Kentaro Watai

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.

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.

Age-specific characteristics of inpatients with severe asthma exacerbation.

BACKGROUND The characteristics of inpatients with severe asthma exacerbation remain unclear. It is considered that the characteristics of inpatients with severe asthma vary depending on age. However, these are rarely investigated. The objective of this study is to investigate the differences in characteristics among different age groups. We considered that it is necessary to understand the characteristics of each age group so that we can establish strategies in preventing severe asthma exacerbation. METHODS All asthma inpatients who were hospitalized between 2004 and 2011 with SpO2 <90% (in room air), were breathless at rest, and showed increased respiratory rate and pulse rate were examined. We compared the characteristics among the young age group, middle age group, and advanced age group. RESULTS The total number of patients was 204. In the young age group, the percentages of patients with irregular visits and non visits to a medical institution were high. This group showed high percentages of smokers and pet owners. The percentage of continuous ICS users in this group was 25.9%. The middle age group had high rates of aspirin-intolerant asthma. The percentage of continuous ICS users in this group was 60.2%. In the advanced age group, the percentages of patients with hypertension/heart disease, diabetes mellitus, and COPD were high. This group showed good treatment adherence. The percentage of continuous ICS users in this group was 77.4%. CONCLUSIONS The characteristics of inpatients with severe asthma vary depending on age. We need to establish countermeasures for asthma exacerbation according to the characteristics of patients depending on age.

PHYSIOLOGIC AIRWAY RESPONSES TO INHALED HISTAMINE AND ACETYLCHOLINE IN PATIENTS WITH MILD ASTHMA AS ANALYZED BY FORCED OSCILLATION.

BACKGROUND AND AIMS 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. METHODS 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). RESULTS 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. CONCLUSION 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.