Asthma is a syndrome with extremely diverse clinical phenotypes in which the onset, severity, and response to treatment are defined by the complex interplay of many genetic and environmental factors. Environmental factors epigenetically affect gene expression, and the disease is driven by a multidimensional dynamic network involving RNA and protein molecules derived from gene expression, as well as various metabolic products. In other words, specific pathophysiological mechanisms or endotypes are dynamic networks that arise in response to individual genotypes and the various environmental factors to which individuals have been exposed since before birth, such as diet, infection, air pollution, smoking, antibiotic use, and the bacterial flora of the intestinal tract, skin, and lungs. A key feature of asthma genome scans is their potential to reveal the molecular pathways that lead to pathogenesis. Endotypes that drive the disease have a significant impact on the phenotypes of asthma patients, including their drug responsiveness. Understanding endotypes will lead to not only the implementation of therapies that are tailored to the specific molecular network(s) underlying the patient's condition, but also to the development of therapeutic strategies that target individual endotypes, as well as to precision health, which will enable the prediction of disease onset with high accuracy from an early stage and the implementation of preventive strategies based on endotypes. Understanding of endotypes will pave the way for the practice of precision medicine in asthma care, moving away from ‘one-size-fits-all’ medicine and population-based prevention approaches that do not take individuals' susceptibility into account.

Biologics have been a key component of severe asthma treatment, and there are currently biologics available that target IgE, IL-5, IL-4/IL-13, and TSLP. Randomized controlled trials have established clinical evidence, but a significant portion of patients with severe asthma in real-life settings would have been excluded from those trials. Therefore, real-world research is necessary, and there is a growing body of information about the long-term efficacy and safety of biologics.

Multiple clinical phenotypes of severe asthma exist, and it is crucial to choose patients based on their phenotypes. Blood eosinophil count is an important biomarker for anti-IL-5 therapies, and FeNO and eosinophil counts serve as prediction markers for dupilumab. Reliable markers for predicting response, however, have not yet been fully established for omalizumab. Identification of clinical or biological prediction factors is crucial for the path toward clinical remission because the current treatment goal includes clinical remission, which is defined as a realistic goal for remission off treatment.

Additionally, since there are now multiple biologic options and overlaps in eligibility for biologics in clinical practice, the evidence regarding the effectiveness of switching the biologics is crucial. Investigations into the clinical trajectory following the cessation of biologics are another important issue.

Recent research on omalizumab, mepolizumab, benralizumab and dupilumab's real-world effectiveness, the prediction factor for the efficacy, and the impact of switching or discontinuation will be reviewed and discussed in this review.

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that plays a vital role in the induction of type 2 inflammation via both innate and acquired immune cascades. Tezepelumab, a human IgG2 monoclonal antibody that inhibits the binding of TSLP to the TSLP receptor, is the latest biologic for asthma. To evaluate the efficacy and mechanism of tezepelumab in asthma, the PATHWAY, NAVIGATOR, NOZOMI, UPSTREAM, CASCADE, SOURCE, and DESTINATION studies have been conducted. These results suggested that tezepelumab is a broad-target biologic, which is expected to be effective in patients with poorly controlled moderate to severe asthma regardless of the phenotype, although its efficacy in oral corticosteroids-dependent asthma, biological mechanism in non-type 2 phenotype, and long-term safety remain unknown. In this review, we summarize the results of clinical trials of tezepelumab in asthma and discuss the differences between tezepelumab and other biologics.

Biologics targeting the molecules associated with type 2 inflammation have significantly improved the outcomes of patients with severe eosinophilic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). Chronic eosinophilic airway/lung diseases including chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis/mycosis, eosinophilic bronchitis, and eosinophilic granulomatosis with polyangiitis share clinical features with eosinophilic asthma and CRPwNP, which are mostly adult-onset and may develop simultaneously or consecutively. These eosinophilic airway/lung diseases respond well to initial treatment with systemic corticosteroids, but often recur when the corticosteroids are tapered. The management of these “refractory” cases is an unmet need for clinicians. We first reviewed the standard treatments for these chronic eosinophilic airway/lung diseases, followed by the definition and prevalence of refractory diseases and the role of biologics in their management. The available evidence varies from case reports and case series to randomized control trials, depending on the type of disease; however, these studies provide not only a direction for clinical practice, but also insights into the pathophysiology of each disease. Physicians should discuss the efficacy and costs of biologics in patients with refractory eosinophilic airway/lung diseases to minimize not only the current symptoms, but future risks as well.

