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Background: The mainstay of treatment for eosinophilic granulomatosis with polyangiitis (EGPA) is systemic corticosteroid therapy; some patients also receive intravenous immunoglobulins, other immunosuppressive agents, and biologics. Mepolizumab, an anti-interleukin-5 monoclonal antibody, in EGPA patients induces remission and decreases the daily dose of corticosteroids; however, the prognosis of long-term mepolizumab treatment for EGPA and its clinical efficacy are unknown. Methods: Seventy-one EGPA patients were treated at Hiratsuka City Hospital, Japan, between April 2018 and March 2022. We administered mepolizumab for mean 2.8±1.7 years to 43 patients in whom remission could not be induced by conventional treatment. After excluding 18 patients who received mepolizumab for less than 3 years, we classified 15 patients in the “super-responder group” (the daily dose of corticosteroids or another immunosuppressant could be decreased, or the interval between IVIG treatments could be prolonged) and 10 patients in the “responder group” (neither of these changes could be achieved). Eosinophil numbers, serum IgG levels, daily doses of corticosteroids and other immunosuppressants, the Birmingham Vasculitis Activity Score (BVAS), and relapse frequency before and after mepolizumab initiation were determined. Results: Eosinophil numbers at diagnosis or the lowest serum IgG level before mepolizumab treatment were higher in the super-responder group than in the responder group (p < 0.05). In the super-responder group, the prednisolone dose at last visit after mepolizumab initiation was lower than before treatment (p < 0.01) and in the responder group (p < 0.01). In both groups, the number of peripheral blood eosinophils and BVAS decreased after starting mepolizumab compared to before treatment (P < 0.01). BVAS before mepolizumab (p < 0.05) and at the last visit (p < 0.01) in the super-responder group were lower than in the responder group. Relapse rates every year after the start of mepolizumab were lower in the super-responder group than in the responder group (p p p Conclusions: Treatment with mepolizumab in the super-responder group durably reduced the relapse rate.

Background: In some patients with eosinophilic granulomatosis with polyangiitis (EGPA), remission cannot be induced, despite treatment with corticosteroids and immunosuppressants. We evaluated the clinical features of patients with EGPA in whom mepolizumab was effective. Methods: There were 59 EGPA patients treated at Hiratsuka City Hospital, Japan, between April 2018 and September 2020, and 30 of them received mepolizumab. Twenty (66.7%) experienced a “marked effect” (the daily dose of corticosteroid or immunosuppressant could be decreased, or the interval between intravenous immunoglobulin (IVIG) treatments could be prolonged) and 10 (33.3%) experienced a “weak effect” (these measures were not achieved). Eosinophil numbers, serum IgG levels, daily doses of corticosteroids and immunosuppressants, and the interval between IVIG treatments at diagnosis and before and after mepolizumab initiation were determined. Results: Eosinophil numbers at diagnosis were significantly higher in the marked-effect group than in the weak-effect group (p < 0.05) but not before mepolizumab initiation or at the last visit. Birmingham Vasculitis Activity Scores (BVASs) before mepolizumab initiation (p < 0.05) and at last visit (p < 0.01), and frequency of relapse before treatment initiation (p < 0.05) were significantly higher, and the serum IgG level before mepolizumab treatment was significantly lower in the weak-effect group than in the marked-effect group. The weak-effect group received higher doses of corticosteroids, even if the corticosteroid dose could be reduced for a while after mepolizumab initiation. Conclusion: High peripheral blood eosinophil numbers at EGPA diagnosis were suggestive of a positive clinical response to mepolizumab.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by an abnormally high number of eosinophils in the peripheral blood and tissues. EGPA is an extremely rare disorder, with an incidence of 0.5 to 3.7 new cases per million people per year and an overall prevalence of 2.4 to 14 per million adults. There is little knowledge about the genetic factors that influence this disease. There are only two reports of familial EGPA: one in Japan and one in Turkey. We herein report a third case of familial EGPA in a brother and sister who were negative for myeloperoxidase-antineutrophil cytoplasmic antibodies.

Objective: We investigated the prevalence of asthma, rhinitis, and atopic dermatitis in children, evaluated the mite allergen levels in their bedding after the Great East Japan Earthquake, and assessed changes in allergic symptoms in children and their families after allergen avoidance practices. Methods: We performed a survey for the International Study of Asthma and Allergies in Childhood (ISAAC) comprising 1109 children, aged 7–8 years, living in Ishinomaki, Japan. We collected responses from 464 children, and in 2016, measured the level of Dermatophagoides group 1 (Der 1) in the bedding of 202 of these children. The intervention group of children attended at least one allergen avoidance seminar. The levels of Der 1 in their bedding were measured, along with changes in allergic symptoms, in 17 children in 2017 and 14 children in 2018. The nonintervention group comprised children who did not attend an allergen avoidance seminar at any time. Results: Of the 464 children who participated in the ISAAC, 50 (10.8%) reported having asthma, 179 (38.8%) allergic rhinitis, and 126 (27.3%) atopic dermatitis. The average level of Der 1 measured in the bedding of the 202 children in 2016 was 295.8 ng/m2. The levels of Der 1 in the intervention group—but not in the nonintervention group—significantly decreased in 2017 and 2018. The symptoms of asthma, allergic rhinitis, and atopic dermatitis in the children of intervention group and their families decreased after allergen avoidance practices. Conclusions: Allergen avoidance practices relieved allergic symptoms in school children after the Great East Japan Earthquake.

