Inhalation adherence for asthma and COPD improved during the COVID-19 pandemic: a questionnaire survey at a university hospital in Japan.

Background: Good adherence to an inhaled medication protocol is necessary for the management of asthma and chronic obstructive pulmonary disease (COPD), and several interventions to improve adherence have been reported. However, the impact of patient life changes and psychological aspects on treatment motivation is obscure. Here, we investigated changes in inhaler adherence during the COVID-19 pandemic and how lifestyle and psychological changes affected it.Methods: Seven-hundred sixteen adult patients with asthma and COPD who had visited Nagoya University Hospital between 2015 and 2020 were selected. Among them, 311 patients had received instruction at a pharmacist-managed clinic (PMC). We distributed one-time cross-sectional questionnaires from January 12 to March 31, 2021. The questionnaire covered the status of hospital visits, inhalation adherence before and during the COVID-19 pandemic, lifestyles, medical conditions, and psychological stress. The Adherence Starts with Knowledge-12 (ASK-12) was used to assess adherence barriers.Results: Four-hundred thirty-three patients answered the questionnaire. Inhalation adherence was significantly improved in both diseases during the COVID-19 pandemic. The most common reason for improved adherence was fear of infection. Patients with improved adherence were more likely to believe that controller inhalers could prevent COVID-19 from becoming more severe. Improved adherence was more common in patients with asthma, those not receiving counseling at PMC, and those with poor baseline adherence.Conclusions: Inhalation adherence for asthma and COPD improved in the COVID-19 pandemic. The patients seemed to realize the necessity and benefits of the medication more strongly than before the pandemic, which motivated them to improve adherence.

Non-invasive early prediction of immune checkpoint inhibitor efficacy in non-small-cell lung cancer patients using on-treatment serum CRP and NLR.

PURPOSE: We determined the clinical relevance of early C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) change in blood as surrogate markers of pro-tumor inflammation (PTI) for predicting clinical outcome of programmed cell death (PD)-1/programmed cell death ligand (PD-L) 1 inhibitor treatment in non-small-cell lung carcinoma (NSCLC). METHODS: We retrospectively reviewed NSCLC patients treated with anti-PD-1 or PD-L1 inhibitors. Early CRP change was defined as the ratio of 6 weeks CRP to baseline CRP, and early NLR change was defined as that of the 6 weeks NLR to baseline NLR. PTI index was determined by combinatorial evaluation of early CRP change and early NLR change, PTI index low: both of these were low, intermediate: either of these was low, high; both of these were high. RESULTS: The study included 217 patients. Early CRP change and early NLR change were both associated with PFS and OS. The combinatorial evaluation using these two markers enabled the clear stratification of PFS and OS. The median PFS in patient with PTI index low was 13.9 months, while the median PFS in those with PTI index high was 2.5 months (p < 0.01, log-rank test). The median OS in patients with PTI index low was not reached; the median OS in those with PTI index high was only 15.4 months (p < 0.01, log-rank test). CONCLUSIONS: The combinatorial early CRP change and early NLR change as PTI biomarkers have clinical potential in identifying NSCLC patients who can achieve a durable response and long-term survival using PD-1/PD-L1 inhibitors.

Diagnostic value and safety of endobronchial ultrasonography with a guide sheath transbronchial biopsy for diagnosing peripheral pulmonary lesions in patients with interstitial lung disease.