The Practical Guideline for the Management of Allergic Rhinitis, the fist guideline for allergic rhinitis in Japan, was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 9th edition was published in 2020 and is widely used today.

The most recent collection of evidence from the literature was supplemented to the revised guideline to incorporate evidence-based medicine. The revised guideline includes updated epidemiology of allergic rhinitis in Japan, a figure representing the mechanisms of allergic rhinitis in both the onset and sensitization phases with the introduction of regulatory T cells and type 2 innate lymphoid cells, practical assessment for diagnosis, new pharmacotherapy agents such as anti-IgE mAb and a new drug delivery system for antihistamines, sublingual immunotherapy for children, dual sublingual immunotherapy for house dust mites and Japanese cedar pollen extract, new classification for surgery for allergic rhinitis, and treatment and prescriptions for older adults. An evidence-based step-by-step strategy for treatment is also described.

Monoclonal antibodies (mAbs) have been shown to be effective and generally safe across a continually expanding list of therapeutic areas. We describe the advantages and limitations of mAbs as a therapeutic option compared with small molecules. Specifically, we discuss a novel mAb in the treatment of hereditary angioedema (HAE), a rare and potentially life-threatening condition characterized by recurrent unpredictable swelling attacks. HAE is mediated by dysregulation of plasma kallikrein activity leading to overproduction of bradykinin. Current prophylactic treatment for HAE includes androgens or replacement of the endogenous plasma kallikrein inhibitor, C1 inhibitor. However, there remains an unmet need for an effective, less burdensome treatment option. Lanadelumab is a fully human mAb targeting plasma kallikrein. Results from clinical trials, including a pivotal Phase 3 study and its ensuing open-label extension study, demonstrated that lanadelumab is associated with few treatment-related adverse events and reduced the rate of HAE attacks. This novel treatment option has the potential to significantly improve the lives of patients with HAE.

Background: Asthma is a heterogeneous disease, and phenotyping can facilitate understanding of disease pathogenesis and direct appropriate asthma treatment. This nationwide cohort study aimed to phenotype asthma patients in Japan and identify potential biomarkers to classify the phenotypes.

Methods: Adult asthma patients (n = 1925) from 27 national hospitals in Japan were enrolled and divided into Global Initiative for Asthma (GINA) steps 4 or 5 (GINA 4, 5) and GINA Steps 1, 2, or 3 (GINA 1-3) for therapy. Clinical data and questionnaires were collected. Biomarker levels among GINA 4, 5 patients were measured. Ward's minimum variance hierarchical clustering method and tree analysis were performed for phenotyping. Analysis of variance, the Kruskal-Wallis, and chi-square tests were used to compare cluster differences.

Results: The following five clusters were identified: 1) late-onset, old, less-atopic; 2) late-onset, old, eosinophilic, low FEV₁; 3) early-onset, long-duration, atopic, poorly controlled; 4) early-onset, young, female-dominant, atopic; and 5) female-dominant, T1/T2-mixed, most severe. Age of onset, disease duration, blood eosinophils and neutrophils, asthma control questionnaire Sum 6, number of controllers, FEV₁, body mass index (BMI), and hypertension were the phenotype-classifying variables determined by tree analysis that assigned 79.5% to the appropriate cluster. Among the cytokines measured, IL-1RA, YKL40/CHI3L1, IP-10/CXCL10, RANTES/CCL5, and TIMP-1 were useful biomarkers for classifying GINA 4, 5 phenotypes.

Conclusions: Five distinct phenotypes were identified for moderate to severe asthma and may be classified using clinical and molecular variables (Registered in UMIN-CTR; UMIN000027776.)

Background: Asthma cases have been increasingly investigated using claims data. However, the validity of defining asthma cases using health insurance claims in Japan is unclear. This study aims to assess the positive and negative predictive values of our proposed discrimination criteria for asthma.