Background Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by a necrotizing vasculitis with tissue and peripheral blood eosinophilia affecting small and medium-sized arteries, capillaries, and veins. Venous thromboembolic events are uncommon in EGPA. Moreover, there are only a few reported cases of EGPA complicated by pulmonary embolism or infarction. Case presentation We report the case of a 43-year-old woman with eosinophilic granulomatosis with polyangiitis and acute respiratory and heart failure due to bilateral pulmonary artery thrombosis and left femoral vein thrombosis 12 years after disease onset. She also had cardiac involvement (myocarditis, pericardial effusion, and diastolic dysfunction), gastrointestinal symptoms, and peripheral neuropathy. The condition was refractory to treatment with systemic corticosteroids, intravenous cyclophosphamide, and mepolizumab, but the thrombosis and associated acute cardiac failure, as well as the cardiac and gastrointestinal symptoms and multiple polyneuropathy, improved after a switch to rituximab. However, the heart failure did not improve sufficiently and the patient continued to need inhaled oxygen at 1 L/min and asthma exacerbations occurred. We then swapped the patient’s mepolizumab treatment for dupilumab. Not only did she have no further asthma attacks after switching to dupilumab, but also her vasculitis symptoms improved. Oxygen therapy was discontinued as the heart failure improved 5 months after starting the dupilumab. Conclusions This may be the first case report of the successful treatment by rituximab of pulmonary thromboembolism associated with EGPA. In addition, in this patient, treatment with dupilumab was effective not only for the asthma symptoms but also for the symptoms of vasculitis and heart failure.

To understand fungal contamination in the indoor environment of the disaster region, a field survey was performed to measure the number of fungal counts and identify isolates in the indoor air of prefabricated temporary housing, privately independent-housing, and rented apartments flooded by the East Japan Great Earthquake disaster tsunami. As a result, the period with the highest detected fungal count was from the rainy season to summer in independent-housing and rented apartments. Moreover, in the temporary housing, the fungal number increased further in winter as indicated by the maximum fungal-number throughout the measurement period. The detection frequency of Aspergillus species was relatively higher in the indoor air of temporary housing than in typical housing in the non-disaster area. Since Aspergillus is known as an allergenic genus, it requires careful attention to the health risk for residents. The extremely high level of fungal condensation in indoor air possibly occurred due to high relative humidity and loss of heat insulation in the building attics. It is suggested that this problem commonly happened in the cold region including the entire disaster region of the East Japan Great Earthquake.

Streptococcus pneumoniae is the most common pathogen for community-acquired pneumonia and is also common in nursing and healthcare-associated pneumonia. Pneumococcal vaccine shows clinical benefit and 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been introduced in a routine immunization program in Japan. However, uptake of PPSV23 remains low, at 40%. One opportunity for capturing unvaccinated subjects is hospital referrals. Identifying factors associated with pneumococcal vaccination among referred subjects is thus important so that pulmonologists can maximize the capture of unvaccinated subjects. We retrospectively reviewed the records of subjects with a first referral to the Department of Respiratory Medicine at Hiratsuka City Hospital from September 2017 to March 2018. Subjects who were ≥65 years old and lived in Hiratsuka were included in this study. We compared the backgrounds of subjects and investigated factors associated with pneumococcal vaccination. A total of 142 individuals were included in this study and the pneumococcal vaccination rate was 44.4% (95% confidence interval (CI), 36.0–52.9%). Of these, 127 subjects regularly visited clinics and/or hospitals for any diseases and their pneumococcal vaccine rate was 44.1% (95%CI, 35.3–53.2%). In multivariate analysis, chronic respiratory diseases (odds ratio 5.7; 95%CI, 2.2–14.9, P

Introduction: We previously reported an increased prevalence of asthma in adults who lived in temporary housing after the 2011 Great East Japan Earthquake. The goal of the current study was to investigate changes in asthma prevalence and mite-specific immunoglobulin E (IgE) titers in temporary housing residents during 2014–2019. Methods: By using the Global Initiative for Asthma guidelines, we diagnosed asthma in Ishinomaki city temporary housing residents aged 15 years or older. We then analyzed serum antigen-specific IgE levels to Dermatophagoides farinae (Der f), Dermatophagoides pteronyssinus (Der p), and Aspergillus fumigatus. Results: The prevalence of asthma exceeded 20% across all age-groups throughout the study period. The proportion of study participants with a “positive” antigen-specific IgE titer (i.e., ≥0.35 IUA/mL) was higher in asthmatics than in nonasthmatics for Der f and Der p but not for Aspergillus fumigatus. Among residents ≥50 years old who were diagnosed with asthma, the percentage with a Der f-specific IgE titer ≥0.10 IUA/mL was higher than the proportion with ≥0.35 IUA/mL. Among study participants, asthma onset occurred before the earthquake, during residence in shelters or temporary housing, and (starting in 2016) after moving out of temporary housing. The Der p-specific IgE level was positively correlated with the duration of temporary housing (p < 0.05, r = 0.41) and inversely correlated with the time elapsed since moving out of temporary housing (p < 0.05, r = −0.35). Conclusion: Mite allergen sensitization was found in both asthmatic and nonasthmatic temporary housing residents after the 2011 Japan earthquake and tsunami; asthma developed even after subjects moved out of temporary housing.