Background: Radial endobronchial ultrasonography transbronchial biopsy with and without a guide sheath is a useful method for diagnosing peripheral pulmonary lesions (PPLs). However, the diagnostic yield and complications of radial endobronchial ultrasonography transbronchial biopsy for PPLs remains elusive in patients with interstitial lung disease (ILD). Methods: We retrospectively analysed 431 patients (69 with and 362 without ILD) who underwent radial endobronchial ultrasonography with a guide sheath transbronchial biopsy (EBUS-GS TBB) for PPLs from April 1, 2011, to March 31, 2020. We investigated the diagnostic yield and complications of the procedure for PPLs and compared them between patients with and without ILD. We also evaluated the factors contributing to successful diagnosis. Results: The diagnostic yield of radial endobronchial ultrasonography in patients with ILD was significantly lower than in those without ILD (62.3% vs. 75.4%, P=0.024). Multivariate analysis showed that the presence of ILD as background lung [odds ratio (OR) =0.517], probe position within the lesion (OR =4.654), and the presence of solid lesion (OR =1.946) significantly affected the diagnostic yield of PPLs. There was a significant difference in the rate of pneumothorax between the patients with ILD and those without ILD (4.3% vs. 0.6%, P=0.031). Conclusions: The presence of ILD as the background lung significantly affected the diagnostic yield of PPLs with radial EBUS-GS TBB. Regarding the complications, pneumothorax occurred more frequently in patients with ILD than in those without ILD.

Epidermal growth factor receptor mutation-positive advanced lung adenocarcinoma presenting with acute respiratory failure diagnosed by thin bronchoscope through transnasal route under high-concentration oxygen mask.

A 59-year-old woman complained of continuous dyspnea. Computed tomography revealed multiple pulmonary nodules, mildly small enlarged mediastinal lymph nodes and a nodule in the liver segment 8. Her dyspnea worsened with respiratory failure 4 days after presentation. Liver biopsy was not possible as she could not hold her breath; thus, we performed bronchoscopy. For biopsy, the pulmonary nodules with a positive bronchus sign were preferred over the mildly small enlarged mediastinal lymph nodes. Bronchoscopy under non-invasive positive pressure ventilation (NPPV) or high-flow nasal cannula (HFNC) was impossible because of the lack of equipment. Therefore, we biopsied via thin bronchoscope through nasal cavity under a high-concentration oxygen mask. Pathological findings revealed epidermal growth factor receptor mutation-positive lung adenocarcinoma. For patients with respiratory failure who cannot undergo bronchoscopy under NPPV or HFNC, thin bronchoscopy through the nasal cavity under a high-concentration oxygen mask may be clinically useful to prevent hypoxaemia during the procedure.

Airway involvement in inflammatory bowel disease: Inflammatory bowel disease patients have bronchial wall thickening.

BACKGROUND: Recent epidemiological studies have revealed a high co-occurrence of asthma or COPD and IBD. Herein, we examined the impact of IBD on the bronchial wall structure using three-dimensional computed tomography (3D-CT). METHODS: Subjects who were diagnosed with IBD and had undergone chest CT were recruited from consecutive medical records. Screening chest CT scan data during the same period were used as normal controls. Airway dimensions were measured by validated software. RESULTS: Overall, 136 IBD and 99 control subjects were recruited. The bronchial walls of patients with IBD were significantly thicker than those of control subjects. Multiple linear regression analysis showed that Crohn's disease and ulcerative colitis were independent determinants of wall area percentage after adjusting for age, sex, and smoking status. CONCLUSIONS: Airway walls in patients with IBD were thicker than those in normal control subjects. Airway involvement in IBD may be more frequent than recognized.

Overexpression of bone morphogenetic protein receptor type 2 suppresses transforming growth factor ß-induced profibrotic responses in lung fibroblasts.

MATERIALS AND METHODS: We investigated BMPR2 expression in pulmonary fibrosis and TGF-ß/BMP signaling in lung fibroblasts. Then we evaluated the impact of BMPR2 upregulation using adenoviral transduction on TGF-ß-induced Smad2/3 phosphorylation and fibronectin production in lung fibroblasts. RESULTS: BMPR2 was distributed in airway epithelium and alveolar walls in rat lungs. BMPR2 expression was decreased in fibrotic lesions in the lungs of rats with bleomycin-induced pulmonary fibrosis and in human lung fibroblasts (HLFs) stimulated with TGF-ß. Although Smad2/3 phosphorylation and fibronectin production were not suppressed solely by BMPs, phosphorylated Smad2/3 was decreased in BMPR2-transduced cells even without BMP stimulation. Fibronectin was decreased only when BMPR2-transduced HLFs were stimulated with BMP7 (but not BMP4). Similar results were also observed in IPF patient HLFs and rat lung fibroblasts. CONCLUSIONS: BMPR2 expression was reduced in fibrotic lungs and lung fibroblasts stimulated with TGF-ß. BMPR2 transduction to lung fibroblasts reduced Smad2/3 phosphorylation, and reduced fibronectin production when treated with BMP7. Upregulation of BMPR2 may be a possible strategy for treating pulmonary fibrosis.

