Metagenomic gut microbiome analysis of Japanese patients with multiple chemical sensitivity/idiopathic environmental intolerance.

BACKGROUND: Although the pathology of multiple chemical sensitivity (MCS) is unknown, the central nervous system is reportedly involved. The gut microbiota is important in modifying central nervous system diseases. However, the relationship　between the gut microbiota and MCS remains unclear. This study aimed to identify gut microbiota variations associated with MCS using shotgun metagenomic sequencing of fecal samples. METHODS: We prospectively recruited 30 consecutive Japanese female patients with MCS and analyzed their gut microbiomes using shotgun metagenomic sequencing. The data were compared with metagenomic data obtained from 24 age- and sex-matched Japanese healthy controls (HC). RESULTS: We observed no significant difference in alpha and beta diversity of the gut microbiota between the MCS patients and HC. Focusing on the important changes in the literatures, at the genus level, Streptococcus, Veillonella, and Akkermansia were significantly more abundant in MCS patients than in HC (p < 0.01, p < 0.01, p = 0.01, respectively, fold change = 4.03, 1.53, 2.86, respectively). At the species level, Akkermansia muciniphila was significantly more abundant (p = 0.02, fold change = 3.3) and Faecalibacterium prausnitzii significantly less abundant in MCS patients than in HC (p = 0.03, fold change = 0.53). Functional analysis revealed that xylene and dioxin degradation pathways were significantly enriched (p < 0.01, p = 0.01, respectively, fold change = 1.54, 1.46, respectively), whereas pathways involved in amino acid metabolism and synthesis were significantly depleted in MCS (p < 0.01, fold change = 0.96). Pathways related to antimicrobial resistance, including the two-component system and cationic antimicrobial peptide resistance, were also significantly enriched in MCS (p < 0.01, p < 0.01, respectively, fold change = 1.1, 1.2, respectively). CONCLUSIONS: The gut microbiota of patients with MCS shows dysbiosis and alterations in bacterial functions related to exogenous chemicals and amino acid metabolism and synthesis. These findings may contribute to the further development of treatment for MCS. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Clinical Trials Registry as UMIN000031031. The date of first trial registration: 28/01/2018.

Uncovering Severe Patient Group With Pollen-Related Extrarespiratory Allergic Symptoms: A Year-Long Diary Survey in Japan.

BACKGROUND: The most common symptoms of pollen allergy are rhinitis and conjunctivitis. However, in real-world clinical practice, we sometimes encounter patients with pollen allergy suffering from severe extrarespiratory symptoms including skin, gastrointestinal, or flu-like symptoms in relation to exposure to sensitized pollen. OBJECTIVE: To elucidate the extrarespiratory symptoms in patients with pollen allergy. METHODS: We performed a non-drug-focused prospective study of patients with pollen allergy (n = 384). During the 1-year observational period, they were asked to complete a weekly electronic diary consisting of visual analog scale (VAS) scores to assess all symptoms experienced in various organs over the past week. An association between seasonal pollen levels and seasonal increase in VAS scores was evaluated using a mixed-effects model for repeated measures. A k-means cluster analysis was performed to identify a group of patients experiencing stronger extrarespiratory symptoms. RESULTS: In patients sensitized to grass or birch pollen, higher seasonal levels of these pollen grains were associated with higher VAS scores for headache, gastrointestinal symptoms, skin symptoms, and fatigue. A cluster analysis identified a group of severe pollen-allergic patients with higher extrarespiratory symptoms (n = 42). This group was characterized by a higher frequency of comorbid food allergy/atopic dermatitis, higher rate of IgE sensitization to pollens, and higher impaired activity and work productivity. CONCLUSIONS: This 1-year survey identified a small but nonnegligible group of patients with pollen-related extrarespiratory symptoms. More attention should be paid to this patient group considering their impaired activity and work productivity.

Clinical characteristics of allergic bronchopulmonary mycosis caused by Schizophyllum commune.

