The term “asthma-COPD overlap” (ACO) has been applied to the condition in which a person has persistent airflow limitation with clinical features of both asthma and COPD. The certain definition and diagnostic criteria for ACO have not yet been established, and ACO prevalence has varied widely in studies: from 0.9% to 11.1% in the general population, from 11.1% to 61.0% in asthma patients, and from 4.2% to 66.0% in COPD patients. Furthermore, the frequency of exacerbations and prognosis in ACO patients have not been clearly demonstrated. Although ACO consists with several subgroups of patients with distinct clinical and pathophysiological features, it would be important to propose a standardized definition of and/or diagnostic criteria for ACO based on biomarkers and objective measures, even if it is tentative. It may lead cohort studies with large population or clinical trials around the world.

It is now widely recognized that asthma and COPD can coexist as asthma-COPD overlap (ACO), but the preliminary attempts at providing universal guidelines for the diagnosis of ACO still need to be improved. We believe that a case can be made for devising guidelines for the diagnosis of this increasingly common disease that are specific to Japan. In this paper, we present our consensus-based description of ACO which we believe is realistic for use in our country. In addition, we cite the scientific evidence for our own “objective” features used to develop the criteria for COPD and asthma diagnosis. We acknowledge that they will need to be validated and updated over time, but hope the results will encourage further research on the characteristics and treatment of this commonly encountered clinical problem.

Asthma and COPD appear as a result of different mechanisms triggered by different pathogeneses and although they present different features and symptoms of airway inflammation and airway obstruction, there are also cases that present the features of both asthma and COPD. This type of pathology is known as asthma-COPD overlap syndrome (ACOS). Asthma-COPD overlap is identified in clinical practice by the features that it shares with both asthma and COPD. This is not a definition, but a description for clinical use, as asthma-COPD overlap includes several different clinical phenotypes and there are likely to be several different underlying mechanisms”. In this paper, the disease that shares several features of both asthma and COPD will be referred to as asthma-COPD overlap (ACO). In this article, we describe the pathogenesis of ACO for understanding the mechanism in asthma and COPD overlap.

Asthma and COPD overlap (ACO) is an important clinical phenotype, due to the low-health-related quality of life (QOL), rapid decline in lung function, frequent exacerbation, and high economic burden. However, no large-scaled therapeutic trials of ACO have been conducted. At present, ACO is treated according to asthma/COPD guidelines. The goals of ACO treatment are to relieve symptoms and improve QOL and lung functions. Treatment must also prevent disease progression, airway remodeling, exacerbation, complications, and comorbidities. To achieve these goals, ACO needs first to be assessed based on pathophysiological findings. Comprehensive long-term management includes medication, reduction of risk factors, environmental improvement, patient education, rehabilitation, and vaccination. Drug treatment for ACO employs a combination of inhaled corticosteroids (ICSs) and long-acting bronchodilators; long-acting muscarinic antagonists and/or long-acting β₂-agonists. The dose of ICS is determined according to ACO severity. Leukotriene receptor antagonists and theophylline are used as add-on drugs. Macrolides and expectorants are recommended for reduction of mucus hypersecretion. Anti-IgE and anti-IL-5 antibodies, oral corticosteroids, and oxygen therapy are additional treatments for the most severe ACO. The therapeutic effects are evaluated using lung function tests, eosinophil counts in sputum and blood, FeNO, and symptom questionnaires. ACO exacerbation is treated by inhalation of short-acting β₂-agonist and systemic corticosteroids. The doses of corticosteroids are determined based on the asthma/COPD component of the exacerbation. Administration of antibiotics is recommended if sputum is purulent. Referral to specialists is necessary in cases of inability to control symptoms by medication, uncertain diagnosis with atypical features, or severe complications and comorbidities.