It is difficult to evaluate neurological signs of multiple mononeuritis (MM) in patients with eosinophilic granulomatosis with polyangiitis (EGPA). We created a new questionnaire about motor and sensory disturbances in EGPA and investigated whether the questionnaire would be a useful tool in the management of MM in EGPA patients.We classified 40 EGPA patients attending Hiratsuka City Hospital into two groups, namely 30 who were treated with intravenous immunoglobulin (IVIG) and 10 who achieved remission by conventional treatment without IVIG. We created a questionnaire for the evaluation of motor and sensory disturbance in EGPA (ANCA related.com). In patients who received IVIG, we evaluated motor and sensory disturbance scores at disease onset, before IVIG, 1 week and 1 month after the end of IVIG. In patients treated without IVIG, we evaluated these scores at disease onset and at the time of the latest examination.The total motor disturbance score at disease onset was significantly lower in EGPA patients who received IVIG than in those who did not receive it. Disease duration was significantly inversely correlated with the change in the sensory disturbance ratio, but not with the motor disturbance ratio. The motor disturbance ratio was significantly correlated with the manual muscle test improvement ratio. In patients who received IVIG, the total motor disturbance score increased significantly, and the total sensory disturbance score decreased significantly, 1 month after IVIG.By using the questionnaire we could evaluate changes in motor and sensory disturbance after IVIG treatment in patients with EGPA. The questionnaire should be useful in the management of MM in EGPA patients.

BackgroundIndoor mold levels typically increase after natural disasters, flooding, and water damage.Eurotium herbariorumis the sexual stage ofAspergillus glaucus.Case PresentationA 66-year-old, Japanese male, ex-smoker had been diagnosed with bronchial asthma when he was five years old; he achieved remission at the age of 13 years. He was displaced from his home during the Great East Japan Earthquake on March 11, 2011 and moved to temporary housing in Miyagi Prefecture in June 2011. He experienced the first episode of chest tightness, coughing, and wheezing in February 2012, when he again was diagnosed as having bronchial asthma. Mycofloral surveillance detected high counts ofEurotiumin the air of his bedroom, kitchen, and living room, with a maximal fungal count of 163,200 colony-forming units per cubic meter (CFU/m3). AlthoughCladosporiumandPenicilliumtypically predominate in the indoor air of residential dwellings, only low levels of these organisms were present in the patient’s home. Morphologic identification confirmed the isolates asE. herbariorum. The patient had positive reactions toE. herbariorumin skin prick testing and the presence of antigen-specific precipitating antibodies toE. herbariorum. Computed tomography of the chest in August 2013 revealed central bronchiectasis and bronchial wall thickening. The patient experienced late reactions after provocation testing withE. herbariorum.ConclusionThis report presents the rare case of a patient who developed allergic bronchopulmonary mycosis (ABPM) due to exposure toE. herbariorumduring temporary housing after the Great East Japan Earthquake.OshikataC,WatanabeM,SaitoA,IshidaM,KobayashiS,KonumaR,KamataY,TerajimaJ,ChoJ,YanaiM,TsurikisawaN.Allergic bronchopulmonary mycosis due to exposure toeurotium herbariorumafter the Great East Japan Earthquake.Prehosp Disaster Med.2017;32(6):688–690.

It is unknown whether disasters such as earthquakes and tsunamis affect asthma development or exacerbation in adults. Here, we investigated whether asthma prevalence increased in those aged ≥15 years living in temporary housing after the Great East Japan Earthquake. We diagnosed asthma according to GINA guidelines in residents aged ≥15 years who were living, or had lived, in temporary housing in the city of Ishinomaki. We analyzed serum antigen-specific anti-immunoglobulin E (IgE) antibody levels to Dermatophagoides farinae (Der f), Aspergillus fumigatus, Aspergillus glaucus, Aspergillus amstelodami, and Aspergillus restrictus. The average age of the 337 inhabitants was 61.3 ± 15.8 years (men, 37.7%). The asthma prevalence was 24.9% according to respiratory specialist diagnosis. The antigen-specific IgE antibody titer against Der f, but none of the other test antigens, was significantly higher in the asthma group than in the no-asthma group (P

