long-term efficacy and safety of dupilumab in Japanese patients aged ≥6 months to <18 years with moderate-to-severe atopic dermatitis.

Background: Allergen sensitization patterns are heterogeneous, and their clinical relevance is often obscured by extensive cross-reactivity. We applied non-negative matrix factorization (NMF) to disentangle overlapping immunoglobulin E (IgE) signals and define clinically meaningful allergen signatures in a large Korean cohort.

Methods: We analyzed 45,065 patients who underwent multiplex allergen testing (35 inhalants and food components) between 2010 and 2025. Class-scaled specific IgE values (0-6) were factorized by NMF (k = 4). Signature weights were related to asthma, allergic rhinitis, and atopic dermatitis using multivariable logistic regression and to peripheral eosinophil counts and total IgE using age- and sex-adjusted linear models.

Results: Four signatures—mite, grass/weed, pet, and tree—explained 77.7 % of the variance in sensitization. The mite signature predominated (57.6 % of patients) and was strongly associated with allergic rhinitis (adjusted OR: 7.21, 95 % CI: 5.66-9.16), as well as marked increases in eosinophils and total IgE. The pet signature was the strongest predictor of asthma (OR: 8.90, 6.48-12.24). The tree signature showed the strongest association with atopic dermatitis (OR: 6.27, 3.81-10.32) and broader multisystem allergic morbidity. The grass/weed signature exhibited a biphasic age trajectory with a late-adult resurgence but had modest clinical impact. All signatures were significant and graded as determinants of blood eosinophil counts and IgE levels.

Conclusions: Data-driven factorization of multiplex IgE panels yields portable allergen signatures that refine attribution of asthma, allergic rhinitis, and atopic dermatitis and link serologic patterns to systemic inflammation.