Chihiro Mitsui

Omalizumab reduces cysteinyl leukotriene and 9α,11β-prostaglandin F2 overproduction in aspirin-exacerbated respiratory disease

To the Editor: Aspirin-exacerbated respiratory disease (AERD) is a distinct phenotype of asthma characterized by sensitivity to aspirin and nonsteroidal anti-inflammatory drugs, nasal polyposis, mast cell activation, and overproduction of cysteinyl leukotrienes. AERD is an important clinical issue because it is strongly related to severe asthma. Some studies suggest that omalizumab is efficacious in patients with severe allergic asthma and other allergic diseases.Markers of TH2-driven inflammation, including fractional exhaled nitric oxide, peripheral blood eosinophil counts, and serum periostin, have been identified as candidate predictors of omalizumab treatment; however, data demonstrating that omalizumab improves other inflammatory biomarkers are scarce. Because AERD causes mast cell activation and serious eosinophilic airway inflammation, the effects of omalizumab may be different from those usually observed in severe asthma. Here, the clinical efficacy of omalizumab against AERD is described, and urinary markers of mast cell activation, leukotriene E4 (LTE4) and prostaglandin D2 metabolite 9a,11bprostaglandin F2 (PGD2M), were evaluated. A total of 21 adults with AERD initiated omalizumab treatment at Sagamihara National Hospital in Japan between July 2009 and September 2013. The Ethics Committee of Sagamihara National Hospital approved this study. All patients provided written informed consent. AERD was diagnosed by a systemic aspirin provocation test. All patients had 1 or more positive results in skin or serum-specific IgE tests for common environmental allergens. Patients had been on their usual asthma treatment for at least 12 months before enrollment, but had not previously received omalizumab. Urinary concentrations of LTE4 and PGD2M, peripheral blood eosinophil counts, respiratory function, and scores for nasal (congestion, anterior rhinorrhea, and anosmia) and asthma-related (dyspnea, wheezing, and cough) symptoms were assessed at enrollment and after 12 months of omalizumab. The number of exacerbations and hospitalizations, and daily corticosteroid dose during the 12 months before enrollment, was compared with those after 12 months of omalizumab treatment. LTE4 and PGD2M were quantified from spot urine samples using enzyme immunoassay after purification with high-performance liquid chromatography, as described previously. The visual analog scale was used to evaluate nasal and asthma-related symptoms. Asthma exacerbation was defined as emergency medical visits, unscheduled doctor’s visits, or the need for additional oral or intravenous steroid therapy. After 12 months of omalizumab treatment, physicians used the Global Evaluation of Treatment Effectiveness to classify responders and nonresponders. Omalizumab dosages were individualized according to body weight and serum IgE level, with administration at 2or 4-week intervals for a minimum dose of 0.016 mg/kg/IgE (IU/mL). Significance testing was performed using the Wilcoxon signed rank test or Mann-WhitneyU test for continuous variables and the Fisher exact test for categorical variables. The study population comprised 21 patients, 3 men and 18 women, with a median age of 60.0 years (interquartile range [IQR], 49.0-64.0 years), a median asthma onset age of 38.0 years (IQR, 23.5-46.5 years), and a median serum IgE level of 77.3 IU/mL (IQR, 53.9-195.0 IU/mL) (see Table E1 in this article’s Online Repository at www.jacionline.org). Among the 21 patients, 16 (76.2%) had received systemic corticosteroid therapy at the time of enrollment. During the 12 months before omalizumab treatment, 14 of 21 patients (66.7%) experienced 3 or more asthma exacerbations (median, 5.0 [IQR, 2.0-7.5]) and 6 of 21 patients (28.6%) had at least 1 hospital admission because of an exacerbation (median, 0 [IQR, 0-1.0]). None of the patients underwent nasal polyp surgery during the study. According to the Global Evaluation of Treatment Effectiveness, 18 of 21 patients were responders (response rate, 85.7%), whereas 3 of 21 were nonresponders (see Fig E1 in this article’s Online Repository at www.jacionline.org). Omalizumab was discontinued by 3 of the 21 patients, and all 3 were nonresponders. The primary reason for discontinuation was high out-of-pocket treatment costs relative to efficacy. Baseline characteristics of responders and nonresponders are presented in Table E2 in this article’s Online Repository at www. jacionline.org. Before omalizumab treatment, systemic corticosteroid doses and visual analog scale scores for anterior rhinorrhea and anosmia were significantly lower in nonresponders, implying that this subset of patients had less severe disease. Table I presents urine biomarker concentrations, peripheral blood eosinophil counts, respiratory function, nasal and asthma-related symptom scores, the number of exacerbations and hospitalizations, and daily corticosteroid doses assessed before and after omalizumab treatment. Omalizumab was associated with a marked reduction in urinary concentrations of LTE4 (76.2%; P < .001) and PGD2M (89.0%; P 5 .002) (Fig 1). The number of exacerbations and hospitalizations, daily doses of systemic corticosteroid, and all nasal and asthmarelated symptom scores were also significantly reduced. Unexpectedly, rapid symptomatic improvement occurred in 11 of 21 patients (52.4%) within the first week of omalizumab treatment. Furthermore, all 18 responders experienced symptomatic improvement within the 3-month treatment period. To the authors’ knowledge, this is the first report to demonstrate that omalizumab displayed rapid clinical effectiveness and inhibited mast cell activation and leukotriene overproduction in AERD. Gevaert et al documented the clinical efficacy of omalizumab for nasal polyps with comorbid asthma, which may be attributed to suppression of local tissue IgE. Our previous study demonstrated a significant decrease in urinary LTE4 concentrations after surgery for nasal polyposis in patients with AERD. Because omalizumab reduces the expression of high-affinity IgE Fc receptors on mast cells, it may suppress mast cell activation. In this report, omalizumab treatment ameliorated both upper and lower respiratory tract symptoms, with a significant reduction in urinary LTE4 and PGD2M concentrations, suggesting that omalizumab may stabilize AERD by suppressing mast cell activation and eosinophilrelated inflammation. Furthermore, no moderate-to-severe adverse events such as anaphylaxis occurred.