BACKGROUND Eosinophilic granulomatosis with polyangiitis (EGPA) is a disease characterized by allergic granulomatosis, necrotizing vasculitis, and peripheral blood eosinophilia. Interleukin (IL)-33, thymic stromal lymphopoietin (TSLP), and type 2 innate lymphoid cells (ILC2) are involved in the innate and type 2 immune responses in EGPA. However, the relationships among these molecules and the mechanisms underlying the development of EGPA remain unknown. OBJECTIVE We investigated the relationships among peripheral blood eosinophil count, serum IL-33 and TSLP concentration, and peripheral blood ILC2 count in patients with EGPA, chronic eosinophilic pneumonia (CEP), or bronchial asthma (BA). METHODS We recruited 86 patients with EGPA in three groups (remission, relapse, and onset), 25 patients with CEP at active or inactive stages of disease, and 11 patients with BA. In patients with EGPA, CEP, or BA, serum IL-33, sST2, and TSLP concentrations were determined using ELISA and peripheral blood ILC2 counts (as Lin-1- CD127+ CRTH2+ cells) were determined using flow cytometry. RESULTS Peripheral blood eosinophil count or ILC2 count, and serum sST2 or TSLP concentration were higher in patients with EGPA at onset than in those with EGPA at relapse or remission, or in those with BA or CEP. Serum IL-33 concentration was higher in patients with EGPA at relapse than in those with EGPA at onset or remission, or in those with BA or CEP. In a logistic regression model, EGPA disease activity was correlated with serum IL-33 concentration and peripheral blood ILC2 count, but not daily systemic and inhaled corticosteroid dose or immunosuppressant use. Eosinophil count was correlated with peripheral blood ILC2 count and serum TSLP concentration, but not serum IL-33 concentration. CONCLUSIONS Increased peripheral blood ILC2 count and serum IL-33 concentration were associated with disease activity in EGPA. Increases in serum IL-33 concentration may indicate the presence of active vasculitis rather than peripheral or tissue eosinophilia.

The prognosis for patients beyond 1 year after reduction of their inhaled corticosteroid (ICS) dose remains unknown. Predictive factors that can be evaluated before the initiation of asthma treatment or at ICS dose reduction are unknown.We prospectively studied 223 patients in 6 hospitals in the National Hospital Organization of Japan during the 36 months after 50% reduction of their daily ICS dose. All patients recorded their morning and evening peak expiratory flows (PEFs) in their diaries. Lung function, bronchial hyperresponsiveness, fractional nitric oxide levels, number of eosinophils in sputum, and serum IgE levels were measured in most patients. Serum levels of IL-10, IL-33, and thymic stromal lymphopoietin before ICS dose reduction were measured in all patients.During the 36-month study period, asthma control was retained in 127 (59.6%) of the 213 enrolled patients who underwent ICS dose reduction. Multivariate logistic regression analysis revealed that, at the initiation of dose reduction, the factors most predictive of maintenance of asthma control after ICS dose reduction were a low serum IL-33 level (P.01), low PEF variability over 1 week (P = .014), childhood onset of asthma (at age10 years) (P = .03), and high serum IL-10 level (P = .035).We demonstrated that low PEF variability over 1 week, high serum IL-10 level, and low serum IL-33 concentration were useful factors for predicting that an adult's asthma will remain in control for months to years after a 50% reduction in the daily ICS dose.

Objective.We investigated the risk factors for relapse or prognosis of eosinophilic granulomatosis with polyangiitis (EGPA) in Japanese patients presenting to our hospital.Methods.From June 1999 through March 2015, we retrospectively recruited 121 patients with EGPA according to the American College of Rheumatology criteria. Frequent relapse was defined as disease occurrence at least once every 2 years after a period of initial remission. The study endpoint was the last examination performed. We used multiple logistic regression to analyze risk factors for relapse or survival in EGPA.Results.Gastrointestinal (GI) involvement with both abnormalities on endoscopy and biopsy (p < 0.01) and symptoms; myocardial involvement with both abnormalities on 1 or more cardiac investigations and symptoms (p < 0.01); and treatment at initial or maintenance with immunosuppressants (p < 0.01) or administration of intravenous immunoglobulin (IVIG; p < 0.01) were associated significantly more often with frequent relapse than with infrequent. Overall 5-, 10-, and 20-year survival rates were 91.1%, 83.7%, and 68.6%, respectively. Survival in EGPA was associated with age of onset < 65 years. Age at onset of EGPA was the only significant predictor of survival (p < 0.01). Myocardial or GI tract involvement did not affect mortality risk.Conclusion.Patients with myocardial or GI tract involvement had frequent relapses, but these conditions were not reflected in increased mortality. Treatment with immunosuppressants or IVIG in addition to corticosteroids might have improved the prognosis in Japanese patients with EGPA.

We investigated the best strategy for adult asthmatics to avoid exposure to Dermatophagoides group (Der-1) allergens.Adult atopic asthmatics (n = 111) followed a 32-item checklist for avoiding Der-1 allergen exposure. Twenty-five patients were excluded through incomplete sampling; 50 remaining patients encased their pillows/futons/mattresses in microfine-fiber covers, 13 used vacuum cleaners with dust-mite-collection nozzles, and 23 acted as non-intervention controls. During August-October 2010 and August-October 2011, dust samples were collected in Petri dishes placed in bedrooms for 2 weeks and from mattresses/futons by using adhesive tape on one morning. A Der-1 level decrease was defined as a mean 2011 Der-1 level of1 as a ratio of the 2010 level on tape or Petri dish samples. We analyzed the associations between Der-1 level change (by ELISA) and % weekly variability in peak expiratory flow (PEF) or fraction of exhaled nitric oxide (FeNO) after intervention.Der-1 levels decreased significantly in the covers group but not the vacuuming group. FeNO levels and PEF variability were unchanged in both groups. In patients whose Petri dish or tape samples showed decreased Der-1 levels, the % PEF variability was lower in 2011 than in 2010, but FeNO levels were unchanged. Three interventions (vacuuming all family members' mattress/futon surfaces at least weekly or after exposure of the futons to sunlight, and floor wiping before vacuuming), plus using covers, were the most effective management strategy in reducing Der-1 levels.This environmental and bedding maintenance program may help manage adult atopic asthma.