Methods: We developed discrimination criteria for asthma based on both the International Statistical Classification of Diseases and Related Health Problems (ICD)-10 disease codes for asthma and health insurance claims data for prescriptions and the treatment of asthma. Inclusion criteria were patients aged ≥16 years with at least one health insurance claim from April 2018 to March 2019 in all departments of our hospital. Physician-diagnosed asthma documented in the charts was used as the reference standard. Positive and negative predictive values of the discrimination criteria for physician-diagnosed asthma were estimated and compared with those estimated from discrimination criteria based solely on ICD-10 codes.

Results: The new discrimination criteria had a high positive predictive value (PPV) of 86.0%, which was significantly higher than the PPV for the criteria defined solely by the ICD-10 codes (61.5%) (P < 0.01). The negative predictive values for both criteria were 100%. Allergic rhinitis and chronic cough were frequently misclassified as asthma using the discrimination criteria based solely on ICD-10 codes but were more likely to be appropriately classified using our proposed criteria.

Conclusions: Our proposed criteria adequately identified asthma subjects using health insurance claims data in Japan with a high PPV. Further studies are needed for external validation of these criteria.

Background: Tezepelumab, a human monoclonal antibody, blocks the activity of thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab reduced exacerbations by 56% compared with placebo in adults and adolescents with severe, uncontrolled asthma. This analysis evaluated the efficacy and safety of tezepelumab in NAVIGATOR patients recruited in Japan.

Methods: NAVIGATOR was a phase 3, multicenter, randomized, double-blind, placebo-controlled study. Patients (12-80 years old) were randomized 1:1 to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. Endpoints assessed included: the annualized asthma exacerbation rate (AAER) over 52 weeks (primary endpoint) and the change from baseline to week 52 in pre-bronchodilator forced expiratory volume in 1 s (FEV₁) and Asthma Control Questionnaire (ACQ)-6 score. The safety of tezepelumab was also assessed.

Results: Overall, 97 patients recruited in Japan were randomized (tezepelumab, n = 58; placebo, n = 39). The AAER over 52 weeks was 1.54 (95% confidence interval [CI]: 0.90, 2.64) with tezepelumab compared with 3.12 (95% CI: 1.82, 5.35) with placebo (rate ratio: 0.49 [95% CI: 0.25, 0.99]; 51% reduction). For tezepelumab and placebo, the least-squares mean (standard error) change from baseline to week 52 for pre-bronchodilator FEV₁ was 0.23 (0.06) L and 0.19 (0.07) L and the ACQ-6 score was −1.12 (0.15) and -0.97 (0.19), respectively. The frequency of adverse events was similar between treatment groups (tezepelumab, 86.2%; placebo, 87.2%).

Conclusions: Tezepelumab reduced exacerbations compared with placebo, and was well tolerated, in NAVIGATOR patients with severe, uncontrolled asthma recruited in Japan.

Background: Safety and efficacy data for dupilumab beyond 1 year are lacking for patients from Japan with moderate-to-severe asthma.

Methods: The TRAVERSE open-label extension (OLE) study (NCT02134028) assessed the safety and efficacy of dupilumab 300 mg every 2 weeks up to 96 weeks in 2282 patients who completed a previous dupilumab asthma study. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary endpoints included annualized severe exacerbation rate and change from parent study baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV₁), asthma control, quality of life, and blood eosinophil levels. Anti-drug antibodies (ADA) were evaluated. We report results in 160 (7.8% of exposed population) patients recruited from Japanese centers with non-oral corticosteroid (OCS)-dependent asthma rolled over from two parent studies, and in subgroups with a type 2 inflammatory phenotype.

Results: TEAEs were consistent with the parent studies and the known safety profile of dupilumab. One patient permanently discontinued treatment due to TEAEs. Exacerbation rates remained low and were sustained to Week 96, as were improvements in pre-bronchodilator FEV₁. Rapid, sustained improvements were observed in dupilumab-treated patients who previously received placebo in a parent study, while further improvements in exacerbation rates, asthma control, and asthma-related quality of life were observed in those continuing dupilumab. Blood eosinophil levels decreased progressively while on treatment. Treatment-emergent ADA responses were highest in patients who had previously received placebo. Efficacy results were consistent in patients with a type 2 phenotype.

