Kiyoshi Sekiya

Profile of eicosanoid generation in aspirin-intolerant asthma and anaphylaxis assessed by new biomarkers

BACKGROUND It has recently demonstrated that a free radical-mediated pathway generates prostaglandins (PGs) and the corresponding prostaglandin enantiomers (ent-PGs). Aspirin-intolerant asthma and anaphylaxis accompany PGD(2) overproduction, possibly associated with mast cell activation via the COX pathway. However, free radical-mediated PG generation in the pathophysiology of these diseases, which can be demonstrated by measuring urinary ent-PGF(2)alpha, has not been reported. OBJECTIVES To evaluate the characteristic profile of eicosanoid generation via the COX and/or free radical-mediated pathway underlying aspirin-intolerant asthma and anaphylaxis. METHODS A comparative group analysis consisted of asthma (n = 17) and anaphylaxis (n = 8, none with aspirin-induced anaphylaxis) cases. Urinary eicosanoid concentrations were quantified as follows: 2,3-dinor-9alpha,11beta-PGF(2) by gas chromatography-mass spectrometry; leukotriene E(4), 9alpha,11beta-PGF(2), and PGs by enzyme immunoassay. RESULTS 2,3-Dinor-9alpha,11beta-PGF(2) is a more predominant PGD(2) metabolite in urine than 9alpha,11beta-PGF(2). At baseline, the aspirin-intolerant asthma group (n = 10) had significantly higher leukotriene E(4) and lower PGE(2) concentrations in urine than the aspirin-tolerant asthma group. During the reaction, the urinary concentrations of leukotriene E(4) and PGD(2) metabolites correlatively increased, but with markedly different patterns of the mediator release, in the aspirin-intolerant asthma group and the anaphylaxis group, respectively. The urinary PGD(2) metabolites and primary PGs were significantly decreased in the aspirin-tolerant asthma group. Urinary ent-PGF(2)alpha concentrations were significantly increased in the anaphylaxis group but not the aspirin-intolerant asthma group. CONCLUSIONS When assessed by urinary 2,3-dinor-9alpha,11beta-PGF(2), PGD(2) overproduction during aspirin-intolerant bronchoconstriction was clearly identified, regardless of COX inhibition. It is evident that free radical-mediated PG generation is involved in the pathophysiology of anaphylaxis.

Bronchial hyperresponsiveness to histamine correlates with airway remodelling in adults with asthma

BACKGROUND Chronic eosinophilic inflammation may promote bronchial hyperresponsiveness (BHR), which involves reversible reduction of airflow and airway remodelling such as a thickening of the reticular basement membrane (RBM) and hypertrophy and hyperplasia of airway smooth muscle (ASM). BHR to histamine (Hist) and acetylcholine (ACh) cannot differentiate airway inflammation and remodelling. OBJECTIVE To examine the correlations between eosinophilic inflammation or airway remodelling and BHR to Hist or ACh in adults with severe asthma. METHODS We examined eosinophils in the sputum of 50 adult patients with severe asthma before inhaled corticosteroid (ICS) treatment. Airway responses to ACh and Hist were measured on separate days after the first hospital visit and before bronchofiberscopy. Bronchial specimens were obtained by bronchofibrescopy for evaluation of RBM and ASM thickening after systemic corticosteroid treatment. RESULTS Eosinophil scores in the sputum before ICS treatment were correlated with BHR to ACh but not to Hist. Asthma duration was inversely correlated with % forced expiratory volume in 1 s, %V(50), %V(25), BHR to Hist, and ASM thickness, but not BHR to ACh or RBM. A multivariate logistic regression model showed that Long duration of asthma affected ASM thickness more than it affected %V(50). ASM thickness was inversely correlated with BHR to Hist but not to ACh. CONCLUSION In adult patients with severe asthma, BHR to ACh is related to the degree of eosinophilic airway inflammation, whereas BHR to Hist indicates airway remodeling, particularly ASM hypertrophy.

Obesity and aspirin intolerance are risk factors for difficult‐to‐treat asthma in Japanese non‐atopic women

Asthma is a clinical syndrome characterized by variabilities in disease expression and severity. The pathophysiological mechanism underlying anti‐asthma treatment resistance is also assumed to be different between disease phenotypes.

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.

Bronchial Reactivity to Histamine Is Correlated With Airway Remodeling in Adults With Moderate to Severe Asthma

Background. 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. Methods. 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) of >20% 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. Results. 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. Conclusions. In adult patients with moderate to severe asthma, a strong bronchial contraction provoked by Hist and a subsequent small recovery indicate airway remodeling.

Molecular-based allergy diagnosis of allergic bronchopulmonary aspergillosis in Aspergillus fumigatus-sensitized Japanese patients.

Distinguishing between patients with allergic bronchopulmonary aspergillosis (ABPA) and Aspergillus fumigatus (Af)‐sensitized asthmatic patients without ABPA is sometimes difficult owing to the IgE‐cross‐reactivity between Af and other fungal allergens.

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.

Selective cyclooxygenase-2 inhibitor cross-reactivity in aspirin-exacerbated respiratory disease.

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.

Increase in Salivary Cysteinyl-Leukotriene Concentration in Patients with Aspirin-Intolerant 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.