Chronic spontaneous urticaria (CSU) is a common skin disorder characterized by daily or almost daily recurring skin edema and flare with itch. Recently, the activation of the blood coagulation cascade has been suggested to be involved in CSU, but the trigger of the coagulation cascade remains unclear. In this article, we review recent understanding of the relationship between the pathogenesis of CSU and extrinsic coagulation reactions. In CSU, vascular endothelial cells and eosinophils may play a role as TF-expressing cells for activating the extrinsic coagulation pathway. Moreover, the expression of TF on endothelial cells is synergistically enhanced by the activation of Toll-like receptors and histamine H₁ receptors. The activated coagulation factors may induce plasma extravasation followed by degranulation of skin mast cells and edema formation recognized as wheal in CSU. Molecules involved in this cascade could be a target for new and more effective treatments of urticaria.

Background: The appropriate usage of an adrenaline auto-injector (AAI, Epipen^®) is a key aspect of patient and social education in the management of anaphylaxis. However, although AAIs are being prescribed increasingly frequently, there are few reports on their actual use.

Methods: The Anaphylaxis Working Group of the Japanese Society of Pediatric Allergy and Clinical Immunology requested that society members register cases in which AAIs were used. Two hundred and sixty-six cases were collected from March 2014 to March 2016.

Results: The cases included 240 events of immediate-type food allergies caused by cow's milk (n = 100), hen's egg (n = 42), wheat (n = 40), and peanuts (n = 11). Exercise-related events were reported in 19 cases; however, the diagnosis of food-dependent exercise-induced anaphylaxis with a specific causative food was only made in 4 cases (wheat, n = 2; fish, n = 1; squid, n = 1). The frequent reasons for the causative intake included programmed intake (n = 48), failure to check the food labeling (n = 43), and consuming an inappropriate food (n = 26). AAIs were used at schools or nurseries in 67 cases, with school or nursery staff members administering the AAI in 39 cases (58%). On arriving at the hospital, the symptom grade was improved in 71% of the cases, while grade 4 symptoms remained in 20% of the cases. No lethal cases or sequelae were reported.

Conclusions: AAIs were used effectively, even by school teachers. The need to visit a hospital after the use of an AAI should be emphasized because additional treatment might be required.

Background: Sublingual immunotherapy (SLIT) can improve the symptoms of allergic rhinitis and modify its natural history; however, its efficacy varies among patients. This study aimed to determine which factors modify the effect of SLIT through post hoc analysis of a previous phase 3 trial of standardized Japanese cedar (JC) pollen extract (CEDARTOLEN^®).

Methods: The study included 482 patients who had previously completed a phase 3 trial during two seasons. The SLIT and placebo groups each contained 241 subjects. Because pollen dispersal differed in the two seasons, we identified good and poor responders from the SLIT group in the 2nd season. We compared patient baseline characteristics, changes in serum immunoglobulin, and severity of symptoms in the 1st season between good and poor responders, as well as between SLIT and placebo groups.

Results: When we compared the baseline characteristics of good and poor responders, a significant difference was observed in body mass index (BMI) such that the patients with BMI ≥25 presented with lower treatment efficacy. No significant difference was observed in correlation with any other factors or treatment-induced alterations of serum immunoglobulin levels. We found that 75.3% of the patients with moderate symptoms and 50.9% of the patients with severe or very severe symptoms in the 1st season met our criteria for good responders in the 2nd season.

Conclusions: BMI might modify the effect of SLIT; however, other factors were not related clearly. The severity of symptoms in the 1st season of treatment does not predict that in the 2nd season.

Background: Patients with food allergies and their families have a significantly reduced health-related quality of life (QOL).

Methods: We performed a multicenter, randomized, parallel-group, delayed-start design study to clarify the efficacy and safety of rush oral immunotherapy (rOIT) and its impact on the participants' daily life and their guardians (UMIN000003943).

Forty-five participants were randomly divided into an early-start group and a late-start group. The early-start group received rOIT for 3 months, while the late-start group continued the egg elimination diet (control). In the next stage, both groups received OIT until all participants had finished 12 months of maintenance OIT.