BACKGROUND: Allergic bronchopulmonary mycosis (ABPM) is an allergic disease caused by type I and type III hypersensitivity to environmental fungi. Schizophyllum commune, a basidiomycete fungus, is one of the most common fungi that causes non-Aspergillus ABPM. OBJECTIVE: Herein, we attempted to clarify the clinical characteristics of ABPM caused by S. commune (ABPM-Sc) compared with those of allergic bronchopulmonary aspergillosis (ABPA). METHODS: Patients with ABPM-Sc or ABPA were recruited from a nationwide survey in Japan, a multicenter cohort, and a fungal database at the Medical Mycology Research Center of Chiba University. The definition of culture-positive ABPM-Sc/ABPA is as follows: (1) fulfills five or more of the 10 diagnostic criteria for ABPM proposed by Asano et al., and (2) positive culture of S. commune/Aspergillus spp. in sputum, bronchial lavage fluid, or mucus plugs in the bronchi. RESULTS: Thirty patients with ABPM-Sc and 46 with ABPA were recruited. Patients with ABPM-Sc exhibited less severe asthma and presented with better pulmonary function than those with ABPA (p = 0.008-0.03). Central bronchiectasis was more common in ABPM-Sc than that in ABPA, whereas peripheral lung lesions, including infiltrates/ground-glass opacities or fibrotic/cystic changes, were less frequent in ABPM-Sc. Aspergillus fumigatus-specific immunoglobulin (Ig)E was negative in 10 patients (34%) with ABPM-Sc, who demonstrated a lower prevalence of asthma and levels of total serum IgE than those with ABPM-Sc positive for A. fumigatus-specific IgE or ABPA. CONCLUSIONS: Clinical characteristics of ABPM-Sc, especially those negative for A. fumigatus-specific IgE, differed from those of ABPA.

Allergic bronchopulmonary aspergillosis with atopic, nonatopic, and sans asthma-Factor analysis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) develops in the presence or absence of asthma, either atopic or nonatopic. We have tried to explore the essential components in the pathogenesis of the disease, which are either consistent and variable according to the presence and type of asthma. METHODS: Non-cystic fibrosis ABPA cases satisfying Asano's criteria were extracted from a prospective registry of ABPA and related diseases in Japan between 2013 and 2023. According to the type of preceding asthma, ABPA was classified into three groups: ABPA sans asthma (no preceding asthma), ABPA with atopic asthma, and ABPA with nonatopic asthma. Exploratory and confirmatory factor analyses were performed to identify the components that determined the clinical characteristics of ABPA. RESULTS: Among 106 cases of ABPA, 25 patients (24%) had ABPA sans asthma, whereas 57 (54%) and 24 (23%) had ABPA with atopic and nonatopic asthma, respectively. Factor analysis identified three components: allergic, eosinophilic, and fungal. Patients with atopic asthma showed the highest scores for the allergic component (p < .001), defined by total and allergen-specific IgE titers and lung opacities, and the lowest scores for the fungal component defined by the presence of specific precipitin/IgG or positive culture for A. fumigatus. Eosinophilic components, including peripheral blood eosinophil counts and presence of mucus plugs/high attenuation mucus in the bronchi, were consistent among the three groups. CONCLUSION: The eosinophilic component of ABPA is considered as the cardinal feature of ABPA regardless of the presence of preceding asthma or atopic predisposition.

Computed tomography findings of paranasal sinuses in patients with eosinophilic granulomatosis with polyangiitis: Comparison with other eosinophilic sinus diseases and clinical relevance of their severity.

BACKGROUND: Although paranasal sinuses are one of the most representative organs affected by eosinophilic granulomatosis with polyangiitis (EGPA), they have not been studied sufficiently. The aim of this study was to compare computed tomography (CT) findings in paranasal sinuses of EGPA with those of other eosinophilic sinus diseases and elucidate the clinical relevance of their severity. METHODS: CT findings of paranasal sinuses in EGPA patients prior to therapeutic intervention (n = 30) were evaluated using the Lund-Mackay staging (LMS) system and compared with those of three control diseases [(NSAID-exacerbated respiratory disease (N-ERD), aspirin-tolerant asthma, and eosinophilic chronic rhinosinusitis without asthma (ECRS)]. We divided EGPA patients into three groups based on their LMS scores and examined their association with disease manifestation. RESULTS: Total scores of the LMS system in EGPA were significantly lower than those of N-ERD and ECRS without asthma. There was a large variation in total LMS scores in EGPA, suggesting considerable heterogeneity of their sinus lesions. Although EGPA with low LMS system scores showed only minor findings in maxillary and anterior ethmoid regions, those with high LMS system scores were characterized by high scores in the ostiomeatal complex. However, the frequencies of patients with a Five-Factor Score ≥2 and with cardiac involvement were significantly higher for EGPA with low LMS system scores. CONCLUSIONS: Although paranasal sinus lesions in EGPA were less severe than those of other eosinophilic sinus diseases, their milder CT findings may be associated with a higher frequency of extra-respiratory organ involvement.