Oral Mite Anaphylaxis Caused by Mite-Contaminated Okonomiyaki/Pancake-Mix in Japan: 8 Case Reports and a Review of 28 Reported Cases.

BACKGROUND Anaphylaxis after the ingestion of foods contaminated with mites has recently been recognized. Case series and case reports thus far have shown that mite-contaminated wheat flour is the major cause of oral mite anaphylaxis. However, we have found 8 cases of oral mite anaphylaxis which were caused by mitecontaminated okonomiyaki-mix, a savory Japanese style pancake mix, in our hospital. METHODS In addition to our 8 cases, the databases of MEDLINE and ICHUSHI were systematically searched for patients with oral mite anaphylaxis in Japan. RESULTS Thirty-six patients including our 8 cases with oral mite anaphylaxis were identified. Thirty-four out of 36 cases (94%) ingested okonomiyaki or takoyaki, prepared at home using okonomiyaki-mix or takoyaki-mix which was previously opened and stored for months at ambient temperature. Microscopic examination of culprit mixes of 16 cases including our 1 case revealed contamination of mites such as Dermatophagoides farina (Der f) (5 cases), Tyrophagus putrescentiae (Tyr p) (4 cases), and Dermatophagoides pteronyssinus (Der p) (3 cases). The specific IgE to each mite is generally upregulated in these patients. Especially, the titers of specific IgE to Der p and Der f were more than class 2 in all cases. CONCLUSIONS Mite-contaminated flavored flour is the major cause of oral mite anaphylaxis in Japan.BACKGROUND Anaphylaxis after the ingestion of foods contaminated with mites has recently been recognized. Case series and case reports thus far have shown that mite-contaminated wheat flour is the major cause of oral mite anaphylaxis. However, we have found 8 cases of oral mite anaphylaxis which were caused by mite-contaminated okonomiyaki-mix, a savory Japanese style pancake mix, in our hospital. METHODS In addition to our 8 cases, the databases of MEDLINE and ICHUSHI were systematically searched for patients with oral mite anaphylaxis in Japan. RESULTS Thirty-six patients including our 8 cases with oral mite anaphylaxis were identified. Thirty-four out of 36 cases (94%) ingested okonomiyaki or takoyaki, prepared at home using okonomiyaki-mix or takoyaki-mix which was previously opened and stored for months at ambient temperature. Microscopic examination of culprit mixes of 16 cases including our 1 case revealed contamination of mites such as Dermatophagoides farina (Der f) (5 cases), Tyrophagus putrescentiae (Tyr p) (4 cases), and Dermatophagoides pteronyssinus (Der p) (3 cases). The specific IgE to each mite is generally upregulated in these patients. Especially, the titers of specific IgE to Der p and Der f were more than class 2 in all cases. CONCLUSIONS Mite-contaminated flavored flour is the major cause of oral mite anaphylaxis in Japan.