Results: The ratio of the participants in whom an increase of the TD was achieved in the first stage was significantly higher in the early-start group (87.0%), than in the late-start group (22.7%). The QOL of the guardians in the early-start group significantly improved after the first stage (65.2%), in comparison to the late-start group (31.8%). During 12 months of rOIT, the serum ovomucoid-specific IgE levels, the percentage of CD203c⁺ basophils upon stimulation with egg white, and the wheal size to egg white were decreased, while the serum ovomucoid-specific IgG4 levels were increased. However, approximately 80% of the participants in the early-start group showed an allergic reaction during the first stage of the study, whereas none of the patients in the late-start group experienced an allergic reaction.

Conclusions: rOIT induced desensitization to egg and thus improved the QOL of guardians; however, the participants experienced frequent allergic reactions due to the treatment.

Background: An increasing number of studies in children is highlighting the importance of transdermal routes of exposure to food allergens through damaged skin in the pathogenesis of food allergies. However, data on this in adults are limited. A few case-series studies has documented development of food allergy among kitchen workers with hand eczema after direct contact exposure to foods.

Methods: To explore the significance of hand eczema as a risk factor for food allergies in adults at the epidemiological level, we performed a cross-sectional web-based questionnaire survey on kitchen workers whose exposures were classed as occupational (cooks and food handlers, n = 1592) or non-occupational (housewives, n = 1915). Logistic regression was used to explore the association between the presence/severity of hand eczema and the risk of food allergy after adjustment for potential confounders.

Results: Current hand eczema and current diagnosed food allergy were more common among occupational kitchen workers (OKW) than among non-occupational kitchen workers (NOKW) (32.3%-vs-29.9% and 9.9%-vs-3.8%, respectively). Current hand eczema was significantly associated with increased risk of current diagnosed food allergy in OKW (adjusted odds ratio 2.4, 95% CI 1.6-3.7). Those with more severe hand eczema were more likely to suffer from allergic symptoms for foods, and diagnosed food allergy.

Conclusions: This study illustrates a significant public health problem in the adult population, documenting a major impact of hand eczema on the ongoing adult food allergy epidemic.

Background: Solar irradiation affects sensitization to aeroallergens and the prevalence of allergic diseases. Little is known, however, about how the time and amount of solar irradiation during pregnancy affects such risks in children. We aimed to find out how solar irradiation during pregnancy affects sensitization to aero-allergens and the prevalence of allergic diseases in children.

Methods: This population-based cross-sectional study involved 7301 aged 6 years and aged 12 years children. Maternal exposure to solar irradiation during pregnancy was evaluated using data from weather stations closest to each child's birthplace. Monthly average solar irradiation during the second and third trimesters was calculated with rank by quartiles. Risks of allergic sensitization and allergic disease were estimated.

Results: Relative to the first (lowest) quartile, the adjusted odds ratio (aOR) for allergic sensitization in the fourth (highest) quartile was lowest within solar irradiation during pregnancy months 5-6 (aOR = 0.823, 95% CI 0.720-0.942, p < 0.05). During months 9-10, the aOR for allergic sensitization for the fourth was higher than the first quartile of solar irradiation (aOR = 1.167, 95% CI 1.022-1.333, p < 0.05). Similar results were observed when solar irradiation was analyzed as a continuous variable during months 5 (aOR = 0.975, 95% CI 0.962-0.989, p < 0.001) and month 9 (aOR = 1.018, 95% CI 1.004-1.031, p = 0.003). Increased solar irradiation during months 7-8 increased the risk of asthma (aOR = 1.309, 95% CI 1.024-1.674, p = 0.032).

Conclusions: Maternal exposure to solar irradiation during the second trimester of pregnancy associated with reduced aeroallergen sensitization, whereas solar irradiation during the third trimester was related to increased sensitization to aeroallergens.