Background Cysteinyl-leukotrienes (CysLTs; LTC4, LTD4, and LTE4) play a considerable role in the pathophysiology of aspirin-intolerant asthma (AIA). Saliva has recently been validated as novel, simple, and noninvasive method for investigating inflammation in patients with asthma. The aim of this study is to clarify the molecular species of CysLT in saliva and to evaluate the CysLT and LTB4 concentrations in saliva in AIA patients. We also examined how the CysLT concentration in saliva reflects that of their corresponding urinary metabolite. Methods We preformed an analytical cross-sectional study. CysLT and LTB4 concentrations in saliva were quantified by enzyme immunoassay (EIA) following purification by high-performance liquid chromatography (HPLC). Results: 1. When analyzed by EIA in combination with HPLC, saliva was found to consist of LTC4, LTD4 and LTE4 in similar amounts. 2. In saliva analysis among the three groups (AIA patients, aspirin-tolerant asthma [ATA] patients, and healthy subjects), both the concentrations of CysLTs and LTB4 were significantly higher in AIA patients than in ATA patients and healthy subjects. 3. We found significant correlations between CysLT concentration and LTB4 concentration in saliva in each group. 4. No significant correlation was found between the concentration of LTE4 in urine and that of CysLTs in saliva. Conclusions In this study, we found higher concentrations of CysLTs and LTB4 in saliva from AIA patients than in saliva from ATA patients, suggesting that the quantification of CysLT and LTB4 concentrations in saliva may be another diagnostic strategy for AIA.

Three years after beginning employment at a bakery, a 32-year-old Japanese man began experiencing acute asthma exacerbations after exposure to rye flour. Antigen-specific serum IgE antibodies were detected to the albumin and globulin, gliadin, prolamin, and glutenin protein fractions of rye flour purified from the crude antigen, but only to the albumin and globulin fraction of wheat flour. The histamine concentration producing one-half maximal effect was lower for all four rye flour fractions than for the wheat flour fractions. After inhalation of the albumin and globulin fraction of rye flour, forced expiratory volume in 1 sec decreased to 77.7% of that pre-provocation. To our knowledge, this is the first report of baker’s asthma due to rye flour in Japan.

Chronic eosinophilic inflammation may promote airway remodeling, including thickening of the reticular basement membrane (RBM), hypertrophy and hyperplasia of the airway smooth muscles (ASM), and an increase in the production of tenascin. The authors examined the correlation between airway remodeling and bronchial reactivity to histamine (Hist) and acetylcholine (ACh) in patients with moderate to severe asthma.In 30 adult patients with asthma, the authors assessed bronchial hyperresponsiveness (BHR) to various concentrations of ACh and Hist by measuring decreases in forced expiratory volume in one second (FEV₁) of20% from the preprovocation state, and % recoveries of FEV₁ after inhalation of β-stimulant. After corticosteroid therapy, the authors evaluated the thickening of RBM and ASM and the production of tenascin in bronchial specimens.The % decrease in FEV₁ was correlated with the % recovery in FEV₁ after provocation by ACh or Hist. Hypertrophy of ASM was correlated with the % decrease in FEV₁ after provocation by Hist, but not by ACh. Thickening of ASM, up-regulation of tenascin in RBM, and duration of asthma were inversely correlated with the % recovery of FEV₁ after provocation by Hist, but not by ACh.In adult patients with moderate to severe asthma, a strong bronchial contraction provoked by Hist and a subsequent small recovery indicate airway remodeling.

Background Exhaled nitric oxide (eNO) is a useful marker of eosinophilic airway inflammation in asthmatics. There have been no studies to show the relationship between eNO measured by offline methods and the degree of bronchial hyperresponsiveness in asthmatic patients treated with inhaled corticosteroids. Methods The study population comprised asthmatics at our outpatient clinic. We measured eNO levels by two methods ("eNOs" was measured with a Sievers kit; and "eNOc" was measured with a kit from the Center for Environmental Information Science, Japan). We also used spirometry to test bronchial hyperresponsiveness to acetylcholine (PC 20Ach ). Results We recruited 192 stable asthmatics. There was a significant relationship between eNOs and eNOc ( r = 0.919, p 20Ach levels were negatively correlated with eNOs or eNOc levels (eNOs, r = −0.31, p r = −0.23, p = 0.0013). We classified the subjects into two groups based on eNOs levels ((A) the subjects with high eNOs levels ( n = 92) and (B) the subjects with normal eNOs levels ( n = 100) ); logPC 20Ach was significantly correlated with eNOs ( r = −0.34, p = 0.001) or eNOc ( r = −0.28, p = 0.0075) but not correlated with %FEV 1 in (A), whereas logPC 20Ach was not significantly correlated with eNO but significantly correlated with %FEV 1 ( r = 0.33, p = 0.002) in (B). Conclusions Levels of eNOs and eNOc were correlated with the degree of bronchial hyperresponsiveness to acetylcholine in adult asthmatics treated with inhaled corticosteroids. Our findings suggest that offline monitoring of eNO will facilitate the management of bronchial asthma in patients treated with these drugs.