Omalizumab ameliorates extrarespiratory symptoms in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Omalizumab, an anti-IgE antibody, has clinical efficacy against respiratory symptoms of aspirin-exacerbated respiratory disease (AERD). However, some patients with AERD also present with extrarespiratory (chest, gastrointestinal, and/or cutaneous) symptoms, which are resistant to conventional treatment but can be alleviated by systemic corticosteroids. OBJECTIVE: We evaluated the efficacy of omalizumab on extrarespiratory symptoms related to AERD. METHODS: In study 1, a total of 27 consecutive patients with AERD initially prescribed omalizumab at Sagamihara National Hospital between July 2009 and March 2019 were retrospectively studied. Frequency of exacerbations of AERD-related extrarespiratory symptoms was compared before and after omalizumab treatment. In study 2, we reported 3 AERD cases with aspirin challenge-induced extrarespiratory symptoms among patients studied in our previous randomized trial (registration UMIN000018777), which evaluated the effects of omalizumab on hypersensitivity reactions during aspirin challenge to AERD patients. Extrarespiratory symptoms induced during the aspirin challenge were compared between placebo and omalizumab phases. RESULTS: In study 1, omalizumab treatment was associated with decrease in frequency of exacerbation of chest pain (no. [%] of patients with exacerbation frequency ≥1 time per year, 6 [22.2%] vs 0; P < .001), gastrointestinal symptoms (9 [33.3%] vs 2 [7.4%]; P = .016), and cutaneous symptoms (16 [59.3%] vs 2 [7.4%]; P < .001), even under conditions of treatment-related reduction in systemic corticosteroid dose. Omalizumab also attenuated all the extrarespiratory symptoms during aspirin challenge in study 2. CONCLUSION: Omalizumab ameliorated extrarespiratory symptoms at baseline (without aspirin exposure) and during aspirin challenge.

Frailty and muscle weakness in elderly patients with asthma and their association with cumulative lifetime oral corticosteroid exposure.

BACKGROUND: Frailty is a geriatric syndrome of age-related physiological decline, which is associated with higher mortality and decreased healthy life expectancy, and muscle weakness is one of the presentations of frailty. We investigated an association between lifetime oral corticosteroid (OCS) exposure with frailty and muscle weakness among elderly patients with asthma. METHODS: We studied 203 consecutive elderly outpatients with asthma aged ≥60 years old. They were classified into three groups according to their cumulative lifetime OCS dose (lifetime non-users, lower-dose users, and higher-dose users), which was retrospectively estimated from the response to a structured questionnaire. The prevalence of frailty determined by the Kihon Checklist was compared between the three groups. Hand-grip strength, and lean mass index were also measured as markers of muscle strength. RESULTS: Thirty-seven percent of the patients studied were considered frail. Higher cumulative lifetime OCS exposure was associated with a significantly higher prevalence of frailty (33% in lifetime non-users, 59% in lower-dose users, and 68% in higher-dose users; P for trend <0.005). This was also associated with lower hand-grip strength in both sexes (P for trend; 0.012 in men, and 0.020 in women), and lower lean mass index in men (P for trend 0.002). However, current doses of OCS were not significantly associated with these outcomes. CONCLUSIONS: Cumulative lifetime OCS exposure was associated with a higher prevalence of frailty and muscle weakness. These findings emphasize the importance of minimizing lifetime OCS exposure for the prolongation of healthy life expectancy in patients with asthma.

Longitudinal changes in the prevalence of adult asthma: An epidemiological survey among Japanese salaried employees and their dependents using healthcare insurance claim from 1999 to 2019.