Conclusions: Long-term dupilumab treatment was well tolerated and efficacious in patients with non-OCS-dependent, moderate-to-severe asthma recruited from Japan.

(Funded by Sanofi and Regeneron Pharmaceuticals, Inc.; ClinicalTrials.gov identifier, NCT02134028)

Background: There is growing data on T helper 2 (Th2) biomarker determinants in adult populations. However, the determinants and typical range of these biomarkers have not been well studied in general populations of children. Therefore, we assessed the determinants and typical range of three Th2 biomarkers, including blood eosinophils, FeNO, and serum total IgE in 9-11-year-old children in a prospective birth cohort.

Methods: We examined the pre- and postnatal factors associated with Th2 biomarkers using multivariable logistic regression analysis (n = 428) and extended the results to the original cohort (n = 17,009) using inverse probability weighting. We also measured typical Th2 biomarker distribution in all examined children and healthy participants without allergic diseases (n = 180).

Results: At age 9-11, wheeze (odds ratio (OR) 7.63), rhinitis (OR 3.14), and eczema (OR 2.46) were significantly associated with increased blood eosinophils. All three allergic conditions were associated with FeNO and total serum IgE, but the ORs were smaller than those for blood eosinophils. Secondhand smoking was inversely associated with the blood eosinophils (OR, 0.38). Similar results were found in the original cohort. Male sex and prenatal factors (maternal smoking and parental history of allergies) were not independent predictors of high Th2 levels.

Conclusions: In addition to wheezing and rhinitis, eczema and secondhand smoke exposure are independent factors for Th2 biomarker interpretation in children. Furthermore, the typical values and cutoff values of blood eosinophils in adults may not be applicable to children.

Background: Eczema patients are commonly immunoglobulin (Ig)E polysensitized. Although atopic dermatitis (AD) phenotypes have been recognized, IgE sensitization patterns based on AD phenotypes have not been well illustrated. We aimed to investigate how eczema phenotypes impact IgE component sensitization patterns.

Methods: This birth cohort study investigated a general population in the Tokyo Children's Health, Illness, and Development Study (T-Child Study) until children reached the age of 13 years. Eczema was assessed using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Allergen component specific IgE antibody titers were measured using a multiplex array ImmunoCAP ISAC.

Results: Persistent eczema phenotype until adolescence was strongly associated with allergic march symptoms, such as wheezing and hay fever, and oral allergy symptoms, and IgE component sensitizations of airborne (Japanese cedar, house dust mite, Timothy, cat, and dog) and cross-reactive allergens (Bet v 1 family) compared to early-remission and late-onset eczema. On the other hand, late-onset eczema did not show any strong associations with allergic symptoms and IgE sensitization. Adolescents with persistent eczema have high comorbidity of symptoms of pollen-food allergy syndrome.

Conclusions: Early-onset eczema is deeply connected with the later allergic march, and late-onset eczema differs from the phenotype of allergic march. Early-onset eczema characterizing IgE sensitization was likely to be an extrinsic type, and late-onset eczema, which was not related to IgE sensitization, was likely an intrinsic type. Pollen-Food Allergy Syndrome is one of the allergic features in allergic march.

Background: Few studies have reported an association between atopic dermatitis and cognitive impairment in children. Therefore, we evaluated the association between atopic dermatitis (AD) and neurodevelopmental dysfunction in children.

Methods: We analyzed 2,395,966 children born between 2008 and 2012 in Korea. All data were acquired from the databases of the Korean National Health Insurance System. AD was defined as five or more diagnoses before age 24 months. The outcome was suspected neurodevelopmental dysfunction in the gross motor skill, fine motor skill, cognition, language, sociality, and self-care domains of the Korean Developmental Screening Test for Infants and Children at age 6 years. The positive control outcome was defined as attention deficit hyperactive disorder (ADHD). The associations were assessed using ordinal logistic regression, adjusting for asthma and allergic rhinitis.