Background: Several methods have been developed to detect allergen-specific IgE in sera. The passive IgE sensitization assay using human IgE receptor-expressing rat cell line RBL-2H3 is a powerful tool to detect biologically active allergen-specific IgE in serum samples. However, one disadvantage is that RBL-2H3 cells are vulnerable to high concentrations of human sera. Only a few human cultured cell lines are easily applicable to the passive IgE sensitization assay. However, the use of human induced pluripotent stem cells (iPSCs) to generate human mast cells (MCs) has not yet been reported.

Methods: The nuclear factor-kappa B (NF-κB)-responsive luciferase reporter gene was stably introduced into a human iPSC line 201B7, and the transfectants were induced to differentiate into MCs (iPSC-MCs). The iPSC-MCs were sensitized overnight with sera from subjects who were allergic to cedar pollen, ragweed pollen, mites, or house dust, and then stimulated with an extract of corresponding allergens. Activation of iPSC-MCs was evaluated by β-hexosaminidase release, histamine release, or luciferase intensity.

Results: iPSCs-MCs stably expressed high-affinity IgE receptor and functionally responded to various allergens when sensitized with human sera from relevant allergic subjects. This passive IgE sensitization system, which we termed the induced mast cell activation test (iMAT), worked well even with undiluted human sera.

Conclusions: iMAT may serve as a novel determining system for IgE/allergens in the clinical and research settings.

Background: Omalizumab, a humanized anti-IgE monoclonal antibody, proved efficacious and well tolerated in patients with chronic spontaneous urticaria (CSU) refractory to H₁ antihistamines (H₁AH) in the POLARIS study (NCT02329223), a randomized, double-blind, placebo-controlled trial in East Asian patients. However, data in Japanese patients, who have specific baseline characteristics (e.g., low angioedema incidence, different background medications) that may impact clinical outcomes, are lacking. This pre-specified analysis presents additional patient-level data over time, pharmacokinetic and pharmacodynamics data for omalizumab and IgE, and efficacy and safety data for omalizumab in Japanese patients.

Methods: Japanese patients (N = 105) were randomized 1:1:1 to omalizumab 300 mg, 150 mg, or placebo by subcutaneous injection every 4 weeks. Efficacy and safety were assessed primarily based on changes from baseline to Week 12 in weekly itch-severity scores (ISS7) and weekly urticaria activity scores (UAS7), and incidence of adverse events (AEs), respectively. Patient-level UAS7 data over time were also reviewed.

Results: At Week 12, least squares mean (LSM) changes from baseline in ISS7 were greater with omalizumab vs. placebo (-9.54 and -7.29 for omalizumab 300 mg and 150 mg, respectively, vs. placebo [-5.17]). Corresponding LSM changes from baseline in UAS7 were -21.61 and -15.59 (vs. placebo [-10.88]). Most responders in the omalizumab 300 mg group displayed improvement of disease activity within 2-4 weeks and had well-controlled symptoms during the treatment period. Overall AE incidence was similar across treatment arms.

Conclusions: This subgroup analysis demonstrated that omalizumab is a well-tolerated, beneficial option for treatment of CSU in H₁AH-refractory Japanese patients.

Background: We report the utility of combining lung sound analysis and fractional exhaled nitric oxide (FeNO) for phenotype classification of airway inflammation in patients with bronchial asthma.

We investigated the usefulness of the combination of the expiration-to-inspiration sound power ratio in the mid-frequency range (E/I MF) of 200-400 Hz and FeNO for comprehensively classifying disease type and evaluating asthma treatment.

Methods: A total of 233 patients with bronchial asthma were included. The cutoff values of FeNO and E/I MF were set to 38 ppb and 0.36, respectively, according to a previous study. The patients were divided into 4 subgroups based on the FeNO and E/I MF cutoff values. Respiratory function, the percentages of sputum eosinophils and neutrophils, and patient background characteristics were compared among groups.