Amelanotic Malignant Melanoma with a BRAF V600E Mutation Mimicking Primary Lung Cancer.

Amelanotic melanoma is a rare type of melanoma that shows little or no melanin pigmentation. When tumor lesions are not detected in cutaneous sites, the presence of melanin is the hallmark sign of malignant melanoma. We herein report a case of amelanotic melanoma with a BRAF V600E mutation mimicking primary lung cancer that was finally diagnosed on an autopsy. The current case suggests important caveats for the differential diagnosis of patients with BRAF V600E mutation-positive poorly differentiated lung tumors. In terms of the pathological diagnosis, routine immunohistochemical staining may be useful, especially in patients with a poorly differentiated lung tumor without TTF-1 expression.

Increased Risk of Thyroid Dysfunction by PD-1 and CTLA-4 Blockade in Patients Without Thyroid Autoantibodies at Baseline.

BACKGROUND: Previous studies showed that although the risk of thyroid dysfunction [thyroid immune-related adverse events (irAEs)] induced by anti-programmed cell death-1 antibodies (PD-1-Ab) was as low as 2% to 7% in patients negative for anti-thyroid antibodies (ATAs) at baseline, it was much higher (30%-50%) in patients positive for ATAs. However, whether a similar increase occurs with combination therapy using PD-1-Ab plus anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) is unknown. METHODS: A total of 451 patients with malignancies treated with PD-1-Ab, CTLA-4-Ab, or a combination of PD-1-Ab and CTLA-4-Ab (PD-1/CTLA-4-Abs) were evaluated for ATAs at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation and then observed until the last clinical visit. RESULTS: Of the 451 patients, 51 developed thyroid irAEs after immunotherapy [41 of 416 (9.9%) treated with PD-1-Ab, 0 of 8 (0%) treated with CTLA-4-Ab, and 10 of 27 (37.0%) treated with PD-1/CTLA-4-Abs]. The cumulative incidence of thyroid irAEs was significantly higher in patients who were positive vs negative for ATAs at baseline after both PD-1-Ab [28/87 (32.2%) vs 13/329 (4.0%), P < 0.001] and PD-1/CTLA-4-Abs [6/10 (60.0%) vs 4/17 (23.5%), P < 0.05] treatments. The risk of thyroid irAEs induced by PD-1/CTLA-4Abs, which was significantly higher than that induced by PD-1-Ab, in patients negative for ATAs at baseline was not statistically different from that induced by PD-1-Ab in patients positive for ATAs at baseline. CONCLUSIONS: This study showed that the incidence of thyroid irAEs was high and not negligible after PD-1/CTLA-4-Abs treatment even in patients negative for ATAs at baseline.

A Pilot Study of Transbronchial Biopsy Using Endobronchial Ultrasonography with a Guide Sheath in the Diagnosis of Peripheral Pulmonary Lesions in Patients with Interstitial Lung Disease.

The occurrence of interstitial lung disease (ILD) with peripheral pulmonary lesions (PPLs) is closely linked to the development of lung cancer. Yet, the best diagnostic approach for identifying PPLs in patients with ILD remains elusive. This study retrospectively investigated the application of transbronchial biopsy (TBB) using endobronchial ultrasonography with a guide sheath (EBUS-GS) to the effective and safe diagnosis of PPLs when compared with conventional TBB. The study sample included a consecutive series of 19 patients with ILD who underwent conventional TBB or TBB using EBUS-GS at Tosei General Hospital between 1 April 2013 and 31 October 2015. The two techniques were compared based on diagnostic yield and associated complications. The diagnostic yield of EBUS-GS TBB was significantly higher than that of conventional TBB (p = 0.009), especially for small lesions (≤20 mm), lesions located in the lower lobes, lesions with a positive bronchus sign, and lesions visible by chest radiography (p = 0.010, p = 0.022, p = 0.006, and p = 0.002, respectively). There were no significant differences in complication rates. Therefore, EBUS-GS is an effective alternative for the diagnosis of PPLs in patients with ILD, without additional complications.