Asthma is a chronic disease characterized by airway inflammation; it is sometimes difficult to diagnose. For clinical diagnosis, forced oscillation technique (FOT) measures airway reactance and resistance. By FOT, we investigated respiratory resistance and ventilation perfusion ratio inequality in adults with mild asthma.We examined 58 adult patients with mild asthma having no inhaled corticosteroid treatment, and 10 adult patients with post-infectious prolonged cough. Using a MostGraph-01 FOT instrument, we evaluated these patients before and after bronchial hyperresponsiveness to acetylcholine (ACh) or histamine (Hist). We measured the following conditions: change of resistance at 5Hz (R5) and 20Hz (R20), R5-R20, reactance at 5Hz, frequency of resonance (Fres), low-frequency reactance area (ALX), and forced expiratory volume in 1 second (FEV1).There were significant changes of R5, R20, R5-R20, X5, Fres, ALX after provocations for ACh or Hist in all patients with asthma, but not in patients with post-infectious prolonged cough. We calculated the percent decrease in FEV1 after provocation with ACh or Hist. For Ach, this decrease in FEV1 correlated with changes in R20 and Fres for all patients. For Hist, the percent decrease in FEV1 correlated with changes in R5, R20, Fres, and ALX for all patients. Furthermore, we investigated these correlations in patients with normalized bronchial hyperresponsiveness to ACh or Hist. For Ach, the percent decrease in FEV1 correlated with changes in Fres or R5-R20. For Hist, this decrease in FEV1 correlated with changes in R5, R20, and Fres. ROC analysis was used to evaluate the diagnostic value of the ratio of change of Fres in BHR to Hist. The area under the curve was 0.7808 (95% CI=0.657-0.904). A reasonably high specificity (100.0%) and a high sensitivity (53.8%) with a cut-off point of 1.5 in the ratio before and after of Fres were obtained.The changes in FOT parameters (before and after bronchial airway responses) may detect airway resistance and ventilation perfusion ratio inequality even in adult patients with asthma having normalized bronchial hyperresponsiveness to ACh or Hist. That results may be useful for an early diagnosis of asthma.

Aims: To investigate a role of helper T (Th) cells in asthma, T cell-transfer model was analyzed for late phase asthmatic response. Methods: Ovalbumin (OVA) specific Th clones were derived from either the regional lymphnodes of Balb/c mice immunized with OVA/CFA or splenocytes of DO11.10 transgenic mice expressing T cell receptor specific for OVA/H-2 d . Th clones were adoptively transferred into unprimed mice. After antigen challenge, airway resistance was continuously monitored by either unrestrained whole body plethysmography(BUXCO) or resistance/compliance analyzer under anesthetized condition. Bronchoalveolar lavage analysis was performed 48 hr after OVA challenge. Supernatants of stimulated Th clones were analyzed for contractile activity using collagen gels embedded with murine primary bronchial smooth muscle cells. Effects of H 1 R and LTR 1 antagonist were analyzed both in vitro and in vivo . Results: When unprimed mice were transferred with Th clones, T5-1, T6-2, T6-4, and T6-7, Penh values were significantly increased 6 hr after challenge with OVA or T cell epitope peptide, OVA 323-339 . In contrast, mice transferred with other Th clones, BF7, T6-1, or T6-10 did not show any change. Airflow limitation was confirmed by a direct measurement of airway resistance under anesthetized, restrained, and intubated conditions. Contractile activity was detected in the supernatants of T6-2 stimulated with immobilized anti-CD3. T cell-induced contraction was not affected by H 1 R or LTR 1 antagonist. Conclusion: Activation of Th cells resulted in an airflow limitation besides eosinophilic inflammation, AHR, and mucous hyperplasia. T cell-derived bronchoconstrictor might be a target for treatment-resistant asthma.

Background Chronic eosinophilic pneumonia (CEP) or eosinophilic gastroenteritis (EG), or both, with asthma precede the onset of eosinophilic granulomatosis with polyangiitis (EGPA) in half of all EGPA patients. It is not known what determines whether patients with CEP or with EG following asthma will develop EGPA. Methods We studied 17 EGPA patients and 12 patients with CEP but without EGPA. We assayed serum ICAM-1, VCAM-1, and VEGF, and the percentage of peripheral blood CD4+ T cells producing IL-17 (Th17 cells), at both onset and remission. We also examined the numbers of submucosal eosinophils and the basement membrane-to-crypt and crypt-to-crypt distance to evaluate edema in the colon submucosa at onset and remission in EGPA and at onset in CEP. Results Nine of 12 (75.0 %) CEP patients had symptoms or endoscopic findings. Colonic submucosal eosinophil counts and edema in EGPA at onset were greater than at remission or in CEP at onset. Th17 cells (%) and serum ICAM-1 levels at onset were greater in EGPA than in CEP. In EGPA, peripheral blood Th17 cells (%) were significantly correlated with serum ICAM-1 level, colonic submucosal eosinophil count, and degree of edematous change; inversely correlated with serum VEGF level; but not correlated with VCAM-1 level. Conclusions Eosinophilia and colonic submucosal edematous change were greater in EGPA than in CEP. The mechanism of vasculitis in EGPA appears related to increases in serum Th17 cell numbers and ICAM-1 levels and decreases in VEGF levels.

