Eosinophilic chronic rhinosinusitis (ECRS) is a subgroup of chronic rhinosinusitis with nasal polyps (CRSwNP), which is associated with severe eosinophilic infiltration and intractable. Its symptoms include dysosmia, nasal obstruction, and visous nasal discharge. The cause of ECRS is not clear, although it is thought that Staphylococcus aureus and its enterotoxins are involved in stimulating the Th2 system to promote IgE production and eosinophil infiltration through various pathways. While, the coagulation system is activated and the fibrinolytic system is suppressed, leading to deposition of fibrinous networks in nasal polyps. Therefore, a fibrin-degrading agent could be a new treatment for ECRS.

Genetic analysis of nasal polyp cells using next-generation sequencing has identified some of the factors involved in ECRS, including periostin, which can be used as a biomarker of this condition. A protease inhibitor could be a therapeutic agent for ECRS. Regarding the role of eosinophils, many researchers have been interested in the mechanism of ETosis. However, the mechanism leading to development of nasal polyps is unknown.

In Japan (as well as in East Asia), the incidence of non-ECRS is decreasing and that of ECRS is increasing, but the reason is also unknown. Thanks to the development of biologics therapy, it is thought that there will be a shift to precision medicine in the future.

Eosinophilic pneumonia (EP) is a rare disorder, comprising several heterogeneous diseases. Two major types of EP are acute eosinophilic pneumonia (AEP) and chronic eosinophilic pneumonia (CEP), both of which are characterized by marked accumulation of eosinophils in lung tissues and/or BAL fluid. AEP and CEP share some similarities in terms of pathophysiology, radiological findings, and treatment response to corticosteroids. However, they distinctly differ in etiology, clinical manifestations, and the nature of disease course. Especially, although AEP and CEP respond well to corticosteroids, relapse frequently occurs in patients with CEP, but rarely in those with AEP. Although CEP occasionally persists and becomes corticosteroid dependent, most patients with AEP completely recover. This article reviews previous studies and discusses the etiology, clinical manifestations, and treatment of AEP and CEP.

Eosinophilic gastrointestinal diseases (EGIDs) are divided into eosinophilic esophagitis (EoE) and eosinophilic gastroenteritis (EGE), depending on the involved gastrointestinal tract, though both are considered to be chronic Th2-type allergic diseases caused by food or environmental allergens. In development of EoE, refluxed gastric acid may also have an important role. For diagnosis of EGIDs, the presence of symptoms possibly originating from the involved gastrointestinal tract and dense eosinophil infiltration are important factors. Imaging studies, including endoscopy and computed tomography, along with histopathological examinations of biopsy specimens are useful for diagnosis, whereas laboratory testing of blood, urine, and stool samples has limited value. Three useful options for treating EoE patients are acid inhibitors, swallowed topical corticosteroids, and an elimination diet, while systemic administration of glucocorticoids is the standard treatment of EGE, though information is limited. Since the prevalence of EGIDs is increasing in Western countries as well as Japan, development of effective treatments based on sufficient evidence is becoming an urgent need.

Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss syndrome) is a rare form of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis characterized by eosinophil-rich granulomatous inflammation and small to medium-size vessel vasculitis associated with bronchial asthma and eosinophilia. Its rarity and unique features such as eosinophilic inflammation have delayed progress of research regarding EGPA for several years, compared to other forms of ANCA-associated vasculitis. However, recently, attention to EGPA as a research subject has been gradually increasing. To resolve problems in existing criteria for EGPA, new classification criteria for EGPA generated by a large international cohort will be launched and is being expected to accelerate future studies. Pathogenesis and roles of ANCA in EGPA are still largely unknown; however, it has been reported that glomerulonephritis is more frequent in ANCA-positive patients than in ANCA-negative patients, while heart failure is more frequent in ANCA-negative patients than in ANCA-positive patients. In addition, a recent genome-wide association study has suggested the presence of two genetically distinct subgroups of EGPA, which correspond to ANCA-positive and -negative subgroups. Although responses to glucocorticoids in EGPA are generally good, patients with EGPA often experience a relapse. Currently, there is no standard therapy for EGPA based on accumulation of clinical trial results. Recently, clinical benefits of mepolizumab for EGPA were proved by a randomized controlled trial and mepolizumab was approved for EGPA. In addition, various new drugs are under evaluation. To find optimal use of these drugs and to resolve unmet needs, such as relapse prevention, will be needed in future.