Markers for Step-Down of Inhaled Corticosteroid Therapy in Adult Asthmatics

BACKGROUND Treatment guidelines recommend the use of inhaled corticosteroids (ICS) as first-line therapy for all stages of persistent asthma. However, it is unknown whether ICS dose reduction in adult asthmatics is compatible with maintaining asthma control. Moreover, there are no predictors of efficacy in maintaining asthma control upon ICS reduction. METHODS We recruited 90 adult patients with moderate or severe asthma but no clinical symptoms of asthma for at least 6 months. All patients reduced their ICS doses by half but continued taking other asthma-related medications. As a primary outcome, we measured asthma exacerbations during the 12 months following ICS reduction. We also further monitored patients from the above study who had maintained total asthma control for 12 months after ICS reduction and who had continued on their reduced doses of ICS or had further reduced, or stopped, their ICS. RESULTS Forty of ninety patients (44.4%) experienced exacerbations after ICS reduction (time to first exacerbation: 6.4 ± 3.6 months). Multivariate logistic regression modeling revealed a rank order of predictors of success in ICS reduction while retaining asthma control: acetylcholine (ACh) PC(20) (p < 0.01); length of time with no clinical symptoms before ICS reduction (p < 0.01); FeNO (p = 0.028); and forced expiratory volume in 1 s (FEV(1); % predicted) (p = 0.03). Finally thirty-nine of 50 patients maintained total asthma control for at least 2 years after the initial ICS reduction. CONCLUSIONS In asthma patients with normalized AChPC(20) of 20mg/mL or 10mg/mL and no clinical symptoms for at least 12 or 24 months it may be possible to successfully reduce ICS without increasing exacerbations for long time.

Non Occupational Chronic Hypersensitivity Pneumonitis due to Aspergillus fumigatus on Leaky Walls

Aspergillus is a common fungus that causes variety of human diseases, depending on the host response. Hypersensitivity pneumonitis (HP) caused by Aspergillus is usually seen in an occupational setting, and case of farmer’s lung caused by Aspergillus fumigatus have also been reported.1-3 It is known that environmental A. fumigatus exposure rarely causes homerelated chronic HP. There are few case reports of nonoccupational chronic HP caused by A. fumigatus, the diagnosis of which was confirmed by a provocation test. A 74-year-old Japanese smoker presented with dry cough dating back 15 years. He lived in a 25-year-old reinforced concrete house. For 20 years, the house leaked when it rained, and the wallpapers of the hallway and bedroom became moldy. He first visited our hospital in November 2009, and high-resolution computed tomography (HRCT) demonstrated bilateral fibrotic shadows in the upper lobes but with poorly defined ground-glass opacity (GGO). Laboratory examinations at that time showed a surfactant protein D (SP-D) level of 167 ng ml and a KL6 level of 783 U ml. He has been seen in patients with idiopathic pulmonary fibrosis (IPF). He removed the moldy wallpaper in the rainy season, and during the next two months his shortness of breath and dry cough worsened. Laboratory examinations in October 2010 showed an SP-D level of 347 ng ml and a KL-6 level of 2390 U ml. Chest x-ray shows diffuse consolidation with small nodules in the bilateral lungs. HRCT showed GGO and fibrosis in the mid-to-lower lobes (Fig. 1). Spirometry revealed a forced vital capacity (FVC) 79.1% of predicted, a forced expiratory volume in 1 second (FEV1) 92.9% of predicted, a FEV1 FVC of 79.3%, and a diffusion capacity (DLCO) 70.9% of predicted. The bronchoalveolar lavage fluid (BALF) revealed lymphocytosis (62%) with a CD4+ CD8+ ratio of 6.01. A transbronchial lung biopsy showed lymphocytic alveolitis. Serum-precipitating antibodies to Aspergillus fumigatus and Aspergillus flavus were positive among 12 fungal species. The precipitate line of A. flavus overlapped with that of A. fumigatus, which indicated the cross reactivity of A. flavus with A. fumigatus. Latephase skin test reaction for A. fumigatus was positive. An allergen-specific lymphocyte stimulation test for the A. fumigatus antigen was performed using peripheral blood mononuclear cells. The stimulation index was 11.5. The IFN-γ, IL-5, and IL-13 concentrations in the culture supernatants were 725.7, 643.5, and 12108.6 pg ml, respectively, and in the absence of the antigen, their concentrations were 15.0, 1.3, and 5.8 pg ml, respectively. Samples from the wallpaper and bedroom-floor dust revealed contamination by A. fumigatus. Cultures of the indoor air obtained by volumetric air sampler in the house grew mainly A versicolor and Penicillium. Cladosporium was most frequently isolated from air samples collected from his house. Environmental sampling was performed using a volumetric air sampler and airborne particles were collected onto dichloran glycerol (DG-18) media.4 The diagnosis was definitively confirmed by performing a specific bronchial provocation test for A. fumigatus. He inhaled 1 ml of an A. fumigatus antigen solutions (10 mg ml) through a nebulizer for 2 minutes. Six hours after the challenge, the patient developed fever, hypoxemia (oxygen arterial pressure deAllergology International. 2012;61:501-502