BACKGROUND: Information on changes in asthma prevalence and the treatment status for asthma is used as basic information for taking medical and administrative measures against asthma. However, this information among adults is relatively limited. METHODS: To elucidate changes in the prevalence of asthma and treatment status over time among Japanese adults, health insurance claim data from some health insurance societies covering salaried employees and their dependents were studied longitudinally. Claim data from FY1999 to 2007 were obtained from two health insurance societies, and data from FY 2011 to 2019 were obtained from three different health insurance societies, and changes in standardized asthma prevalence among subjects aged 20-59 years, proportion of asthma patients prescribed ICS, leukotriene receptor antagonist (LTRA), and LABA, and the mean number of acute asthma exacerbations per year were analyzed. RESULTS: The prevalence of asthma increased from 1.6% in 1999 to 3.0% in 2007 and 2.9% in 2011 to 4.6% in 2019. Increased trends in asthma prevalence from 2011 to 2019 were more noticeable in subjects in their 50s than those in their 20s for both sexes. The number of emergency visits related to asthma was 1.5 per year in 1999, which decreased to 0.8 per year in 2019. The proportion of people prescribed all anti-asthma medications (ICS, LTRA, and LABA) increased over time. CONCLUSIONS: The prevalence of adult asthma among Japanese salaried employees and their dependents has increased over the last 20 years, suggesting more attention should be paid to the prevention of this disease in adults.

Identification of fungi causing humidifier lung: 2 rare cases and a review of the literature.

Background: Humidifier lung (HL) is a hypersensitivity pneumonitis resulting from exposure to humidifiers, with fungi from the humidifier as one of the etiologic agents. However, identification of the fungal species responsible for each case can be challenging because of difficulties in culturing fungi, their accurate identification, and interpreting the results of specific serum IgG testing. Objective: To clarify the best way to determine the causative fungal species of each HL case. Methods: We report 2 cases with HL in which rare fungi were identified as causative agents. In addition, we searched MEDLINE for previous publications on HL caused by fungi and performed a literature review focusing on clinical testing for the determination of causal fungal species. Results: In our 2 cases, we identified Fusarium oxysporum species complex, Purpureocillium lilacinum, Acremonium sclerotigenum/egyptiacum as the causative fungal species, based on findings that these could be cultured from humidifier water (HW) and precipitins against these fungi were also positive. The literature review identified 31 HL cases in which the causative fungal species had been documented. In more than half of the cases (17 of 31) there was a concordance between the fungal species cultured from HW and the presence of specific IgG in the blood. Conclusion: We recommend performing culture of fungi from HW and specific serum IgG testing for the accurate determination of the causative fungal species in HL, and concordance between them serves as a rationale for the determination of causative fungal species.

[Steroid resistance of severe asthma - mechanisms and therapeutic targets].

Asthma therapy in general has improved a lot in recent years, but it is still a major problem that severe asthma, which accounts for 10 to 20%, still suffers from strong symptoms on a daily basis despite all therapeutic agents used in combination. American SARP and European ENFUMOSA started in 2000 to advance pathophysiological insights of severe asthma. Clinical usage of antibodies and inhibitors against IgE, TNF, IL-5, IL-4, IL-13, and TSLP are also accumulating. Some of these molecular-targeted drugs improve respiratory function and reduce acute exacerbations in patients with severe asthma. Until now, cytokines have been assumed to be involved in chronic inflammation, but it is also interesting to elucidate the pathways of how cytokines are involved in respiratory function and acute exacerbations. We registered approximately 100 steroid-dependent asthma patients in Japan. Although long-lasting poor control of the disease was considered the cause of severe asthma in the past, steroid dependence in one third of the cases occurred within 2-3 years after the onset. Steroid resistance seems a key process from the early stage of the disease. Steroid resistance of T cell level was induced by extracellular co-stimulation and cytokine signals. The inhibition may improve steroid sensitivity and treat steroid-resistant asthma. Therefore, we established a steroid-resistant asthma model for the first time by transferring steroid resistant T cell clones, and analyzed the steroid sensitivity recovery effect of CTLA4-Ig. In addition, a multicenter, double-blind, placebo-controlled exploratory trial was performed as a POC study investigating the efficacy of abatacept in treatment-resistant severe asthma. Elucidation of the pathophysiology and mechanism by which steroids do not work is expected to be a breakthrough for the prevention and treatment of severe asthma.

Low-dose mepolizumab is effective as an add-on therapy for treating long-lasting peripheral neuropathy in patients with eosinophilic granulomatosis with polyangiitis.