Eosinophilic fasciitis is a disease originally proposed as “diffuse fasciitis with eosinophilia” by Shulman in 1974. The patients with this disease often have history of strenuous exercise or labor a few days to 1-2 weeks before the onset.

The chief symptoms are symmetrical, full-circumference swelling and plate-like hardness of the distal limbs. This is accompanied by redness and pain in the early stages, with many cases exhibiting systemic symptoms such as fever or generalized fatigue. The lesions have been observed extending to the proximal limbs, though never on the face or fingers.

En bloc biopsies from the skin to the fascia show marked fascial thickening and inflammatory cell infiltration by the lymphocytes and plasma cells. Eosinophilic infiltration is useful for the diagnosis but is only seen in the early stages of the disease.

Recently, “Diagnostic criteria, severity classification, and clinical guidelines for eosinophilic fasciitis” were published.

This review article discusses about eosinophilic faciitis in detail, from its pathophysiology to the treatment.

Background: Identification of sensitized allergens for patients with respiratory allergy is an important step in disease care and environmental allergen control. The Japanese archipelago belongs to various climate categories due to its length from north to south which transverse the subarctic in the north to the subtropical in the south, suggesting substantial regional differences in dominant environmental allergens. However, few studies have assessed the regional differences in the prevalence of sensitization to environmental allergens.

Methods: We requested three major clinical testing laboratories to provide us with summarized results of antigen-specific IgE-antibody (Ab) measurements. These measurements were collected for clinical purposes throughout Japan from 2002 through 2011. The prevalence of positivity for IgE-Ab against 19 environmental allergens was calculated for each prefecture in order to evaluate regional differences.

Results: Test data on specific IgE-Ab of 19,969,753 orders were analyzed. The prevalence of positivity for house dust mites was high and the regional difference was low, whereas apparent regional differences were found for pollen, insects, and fungi. The prevalence of positivity for Japanese cedar was low in Hokkaido and Okinawa, while those to alder was highest in Hokkaido. Higher prevalence for insects was observed in southern areas (Okinawa and prefectures in Kyusyu).

Conclusions: Findings of this study clearly demonstrated regional differences in the prevalence of sensitization to environmental allergens in Japan and the study also provides useful information for the clinician when deciding which allergens should preferentially be measured for IgE-Ab after considering regional difference.

Background: Given increased risk of cardiovascular events in asthma we hypothesized that lipoprotein-associated phospholipase A₂ (Lp-PLA₂), an enzyme involved in atherosclerosis, is associated with proinflammatory and prothrombotic blood alterations in this disease.

Methods: In 164 adult asthmatics (63 with severe asthma) we measured plasma Lp-PLA₂ activity using the PLAC test. We determined its relations to inflammation and prothrombotic blood alterations.

Results: In asthma, Lp-PLA₂ was inversely related to the age (β = -0.1 [-0.18 to -0.02]) and was lower in women (n = 122 [74%], 205 [182-242] vs. 243 [203-262] nmol/min/ml, p = 0.001). Interestingly, Lp-PLA₂ correlated negatively with the asthma severity score (β = -0.15 [-0.23 to -0.07]), being 10.3% higher in those with non-severe (mild or moderate) asthma (n = 101, 62%) as compared to the severe disease subtype (224 [191-261] vs. 203 [181-229], p = 0.006 after adjustment for potential confounders). Lp-PLA₂ activity was positively related to the levels of low-density lipoprotein (β = 0.1 [0.02-0.18]), triglycerides (β = 0.11 [0.03-0.19]) and glucose (β = 0.1 [0.02-0.18]) and inversely to the tumor necrosis factor α (β = -0.27 [-0.35 to -0.2]), high sensitivity C-reactive protein (β = -0.1 [-0.19 to -0.02]) and fibrinogen (β = -0.12 [-0.21 to -0.03]), as well as prothrombin (β = -0.16 [-0.24 to -0.08]), and parameters describing thrombin generation potential, such as endogenous thrombin potential (β = -0.14 [-0.21 to -0.06]) and peak thrombin generated (β = -0.2 [-0.28 to -0.12]).