Results: Among the eligible children, 89,452 and 30,557 were allocated to the control and AD groups, respectively. In the weighted data, the AD group showed a higher risk of suspected neurodevelopmental dysfunction in the total score (weighted adjusted odds ratio [95% CI] 1.10 [1.05-1.16]), gross motor skills (1.14 [1.04-1.25]), and fine motor skills (1.15 [1.06-1.25]) than the control group. The AD with steroids or hospitalization groups showed an increased risk of suspected neurodevelopmental dysfunction. In addition, the AD group showed a significant association with mental retardation, psychological development disorder, and behavioral and emotional disorders as well as ADHD.

Conclusions: AD before age 2 years may be associated with an increased risk of neurodevelopmental dysfunction including gross and fine motor skills in the young childhood period.

Background: Fermented soybean (natto)-induced hypersensitivity reactions (natto allergy) are rare and can result in late-onset anaphylaxis. The allergen in natto is considered to be poly-γ-glutamic acid (PGA), and marine sports are a risk factor for natto allergy due to epicutaneous sensitization to PGA from cnidarian stings. However, no research on natto allergy in fishery workers has yet been performed.

Methods: We conducted a chart review of inpatients diagnosed with anaphylaxis due to natto at Hokkaido Prefectural Haboro Hospital between April 1, 2009, and August 31, 2020. We also administered self-report questionnaires about food hypersensitivity reactions to Japanese fishery workers, including members of the Kitarumoi Fishery Cooperative Association and part-time workers in this area, from February 1 to May 31, 2021.

Results: We found six inpatients (29 inpatients with food-induced anaphylaxis among approximately 11,000 community-dwelling residents) with late-onset anaphylaxis due to natto; all were involved in scallop aquaculture. The questionnaires revealed that 27 participants had natto allergy. We divided the fishery workers into a scallop aquaculture (Scallop) group (n = 211) and other fishery group (n = 106). The Scallop group was significantly associated with natto allergy after adjustments for confounders (OR: 5.73, 95% CI: 1.46-22.56) by logistic regression analysis. In the Scallop group, older age, experience in repairing nets, and a longer length of work experience were significantly related to participants with natto allergy (n = 23), but not participants without natto allergy (n = 181).

Conclusions: Our results indicated an association between scallop aquaculture and natto allergy.

Background: Decreased gut microbiota diversity is associated with gut dysbiosis and causes various diseases, including allergic diseases. We investigated the relationship between gut microbial diversity and sensitization to major inhaled allergens. Furthermore, the relationship of allergic symptom onset with bacterial composition in sensitized individuals was investigated.

Methods: This study included 1092 local residents who had participated in the Iwaki Health Promotion Project in 2016. Blood samples were analyzed to ascertain specific IgE levels against major inhaled allergens (JCP, HD1, Grass-mix, Weed-mix). Nasal symptoms were estimated by questionnaires. Fecal samples were analyzed for bacterial 16S rRNA using next generation sequencing. The diversity index (α-diversity, β-diversity) and the composition of gut microbes in phylum/order levels were compared between patients sensitized or unsensitized to allergen, and symptomatic and asymptomatic groups.

Results: Some α-diversity metrics were significantly decreased in patients who were sensitized to any/all four allergens compared with the unsensitized group. β-diversity differed significantly between those unsensitized and sensitized to all allergens (aged 20-49 years), and between those unsensitized and sensitized to any/all four allergens (aged ≥50 years). The relative abundance of Bacteroidales was significantly lower in the unsensitized than in the sensitized group. The composition and diversity of gut microbiota were similar between the symptomatic and asymptomatic groups.

Conclusions: Our results suggest that lack of diversity in gut microbiota has an effect on sensitization to allergens. Bacteroidales in order level may affect sensitization; however, the onset of allergy symptoms was not significantly associated with bacterial composition and diversity.

Background: Chronic rhinosinusitis is classified into eosinophilic chronic rhinosinusitis (ECRS) and non-eosinophilic chronic rhinosinusitis (NECRS). ECRS is a refractory allergic disease involving a variety of immune and epithelial cells. S100A8 is a damage-associated molecular pattern that is closely related to allergic inflammation. However, the pathological implications of S100A8 in ECRS have not been clarified.