OBJECTIVE: To assess the effectiveness of low-dose mepolizumab as an add-on therapy for treating peripheral neurological symptoms in eosinophilic granulomatosis with polyangiitis (EGPA). METHODS: We prospectively studied 13 EGPA patients with conventional treatment-resistant peripheral neuropathy. Their symptoms (pain, numbness, and muscle weakness) were assessed on a visual analogue scale (VAS) before and after 12 months of mepolizumab therapy (100 mg every 4 weeks). Peripheral eosinophil levels and several biomarkers including urinary levels of eosinophil-derived neurotoxin (EDN) were measured before and after therapy. RESULTS: VAS scores for pain and numbness significantly improved after 12 months of mepolizumab therapy (from 67.0 to 48.0, P = 0.012, and from 67.0 to 51.0, P = 0.017, respectively). However, the VAS score for muscle weakness did not improve (P = 0.36). There were significant correlations between treatment-related changes in urinary EDN levels from baseline to 6 months later and percent changes in the VAS scores of pain and numbness (r = 0.75, P = 0.020; r = 0.88, P = 0.002). CONCLUSIONS: Treatment-resistant peripheral neuropathy in EGPA was significantly improved by low-dose mepolizumab, and effectiveness was correlated with decreased urinary EDN. Because the possibility of a placebo effect cannot be formally excluded, placebo-controlled studies will be required in the future.

Prevalence of inhaled allergen-specific IgE antibody positivity in the healthy Japanese population.

BACKGROUND: Measurement of allergen-specific IgE antibodies to inhaled allergens is important for the diagnosis and risk evaluation of allergic diseases such as asthma and allergic rhinitis. This study aimed to elucidate the prevalence of allergen sensitization among the healthy population in Japan using serum samples stocked in the Japanese Red Cross for blood donation. METHODS: Age- and gender-stratified serum samples (n = 800) from residents in Tokyo aged 20-59 years were randomly selected from the stocked serum obtained for blood donation in 2005. Total and specific IgE antibodies to 17 inhaled allergens were measured by the ImmunoCAP method. Individuals with positive (≥0.35 UA/mL) specific IgE antibodies to at least one inhaled allergen were defined as atopic. Stocked serums from donors aged 20-29 years in Sapporo, Osaka, Fukuoka, and Okinawa (n = 200 each) were also obtained for the measurement of IgE to six common inhaled allergens, to evaluate regional differences in the rate of positivity. RESULTS: Among residents in Tokyo, the prevalence of atopy was 78.0% and highest in men aged 20-29 years (94.0%), which decreased with age. The prevalence of specific IgE antibodies was highest for Japanese cedar pollen (66.8%), followed by cypress pollen (46.8%), Dermatophagoides pteronyssinus (38.3%), and moths (30.1%). Examination of IgE to Japanese cedar pollen, D. pteronyssinus, and moths identified 97.6% of atopic subjects in Tokyo. There were substantial regional differences in the prevalence of pollen IgE positivity. CONCLUSIONS: This study demonstrated an extremely high prevalence of positivity in inhaled allergen-specific IgE antibodies among healthy adults in Japan.

Association between the severity of chronic spontaneous urticaria and sleep-disordered breathing.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a common mast cell-driven disease, presenting with wheals, angioedema, or both. Sleep-disordered breathing (SDB) is also a common condition and contributes to various diseases by causing chronic inflammation. Recent studies have suggested an association between CSU and SDB. METHODS: To determine the association between the severity of SDB and that of CSU, we studied consecutive patients with CSU who visited the Sagamihara National Hospital allergy department or dermatology department between April 1 and October 31, 2018. The severity of CSU and SDB was evaluated based on the urticaria activity score 7 (UAS7) and peripheral arterial tone apnea-hypopnea index (pAHI) derived from out-of-center sleep testing (OCST) findings, respectively; their correlation was examined. RESULTS: Of the 37 patients studied, 19 had symptom-free-to-mild CSU (UAS7 ≤15) and 18 had moderate-to-severe CSU (UAS7 ≥16). The pAHI in the latter group was significantly higher than that in the former group (18 vs. 4.2, p = 0.001). In multivariate logistic analysis, moderate-to-severe SDB (pAHI ≥15) was significantly associated with moderate-to-severe CSU even after adjusting for the BMI (adjusted odds ratio 22 [95% confidence interval, 1.7-285]). CONCLUSIONS: The severity of SDB is correlated with that of CSU independently of the BMI. Physicians should consider comorbid SDB when treating patients with CSU.

Optimal Aspergillus fumigatus and Asp f 1 serum IgG cut-offs for the diagnosis of allergic bronchopulmonary aspergillosis.