Development and treatment of steroid resistant asthma model by adoptive transfer of murine helper t cell clones

Methods For in vitro evaluation of steroid sensitivity, ovalbumin (OVA) reactive Th clones were cultured with antigen presenting cells and OVA in the presence of various concentrations of dexamethasone (DEX). Proliferative responses of Th clones were measured by H-thymidine incorporation. For in vivo evaluation, unprimed BALB/c mice were transferred with Th clones, challenged with OVA, and administered with DEX subcutaneously. Bronchoalveolar lavage fluid (BALF) was obtained 48 hr after challenge, and the number of infiltrating cells was differentially counted. CTLA4-Ig was administered either intravenously or intranasally.

Persistent Airflow Obstruction in Young Adult Asthma Patients

BACKGROUND Lung function determined by spirometry and the severity of dyspnea correlate weakly in asthma patients. We attempted to determine the risk factors in asthma patients having persistent airway obstruction despite of having only mild subjective symptoms, and to examine the possibility of improving FEV1 by treating asthma on the basis of the bronchodilator change in FEV1. METHODS We examined asthma patients in their 20s and who visited Sagamihara National Hospital for the first time over a period of four years, by reviewing their clinical records. They underwent tests on the bronchodilator change in FEV1 and a test of airway hyperresponsiveness to histamine dihydrochloride. RESULTS One hundred thirty-eight subjects (mean age, 25.6 years; 51 males, 87 females; current smoking, 30.4%; history of childhood asthma, 48.6%) were enrolled. Among them, 18.8% (26/138) showed persistent airway obstruction (postbronchodilator FEV1/FVC (%) <80%). Using the multiple logistic regression model, we found that history of childhood asthma and smoking history were the significant isolated risk factors for persistent airway obstruction. Moreover, we determined that the factors associated with the reversibility of airway obstruction in asthma patients without subjective symptoms were history of childhood asthma. CONCLUSIONS In this study, patients not undergoing treatment for asthma were examined. History of childhood asthma and smoking history may be the risk factors for persistent airway obstruction in the asthma patients with mild subjective symptoms. Tests on the bronchodilator change in FEV1 should be performed in patients with history of childhood asthma and smoking history, even if they have only mild subjective symptoms.

Anaphylaxis caused by tipepidine hibenzate, a central antitussive drug.

Tipepidine hibenzate, a central antitussive drug, is widely used in the management of cough and is generally safe and well tolerated. We present here a case of anaphylaxis caused by this drug. When the patient had caught a cold over the previous 10 years, she had received medications, including tipepidine hibenzate, from her family doctor. However, this time, she developed dyspnea, skin eruption, and anaphylactic shock after taking a Chinese herbal medicine and this drug. After her conditions improved due to adequate treatment, she was referred to our hospital to confirm the causative drug. Double‐blind placebo‐controlled oral challenge tests were performed after obtaining informed consent. Oral challenge with one‐third tablet dose of tipepidine hibenzate caused a positive reaction. Urinary leukotriene E4 rose during the challenge with tipepidine hibenzate, but not with control. Clinicians should keep in mind that common antitussive drug use can cause anaphylactic reactions in very rare cases and can be harmful.

Effects of LTRA on T cell-induced bronchoconstriction in the mice

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.

Steroid responsiveness of peripheral blood T cells derived from steroid sensitive, steroid dependent, and steroid resistant asthmatics, and induction of steroid resistance by costimulatory signal

Steroid responsiveness of peripheral blood T cells derived from steroid sensitive, steroid dependent, and steroid resistant asthmatics, and induction of steroid resistance by costimulatory signal Akio Mori, Akemi Abe, Satoshi Kouyama, Miyako Yamaguchi, Yo Iijima, Chihiro Mitsui, Chiyako Oshikata, Hidenori Tanimoto, Kiyoshi Sekiya, Takahiro Tsuburai, Masami Taniguchi, Mamoru Ohtomo, Yuji Maeda, Maki Hasegawa, Kazuo Akiyama, Takayuki Ohtomo, Osamu Kaminuma