Endobronchial Ultrasonography with a Guide Sheath Transbronchial Biopsy for Diagnosing Peripheral Pulmonary Lesions within or near Fibrotic Lesions in Patients with Interstitial Lung Disease.

In patients with interstitial lung disease (ILD), the most frequent locations of lung cancer are within or near fibrotic lesions. However, the diagnostic yield for peripheral pulmonary lesions (PPLs) within or near fibrotic lesions using endobronchial ultrasonography with a guide sheath transbronchial biopsy (EBUS-GS TBB) may be unsatisfactory compared to that for PPLs distant from fibrotic lesions because of the difficulty in reaching the lesions. Our objectives were to evaluate the yield for PPLs using EBUS-GS TBB according to the proximity of PPLs to fibrotic lesions and to determine factors affecting the yield for PPLs. We retrospectively investigated 323 consecutive lesions using EBUS-GS TBB between 1 November 2014 and 31 December 2016. We identified PPLs with ILD in such lesions. PPLs with ILD were divided into PPLs within or near fibrotic lesions which met the criterion of PPLs, and of fibrotic lesions overlapping each other (PPLs-FL) and those distant from fibrotic lesions, which met the criterion of PPLs and the area of fibrotic lesion not overlapping each other (PPLs-NFL). Of the 323 lesions, 55 were included (31 PPLs-FL and 24 PPLs-NFL). The diagnostic yield for PPLs-FL was significantly lower than for PPLs-NFL (45.2% vs. 83.3%, p = 0.004). Multivariate analysis revealed that PPLs-NFL (odds ratio (OR) = 7.509) and a probe position within the lesion (OR = 4.172) were significant factors affecting diagnostic yield. Lesion's positional relation to fibrotic lesions and the probe position were important factors affecting the successful diagnosis via EBUS-GS TBB in these patients.

Fibroblasts positive for meflin have anti-fibrotic properties in pulmonary fibrosis.

The prognosis of elderly individuals with idiopathic pulmonary fibrosis (IPF) remains poor. Fibroblastic foci, in which aggregates of proliferating fibroblasts and myofibroblasts are involved, are the pathological hallmark lesions in IPF to represent focal areas of active fibrogenesis. Fibroblast heterogeneity in fibrotic lesions hampers the discovery of the pathogenesis of pulmonary fibrosis. Therefore, to determine the pathogenesis of IPF, identification of functional fibroblasts is warranted. The aim of this study was to determine the role of fibroblasts positive for meflin, identified as a potential marker for mesenchymal stromal cells, during the development of pulmonary fibrosis.We characterised meflin-positive cells in a single-cell atlas established by single-cell RNA sequencing (scRNA-seq)-based profiling of 243 472 cells from 32 IPF lungs and 29 normal lung samples. We determined the role of fibroblasts positive for meflin using bleomycin (BLM)-induced pulmonary fibrosis.scRNA-seq combined with in situ RNA hybridisation identified proliferating fibroblasts positive for meflin in fibroblastic foci, not dense fibrosis, of fibrotic lungs in IPF patients. A BLM-induced lung fibrosis model for meflin-deficient mice showed that fibroblasts positive for meflin had anti-fibrotic properties to prevent pulmonary fibrosis. Although transforming growth factor-ß-induced fibrogenesis and cell senescence with the senescence-associated secretory phenotype were exacerbated in fibroblasts via the repression or lack of meflin, these were inhibited in meflin-deficient fibroblasts with meflin reconstitution.These findings provide evidence to show the biological importance of meflin expression on fibroblasts and myofibroblasts in the active fibrotic region of pulmonary fibrosis.

Assessment of Extensive Airway Obstruction Using Point-by-Point Lateral Pressure Measurements during Bronchoscopy.