Results: Respiratory function was well controlled in the FeNO low/E/I MF low group (good control). Sputum neutrophil was higher and FEV₁,%pred was lower in the FeNO low/E/I MF high group (poor control). History of childhood asthma and atopic asthma were associated with the FeNO high/E/I MF low group (insufficient control). The FeNO high/E/I MF high group corresponded to a longer disease duration, increased blood or sputum eosinophils, and lower FEV₁/FVC (poor control).

Conclusions: The combination of FeNO and E/I MF assessed by lung sound analysis allows the condition of airway narrowing and the degree of airway inflammation to be assessed in patients with asthma and is useful for evaluating bronchial asthma treatments.

Background: Periostin and squamous cell carcinoma antigen (SCCA) are involved in the pathogenesis of asthma. Acute bronchitis due to respiratory syncytial virus (RSV) infection during infancy exhibits an asthma-like pathogenesis, suggesting that it may be associated with the subsequent development of asthma. However, the mechanism by which RSV infection leads to development of asthma has not yet been fully elucidated.

Methods: Infants younger than 36 months were enrolled and classified into three groups. Group I included patients hospitalized with RSV-induced bronchitis. These patients were further stratified into two sub-groups according to whether the criteria for the modified Asthma Predictive Index (mAPI) had been met: Group I consisted of mAPI (+) and mAPI (-) patients; Group II included patients with food allergy as a positive control group; and Group III included children with no allergy as a negative control group. Serum periostin and SCCA levels were measured in the groups. This study was registered as a clinical trial (UMIN000012339).

Results: We enrolled 14 subjects in Group I mAPI (+), 22 in Group I mAPI (-), 18 in Group II, and 18 in Group III. In Group I, the serum periostin and SCCA levels were significantly higher during the acute phase compared with the recovery phase. However, no significant differences were found between Group I mAPI (+) and mAPI (-).

Conclusions: The serum periostin and SCCA levels increased during acute RSV bronchitis. Both periostin and SCCA may play a role in the pathogenesis of acute bronchitis due to RSV.

Background: In the Phase III CALIMA trial, benralizumab significantly reduced asthma exacerbations, increased lung function, and alleviated symptoms for patients with severe, uncontrolled eosinophilic asthma. The aim of this subgroup analysis was to evaluate the efficacy and safety of benralizumab for Japanese patients in the CALIMA trial.

Methods: CALIMA was a randomised, controlled trial of 1306 patients (aged 12-75 years; registered at ClinicalTrials.gov: NCT01914757) with severe asthma uncontrolled by medium- to high-dosage inhaled corticosteroids and long-acting β₂-agonists (ICS/LABA). Patients received 56 weeks' benralizumab 30 mg either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses Q4W), or placebo Q4W. The primary analysis population was patients receiving high-dosage ICS/LABA with blood eosinophils ≥300 cells/μL. This subgroup analysis covered Japanese patients from this group.

Results: Of 83 patients randomised in Japan, 46 were receiving high-dosage ICS/LABA and had blood eosinophils ≥300 cells/μL. Compared with placebo, benralizumab reduced the annual rate of asthma exacerbations by 66% (Q4W; rate ratio 0.34, 95% CI, 0.11-0.99) and 83% (Q8W; rate ratio 0.17, 95% CI, 0.05-0.60); increased prebronchodilator FEV₁ by 0.334 L (Q4W; 95% CI, 0.020-0.647) and 0.198 L (Q8W; 95% CI, -0.118 to 0.514); and decreased total asthma symptom score by 0.17 (Q4W; 95% CI, -0.82 to 0.48) and 0.24 (Q8W; 95% CI, -0.87 to 0.40). Percentages of adverse events were consistent with the overall CALIMA group.

Conclusions: Benralizumab reduced annual asthma exacerbations and symptoms, increased lung function, and was well-tolerated by Japanese patients with severe, uncontrolled eosinophilic asthma.