Conclusions: Elevated Lp-PLA₂ activity in non-severe asthmatics suggests increased atherosclerotic risk in this group. Lower Lp-PLA₂ activity accompanied by its inverse relationship to inflammatory or prothrombotic blood biomarkers observed in turn in severe asthmatics might be related to the pathogenesis of more severe asthma phenotype.

Background: We explored whether the use of deep learning to model combinations of symptom-physical signs and objective tests, such as lung function tests and the bronchial challenge test, would improve model performance in predicting the initial diagnosis of adult asthma when compared to the conventional machine learning diagnostic method.

Methods: The data were obtained from the clinical records on prospective study of 566 adult out-patients who visited Kindai University Hospital for the first time with complaints of non-specific respiratory symptoms. Asthma was comprehensively diagnosed by specialists based on symptom-physical signs and objective tests. Model performance metrics were compared to logistic analysis, support vector machine (SVM) learning, and the deep neural network (DNN) model.

Results: For the diagnosis of adult asthma based on symptom-physical signs alone, the accuracy of the DNN model was 0.68, whereas that for the SVM was 0.60 and for the logistic analysis was 0.65. When adult asthma was diagnosed based on symptom-physical signs, biochemical findings, lung function tests, and the bronchial challenge test, the accuracy of the DNN model increased to 0.98 and was significantly higher than the 0.82 accuracy of the SVM and the 0.94 accuracy of the logistic analysis.

Conclusions: DNN is able to better facilitate diagnosing adult asthma, compared with classical machine learnings, such as logistic analysis and SVM. The deep learning models based on symptom-physical signs and objective tests appear to improve the performance for diagnosing adult asthma.

Background: The long-term prognosis of asthma with airflow obstruction is poorly understood in Japan. The aim of this retrospective 26-year study was to investigate the long-term mortality risk of airflow obstruction in asthmatics.

Methods: Using data from the Omuta City Air Pollution-related Health Damage Cohort Program, mortality risk ratios of airflow obstruction in Japanese Individuals were analyzed by Cox proportional hazards models. Airflow obstruction was considered to be present when the forced expiratory volume in 1 sec (FEV₁)/forced vital capacity ratio was <0.7 and FEV₁ predicted was <80% based on spirometry.

Results: Among the 3146 victims with chronic respiratory diseases, 697 with adult asthma were selected. Median follow-up period was 26.3 (range 0.9-40.9) years. The airflow obstruction group (n = 193) showed significantly higher rates of mortality related to respiratory problems (risk ratio [95% confidence interval] 1.51 [1.86-1.93], P = 0.0017) and asthma attacks (1.86 [1.30-2.66], P = 0.0011) than the without airflow obstruction group (n = 504). Airflow obstruction was an independent risk factor for both respiratory-related (1.84 [1.36-2.49], P = 0.0001) and all-cause (1.44 [1.17-1.76], P = 0.0008) mortality after adjustment for age, sex, body mass index, and smoking status. More severe airflow obstruction was significantly associated with poorer prognosis.

Conclusions: This long-term cohort program revealed the impacts of asthma with airflow obstruction as an independent mortality risk. Findings suggest that intervention and prevention of airflow obstruction can reduce long-term mortality in patients with asthma.

Background: The comorbidity of asthma and allergic rhinitis is remarkably high, but not much is known about the effects of this combined condition on the quality of life. We aimed to evaluate the factors associated with asthma exacerbations and the effect of the exacerbations on the quality of life (QOL) through a one-year, large-scale, observational study in Japanese patients with asthma and rhinitis.

Methods: A case survey by attending physicians and a patient survey was conducted at each assessment timepoint over a period of one year. Patients were divided into two groups according to the presence or absence of asthmatic attacks after enrollment and were matched using propensity scores to evaluate the factors associated with asthma exacerbations and the effect of the exacerbation on QOL.