Methods: We evaluated the role of S100A8 in the pathogenesis of ECRS. Gene expression profiles of nasal polyps obtained from patients with ECRS or NECRS were evaluated using RNA sequencing.

Results: S100A8 was identified as a significantly upregulated gene in nasal polyps associated with ECRS. Immunohistochemistry consistently revealed intense S100A8 staining in nasal polyps from patients with ECRS. Human nasal epithelial cells expressed the receptor for advanced glycation end products and Toll-like receptor 4. Recombinant S100A8 protein induced interleukin-1β secretion in human nasal epithelial cells.

Conclusions: Our data demonstrate that S100A8 results in production of interleukin-1β in the nasal epithelium, which may be involved in the pathogenesis of ECRS.

Background: Group 2 innate lymphoid cells (ILC2s) contribute to the pathogenesis of eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNPs). However, the role of other subsets of ILCs and the differentiation of ILCs in CRSwNPs is not well understood. This study aimed to characterize the ILC subsets and evaluate the differentiation of ILCs from ILC precursors (ILCPs) in NP tissue.

Methods: ILC subsets and ILCPs were evaluated by flow cytometry in fresh sinonasal mucosa from patients with CRSwNPs and control subjects. Subsets were compared based on clinical variables and immunological features of the patients. Sorted ILCPs (Lin^-CD127⁺CD117⁺CD45RA⁺IL1R1⁺) were cultured with cytokines.

Results: The frequency of ILC1s and IFN-γ-producing ILC1s increased in non-eosinophilic NPs, whereas that of ILC2s and IL-5-producing ILC2s increased in eosinophilic NPs, particularly in patients with comorbid asthma. The frequency of ILC1s and IFN-γ-producing ILC1s, and frequency of ILC2s and IL-5-producing ILC2s positively correlated with that of neutrophils and eosinophils, respectively. The proportion of IFN-γ-producing ILC1s positively correlated with clinical severity and levels of IFN-γ and IL-8. The proportion of IL-5-producing ILC2s positively correlated with levels of IL-5, CCL24, and total IgE. ILCPs were identified in NP tissue and differentiated into IFN-γ-producing or IL-5-producing ILCs in response to increased IL-12 and IL-18 or IL-25 and IL-33 in non-eosinophilic NPs and eosinophilic NPs, respectively.

Conclusions: ILC1s and ILC2s may be associated with neutrophilic and eosinophilic inflammation in CRSwNPs, respectively. In addition, ILCPs located in the sinus mucosa could differentiate into IFN-γ- or IL-5-producing cells in response to local cytokine stimuli.

Background: Patients with eosinophilic chronic rhinosinusitis (ECRS) respond poorly to many treatment modalities. Overproduction of periostin in the nasal mucosa is reported to contribute to polyp formation. This study examined periostin levels in patients with ECRS in comparison with levels in patients with non-ECRS.

Methods: Fifty-nine patients with chronic rhinosinusitis were grouped into those with ECRS and those with non-ECRS. We compared the relationships between peripheral blood eosinophil level, serum periostin level, histopathological findings, clinical and laboratory findings, nose findings, diagnostic score of the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis Study, and postoperative recurrence of nasal polyps in each group.

Results: In the ECRS group, a positive correlation was found between peripheral blood eosinophil level and serum periostin level (r_s = 0.49, P < 0.01: Spearman's rank correlation coefficient). ROC curve analysis was used to evaluate the serum periostin level that could predict postoperative recurrence of nasal polyps in the ECRS group: the area under the curve (AUC) was 0.95, sensitivity was 92%, and specificity was 100%; the serum periostin cutoff value for postoperative recurrence of nasal polyps was 130 ng/ml. In ROC curve analysis to evaluate peripheral blood eosinophil level, the AUC was 0.73, sensitivity was 69.2%, and specificity was 85.0%; the cutoff value was 8.8%.

Conclusions: periostin was implicated in the pathophysiology of ECRS. Periostin shown to be a more useful biomarker than eosinophils in ECRS. Periostin was shown to likely be an important biomarker for pathological severity of ECRS and postoperative recurrence of nasal polyps.