Disturbances in fibrinolytic activity have been linked with an increased risk for stroke. The insertion/deletion (4G/5G) variation in the plasminogen activator inhibitor-1 (PAI-1) gene promotor has been raised as a risk for cerebrovascular diseases because of its association with the transcription and the increased plasma PAI-1 levels. However, the association between the 4G/5G polymorphism and stroke has been controversial. Therefore, we evaluated the prevalence of PAI-1 genotype in 72 cerebral infarction, 60 cerebral hemorrhage and 94 healthy subjects in northern Japan. The specific genotypes for the 4G/5G polymorphism were isolated using restriction fragment length polymorphism. The distribution of 4G/5G genotypes in the healthy control group was 40.4% for 4G/4G, 45.8% for 4G/5G and 13.8% for 5G/5G, respectively. We found no association in the 4G/5G polymorphism of the PAI-1 gene with cerebral infarction or cerebral hemorrhage. Our results suggest that the PAI-1 4G/5G gene polymorphism may not be a genetic risk factor for stroke in northern Japan.

Aspirin-induced asthma (AIA) is a severe and difficult-to-treat allergic disease in which acute asthma attacks are induced by nonsteroidal anti-inflammatory drugs. Patients with AIA rarely experience asthma attacks when taking celecoxib, a specific inhibitor of cyclooxygenase (COX) 2. A 33-year-old woman had a severe asthma attack with hypoxia and lost consciousness after oral provocation testing with 15 mg of aspirin and also with 50 mg of celecoxib. After 2 months of treatment with 10 mg/day of oral prednisolone, 1600 μg/day of inhaled fluticasone propionate, montelukast as a leukotriene receptor antagonist (LTRA), and long-term beta-agonist, we again challenged her with a provocation test with up to 200 mg of celecoxib; this time there were neither allergic symptoms nor decrease in forced expiratory volume in 1 second. Patients with severe or poorly controlled asthma may experience asthma attacks even if using selective COX-2 inhibitors. However, treatment with steroids and an LTRAs may inhibit asthma attacks induced by celecoxib.

Background Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare disease characterized by the presence of allergic granulomatosis and necrotizing vasculitis with eosinophilic infiltration. The etiology of EGPA is unknown. Dendritic cells (DCs) are not only critical for the induction of primary immune responses; they may also be important for the induction of immunological tolerance and the regulation of the type of T-cell-mediated immune response. To investigate whether DC maturation is associated with EGPA disease status, we examined the relationship between the maturation of DCs and the differentiation of regulatory T (Treg) cells in EGPA patients. We exposed the CD14+ blood monocytes of 19 patients with EGPA in remission or relapse to stimulation with GM-CSF and IL-4 for 6 d and lipopolysaccharide for 24 h to obtain mature CD83+ DCs and immature CD206+ DCs. Using immunohistochemistry, we examined four patients for the presence of CD83+ and CD206+ DCs in the lung at the onset of EGPA. Results The percentage of CD83+ cells among DCs differentiated from CD14+ monocytes was lower for EGPA patients in relapse than in remission. The percentage of CD83+ DCs was inversely correlated with the percentage of CD206+ DCs and was significantly correlated with the numbers of naturally occurring CD4+ regulatory Treg (nTreg; FOXP3+CD4+) cells and inducible Treg (iTreg; CD4+CD25+ T cells producing IL-10 or TGF-β) cells but not the number of eosinophils. The percentage of CD206+ DCs was significantly inversely correlated with the percentages of nTreg and iTreg cells but not the number of eosinophils. Immunohistochemistry revealed both CD206+ DCs and CD83+ DCs in alveoli and interstitial spaces at the onset of EGPA. Conclusion The maturation of DCs from monocytes was related to disease activity in patients with EGPA. Increased CD83+ DCs in EGPA patients may induce the differentiation of iTreg and nTreg cells, thereby suppressing inflammation and disease activity.