Results: Potential factors associated with asthma exacerbations included high body mass index value, low forced expiratory flow 75% of forced vital capacity (FEF75%), severe rhinitis as determined based on ARIA (Allergic Rhinitis and its Impact on Asthma). Although patients with asthma exacerbations had significantly impaired quality of life at baseline as evidenced by the economic aspects, in addition to physical, mental, and social activities, no further reduction with the attacks was observed.

Conclusions: This study suggested that higher body mass index (BMI) and severe asthma as well as severe rhinitis were factors associated with asthma exacerbations. Although patients with asthma exacerbations had impaired QOL, attacks caused no further reduction.

Background: While gastroesophageal reflux disease (GERD) is one of the commonest causes of subacute/chronic cough along with cough-variant asthma (CVA) and rhinosinusitis, its clinical impact remains unknown. Therefore, we sought to investigate the impact of GERD in patients with subacute/chronic cough.

Methods: Between April 2012 and March 2018, a total of 312 patients presenting subacute or chronic cough lasting for ≥3 weeks [median cough duration, 4.9 (0.7-434) months] underwent diagnostic tests. GERD symptoms and cough-specific QoL were evaluated through the Frequency Scale for Symptoms of Gastroesophageal reflux (FSSG) and the Japanese version of the Leicester Cough Questionnaire (J-LCQ). According to the FSSG domains, patients with GERD were arbitrarily categorized into 3 groups; acid-reflux predominant, dysmotility predominant, and pauci-symptoms groups, respectively.

Results: The average scores of J-LCQ was 12.5 (SD3.7). One hundred-forty three were diagnosed as having GERD-related cough based on classical reflux symptoms including heartburn and characteristic triggers of cough such as phonation, rinsing, lying, and eating. Most of them (89.8%) had other causative diseases including CVA. Cough lasted longer (p = 0.019) and required a longer time until alleviation (p = 0.003) in patients with GERD than in those without GERD. They also scored lower J-LCQ than counterpart group (p < 0.0001). In terms of symptom stratification, dysmotility predominant group showed significant more response to specific GERD treatments than the remnants (p = 0.002).

Conclusions: These results indicate that GERD is associated with the aggravation of other causes including CVA. Particularly, dysmotility symptoms may be potential therapeutic target for GERD-related cough.

Background: Dengue fever (DF) is the most rapidly spreading mosquito-borne viral disease. Practical vaccines or specific therapeutics are still expected. Environmental factors and genetic factors affect the susceptibility of Dengue virus (DV) infection. Asthma is a common allergic disease, with house dust mites (HDMs) being the most important allergens. Asthmatic patients are susceptible to several microorganism infections.

Methods: A nationwide population-based cohort analysis was designed to assess whether to determine whether asthma can be a risk factor for DF.

Results: Unexpectedly, our data from a nationwide population-based cohort revealed asthmatic patients are at a decreased risk of DF. Compared to patients without asthma, the hazard ratio (HR) for DF in patients with asthma was 0.166 (95% CI: 0.118-0.233) after adjustment for possible confounding factors. In the age stratification, the adjusted HR for DF in young adult patients with asthma was 0.063. Dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) of dendritic cells (DCs) is an important entry for DV. Through another in vitro experiment, we found that HDM can diminish surface expression of DC-SIGN in monocyte-derived DCs and further decrease the cellular entry of DV.

Conclusions: Decreased DC-SIGN expression in DCs of allergic asthmatic patient may be one of many factors for them to be protected against DF. This could implicate the potential for DC-SIGN modulation as a candidate target for designing therapeutic strategies for DF.

Background: We conducted a randomized, placebo-controlled, double-blind clinical trial to investigate the optimal dose and long-term efficacy and safety of Japanese cedar (JC) pollen tablets for SLIT (JapicCTI-142579). Here, we report details of the effects of the JC pollen SLIT tablet on rhinitis and conjunctivitis symptoms over three pollen dispersal seasons.