BACKGROUND: The presence of IgG antibodies (Abs) to Aspergillus fumigatus (Af) is a crucial diagnostic criterion for allergic bronchopulmonary aspergillosis (ABPA). Although precipitation is traditionally used to document IgG Abs, anti-Af serum IgG levels can also be measured by enzyme immunoassay (EIA). However, there are insufficient data on the optimal cut-offs to assess diagnostic performance of the EIA method. This study aimed to determine cut-off levels of IgG binding crude Af extracts or recombinant Asp f 1 (by ImmunoCAP®) and to compare their efficacy for ABPA diagnosis with Af-precipitating Abs. METHODS: The age distribution of levels of IgG to crude extracts of Af (Af-IgG) and recombinant Asp f 1 (Asp f 1-IgG) was established using sera from 694 healthy controls (HC). Receiver operating characteristic analysis for Af-IgG and Asp f 1-IgG levels for the purpose of ABPA diagnosis was performed in 306 Af-sensitized asthma patients (including 49 ABPA), and cut-offs were determined. RESULTS: An age-dependent decline in the levels of Af-IgG was observed in HC. Thus, cut-offs for Af-IgG levels were determined separately by age as 60 mg/L for patients aged <55 years, and 45 mg/L for those aged ≥55 years. For Asp f 1-IgG, 6.6 mg/L was set as the cut-off regardless of age. Although such IgG testing by EIA allowed a sufficiently good diagnostic performance, Af-precipitating Abs had better diagnostic applicability for ABPA. CONCLUSIONS: We determined cut-offs for Af-IgG and Asp f 1-IgG measured by EIA, which can be useful in clinical settings where precipitating Abs are unavailable.

The First Death in Japan Attributed to COVID-19: A Brief Report.

Our hospital encountered the first coronavirus disease 19 (COVID-19) pneumonia death in Japan. Moreover, we prevented nosocomial infection by taking appropriate infection control measures, without a negative pressure chamber. The patient was an 82-year-old woman who had no history of traveling to Wuhan or any direct contact with individuals who had been to Wuhan. Our patient had a seven-day history of fatigue, sudden fever, and hypoxemia. Chest computerized tomography images revealed peripheral ground-glass opacities in her lungs. A diagnostic COVID-19 reverse-transcription polymerase chain reaction (RT-PCR) analysis was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The patient did not respond to any treatment and died 13 days after admission. The possibility of COVID-19 in a patient must always be considered, especially in the current scenario, to prevent nosocomial infection from spreading.

Omalizumab for Aspirin Hypersensitivity and Leukotriene Overproduction in Aspirin-exacerbated Respiratory Disease. A Randomized Controlled Trial.

Rationale: Aspirin-exacerbated respiratory disease is characterized by severe asthma, nonsteroidal antiinflammatory drug hypersensitivity, nasal polyposis, and leukotriene overproduction. Systemic corticosteroid therapy does not completely suppress lifelong aspirin hypersensitivity. Omalizumab efficacy against aspirin-exacerbated respiratory disease has not been investigated in a randomized manner.Objectives: To evaluate omalizumab efficacy against aspirin hypersensitivity, leukotriene E4 overproduction, and symptoms during an oral aspirin challenge in patients with aspirin-exacerbated respiratory disease using a randomized design.Methods: We performed a double-blind, randomized, crossover, placebo-controlled, single-center study at Sagamihara National Hospital between August 2015 and December 2016. Atopic patients (20-79 yr old) with aspirin-exacerbated respiratory disease diagnosed by systemic aspirin challenge were randomized (1:1) to a 3-month treatment with omalizumab or placebo, followed by a >18-week washout period (crossover design). The primary endpoint was the difference in area under logarithm level of urinary leukotriene E4 concentration versus time curve in the intent-to-treat population during an oral aspirin challenge.Measurements and Main Results: Sixteen patients completed the study and were included in the analysis. The area under the logarithm level of urinary leukotriene E4 concentration versus time curve during an oral aspirin challenge was significantly lower in the omalizumab phase (median [interquartile range], 51.1 [44.5-59.8]) than in the placebo phase (80.8 [interquartile range, 65.4-87.8]) (P < 0.001). Ten of 16 patients (62.5%) developed oral aspirin tolerance up to cumulative doses of 930 mg in the omalizumab phase (P < 0.001).Conclusions: Omalizumab treatment inhibited urinary leukotriene E4 overproduction and upper/lower respiratory tract symptoms during an oral aspirin challenge, resulting in aspirin tolerance in 62.5% of the patients with aspirin-exacerbated respiratory disease.