The fraction of exhaled nitric oxide (FeNO) is a useful marker of eosinophilic airway inflammation in asthmatics. Clinical application of FeNO measurement in Japan is expected increase because the procedure is now covered through health insurance. However, the measurement system used is known to affect FeNO results, and it remains unknown whether results from offline methods correlate with those from traditional online methods, such as NO breath®.The study population comprised 48 patients at our hospital. FeNO levels were measured by using two offline methods (Sievers and CEIS) and a standard online method, NO breath®FeNONO breath levels were significantly correlated with FeNOSievers(r=0.875) and FeNOCEIS(r=0.888) levels. FeNONO breath levels were nearly equal to FeNOSievers results (FeNONO breath=1.05×FeNOSievers), but both of these levels were lower (p=0.02) than FeNOCEIS data (FeNONO breath=0.74×FeNOCEIS). A Bland-Altman plot of values obtained by the NO breath® and Sievers methods revealed that the NO breath® result was lower than the Sievers level when FeNO was low but was higher than the Sievers level when FeNO was high.Differences exist in the levels of FeNO measurement by three methods (two offline methods and NO breath®): conversion equations are needed to compare the FeNO levels obtained by using these three methods. In addition, NO breath® may be more useful to distinguish asthmatic patients from non-asthmatics, compared with Sievers method.

Effective management of respiratory tract involvement is very important in improving the prognosis of relapsing polychondritis (RPC). This case report describes a 19-year-old patient with RPC, who required frequent hospitalization due to recurrent exacerbations of airway obstruction. Use of high-dose fluticasone propionate effectively reduced the amount of oral corticosteroid necessary to control inflammation of the airway mucosa and dramatically decreased the patient's obstructive airway impairment. This report is the first illustrating the effectiveness and safety of inhaled corticosteroids in the control of the respiratory manifestations of RPC.

Churg-Strauss syndrome (CSS) is an uncommon systemic vasculitis with an increase in the number of eosinophils in the peripheral blood and tissues. Its pathogenesis is unknown, and there is no evidence that genetic factors influence susceptibility to this disease. We present a case of familial CSS in two sisters with atopic-type bronchial asthma and negative perinuclear anti-neutrophil cytoplasmic antibody results. We investigated the human leukocyte antigen typing of the sisters and their six living siblings but found no evidence for heritability of CSS. To our knowledge, this is the first report of familial CSS.

Background Studies of avoidance of exposure to group 1 allergens of the Dermatophagoides group (Der p 1) have not yielded consistent improvements in adult asthma through avoidance. We explored whether the use of pillow and bed covers and allergen-avoidance counseling resulted in Der 1-level reduction, as measured by enzyme-linked immunosorbent assay, and thus improved asthma symptoms in adult patients. Methods Twenty-five adult patients with moderate or severe atopic asthma were randomized into intervention and control groups. Intervention patients slept on pillows and mattresses or futons encased in microfine-fiber covers and were counseled in allergen avoidance through bedroom cleaning. Control patients received neither special covers nor counseling. In the period August to October in 2009 (pre-intervention) and 2010 (post-intervention), dust samples were collected in open Petri dishes placed in bedrooms for 2 weeks and by rapid lifting of dust from bedding and skin using adhesive tape on the morning of 1 day of Petri dish placement. We examined the associations between changes in Der 1 level (as measured by enzyme-linked immunosorbent assay) and clinical symptom score, minimum % peak expiratory flow, and fraction of exhaled nitric oxide. Results Der 1 allergen levels on the mattress/futon covers and near the floor of the bedrooms of intervention patients, but not controls, were lower in 2010 than in 2009. From 2009 to 2010, asthma symptom scores decreased significantly, and minimum % peak expiratory flow increased significantly, in intervention patients. The fall in Der p 1 concentration was correlated with a reduction in the fraction of exhaled nitric oxide. Conclusions Minimization of Der 1 allergen exposure by encasing pillows and mattresses or futons and receiving counseling on avoiding exposure to indoor allergens improved asthma control in adult patients.

Background: We investigated the cytokine production profiles of antigen-presenting cells (APCs) and the status of patients with eosinophilic granulomatosis with polyangiitis (EGPA) in order to identify the cytokine profile that contributes to inducing differentiation of CD4+ effector Th cells and regulatory T cells. Methods: We counted the number of CD4+FOXP3+ T cells, CD4+CD25+CTLA-4+ T cells, CD4+ T cells that predominantly produce IL-10 (Tr1 cells) and IL-17 (Th17 cells) and monocytes and monocyte-derived dendritic cells (mDCs) expressing Toll-like receptor (TLR)2 and TLR4 in the peripheral blood of 47 EGPA patients and 40 bronchial asthma patients (who did not have EGPA) and calculated the percentages of monocytes and mDCs that produced IL-23p19 and IL-27 in response to lipopolysaccharide (LPS) stimulation. Results: Lower TLR4 expression was observed on the monocytes of relapsed EGPA patients and lower expression of both TLR2 and TLR4 on their mDCs than on the cells from EGPA patients in remission or non-EGPA patients. The percentages of monocytes expressing TLR4 were positively correlated with the percentages of regulatory T cells in peripheral blood. In addition, the percentages of monocytes and the percentages of mDCs that produced IL-27 and IL-23p19 in response to LPS stimulation were positively correlated with the percentages of Tr1 cells and Th17 cells in peripheral blood. A positive correlation was also found between the percentages of mDCs that produced IL-27 and the percentages of Tr1 cells. Conclusion: Increased dominancy of IL-23p19 and IL-27 production by the APCs of EGPA patients may be linked to differentiation of Th17 cells and Tr1 cells.