Methods: A total of 1042 JC pollinosis patients (aged 5-64 years) were randomized to receive tablets containing placebo (P), 2000, 5000, or 10,000 Japanese allergy units (JAU) of JC pollen for 15 months to identify an optimal dose. Patients receiving P (n = 240) and the optimal dose (5000 JAU; A, n = 236) were then randomized to receive P or A for an additional 18 months (AA, AP, PA, and PP groups, allocation ratio 2:1:1:2). Nasal and ocular symptoms, rescue medication use, and quality of life (QOL) were assessed on quantitative scales.

Results: In the second and third seasons, the AA, AP, and PA groups exhibited significantly better improvements in nasal, ocular, and medication scores compared with the PP group in the order AA > AP > PA > PP during the second season and AA > PA > AP > PP during the third season. Rescue medication use and QOL scores were also significantly better in the AA, AP, and PA groups compared with the PP group.

Conclusions: The JC pollen SLIT tablet relieved nasal and ocular symptoms and medication use and improved QOL in a treatment duration-dependent manner. Continuous dosing regimens appear to enhance the efficacy of the drug.

Background: Shrimp tropomyosin (TM) is a major food allergen that may cause serious allergic responses, lactic acid-producing bacteria (LAPB) are believed to alleviate food allergy, but the mechanisms have not been fully clarified. The aim of this work is to investigate the mechanisms of LAPB in ameliorating food allergy-induced intestinal mucosal disorders and to investigate whether or not these disorders occur by the regulation of gut microbiota and metabolism.

Methods: A TM allergy BALB/c mouse model was established, and two LAPB strains, Bifidobacterium longum (Bi) and Bacillus coagulans (Bc), were used for oral treatment in sensitized mice. The allergic mucosal disorders were assessed by histological analysis and ELISAs. Additionally, microbiota and metabolic modifications were determined by 16S rRNA gene amplicon sequencing and GC-TOF-MS, respectively.

Results: YSPB administration suppressed TM-induced intestinal mucosal disorders, restored allergenic Th2 cell over-polarization and dysbiosis, and regulated gut arginine and proline metabolism pathways. Statistical analysis suggested the metabolites aspartate and arginine, as well as several commensal flora groups, to be the critical mediators in the process.

Conclusions: These data demonstrated the correlation between allergic mucosal disorder, T cell subtype differentiation, gut microbiota composition and intestinal metabolism especially the arginine and proline metabolism pathways. We also revealed the significant effects of LAPB in ameliorating food allergy and maintaining the mucosal ecosystem. This study confirmed the efficiency of LAPB in relieving food allergy, provided Bi and Bc as the potential treatment approaches, and suggested amino acid metabolism pathways might be the novel targets for potential clinical applications.

Background: Asthma often coexists with chronic rhinosinusitis (CRS). Recent studies revealed that sinus inflammation in asthmatic patients was related to eosinophilic inflammation. However, the relationship between the severity of CRS and four different sputum inflammatory phenotypes as defined by the proportion of eosinophils and neutrophils is unknown. The aim of this study was to examine the impact of the severity of CRS on lower airway and systemic inflammation in asthmatic patients.

Methods: We enrolled 57 adult asthmatic patients who underwent sinus computed tomography (CT). The severity of CRS was evaluated by the Lund-Mackay score (LMS). The induced sputum inflammatory phenotype was defined by eosinophils (≥/<2%) and neutrophils (≥/<60%). Peripheral blood mononuclear cells (PBMC) were collected to examine cytokine productions.

Results: The median LMS of subjects was 6 (interquartile range, 0-11.5). The sputum inflammatory cell phenotype was categorized as paucicellular (n = 14), neutrophilic (n = 11), eosinophilic (n = 20), or mixed (n = 12). LMS was positively correlated with the percentage of blood eosinophils, sputum eosinophils, and mean fluorescence intensity (MFI) of IL-5 on CD4⁺ T cells. In the severe CRS group (LMS, 12-24), the number of mixed cellular phenotypes was higher than that in the group without CRS (LMS, 0-4) and mild-to-moderate CRS group (LMS, 5-11).

Conclusions: In asthmatic patients with severe CRS, the proportion of the mixed cellular inflammatory phenotype was increased as well as eosinophilic inflammation.