BACKGROUND: The positioning of the stent at the flow-limiting segment is crucial for patients with extensive airway obstruction to relieve dyspnea. However, CT and flow-volume curves cannot detect the area of maximal obstruction. OBJECTIVES: The aim of this study is to physiologically evaluate extensive airway obstruction during interventional bronchoscopy. METHODS: We prospectively measured point-by-point lateral airway pressure (Plat) at multiple points from the lower lobe bronchus to the upper trachea using a double-lumen catheter in 5 patients. The site of maximal obstruction was evaluated continuously to measure point-by-point Plat at multiple points when the airway catheter was withdrawn from the lower lobe bronchus to the upper trachea. RESULTS: Remarkable pressure differences occurred at the site of maximal obstruction assessed by point-by-point Plat measurements. After initial stenting in 1 case, migration of the maximal obstruction to a nonstented segment of the weakened airway was seen with extensive stenosis from the trachea to the bronchi. In the second case, in addition to radiological analysis, point-by-point Plat measurements could identify the location of the maximal obstruction which contributed to dyspnea. CONCLUSIONS: Point-by-point Plat measurement could be used to detect the site of maximal obstruction physiologically. Furthermore, Plat measurement could assess the need for additional procedures in real time in patients with extensive airway obstruction.

The Importance of Appropriate Diagnosis in the Practical Management of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is projected to continue to contribute to an increase in the overall worldwide burden of disease until 2030. Therefore, an accurate assessment of the risk of airway obstruction in patients with COPD has become vitally important. Although the Global Initiative for Chronic Obstructive Lung Disease (GOLD), the American Thoracic Society (ATS) and European Respiratory Society (ERS), and the Japanese Respiratory Society (JRS) provide the criteria by which to diagnose COPD, many studies suggest that it is in fact underdiagnosed. Its prevalence increases, while the impact of COPD-related systemic comorbidities is also increasingly recognized in clinical aspects of COPD. Although a recent report suggests that spirometry should not be used to screen for airflow limitation in individuals without respiratory symptoms, the early detection of COPD in patients with no, or few, symptoms is an opportunity to provide appropriate management based on COPD guidelines. Clinical advances have been made in pharmacotherapeutic approaches to COPD. This article provides a current understanding of the importance of an appropriate diagnosis in the real-world management of COPD.

Unusual presentation of recurrent follicular lymphoma as diffuse granular shadow.

A 75-year-old man was diagnosed with advanced follicular lymphoma because of enlarged cervical lymph nodes. He received chemotherapy and was in complete remission for four years. However, after four years, he developed diffuse lymphadenopathy in the abdominal and iliac area suspected to be recurrent follicular lymphoma. At the time, he was asymptomatic and did not have any accompanying lung lesions. Due to his asymptomatic state, careful monitoring was chosen. Later, he developed diffuse granular shadow in the lung fields. A definite diagnosis was difficult to achieve without histological findings. Therefore, transbronchial lung biopsy of the lesions was performed. The pathology and immunohistochemistry of the lesions revealed recurrent follicular lymphoma. Although the frequency of recurrent follicular lymphoma presenting with diffuse granular shadow is uncommon, recurrent malignant lymphoma should be considered as a differential diagnosis in case with a history of malignant lymphoma.

Surgical strategy and optimal timing of tracheostomy in patients with COVID-19: Early experiences in Japan.

OBJECTIVE: Tracheostomy is an important surgical procedure for coronavirus disease-2019 (COVID-19) patients who underwent prolonged tracheal intubation. Surgical indication of tracheostomy is greatly affected by the general condition of the patient, comorbidity, prognosis, hospital resources, and staff experience. Thus, the optimal timing of tracheostomy remains controversial. METHODS: We reviewed our early experience with COVID-19 patients who underwent tracheostomy at one tertiary hospital in Japan from February to September 2020 and analyzed the timing of tracheostomy, operative results, and occupational infection in healthcare workers (HCWs). RESULTS: Of 16 patients received tracheal intubation with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, five patients (31%) received surgical tracheostomy in our hospital. The average consultation time for surgical tracheostomy was 7.4 days (range, 6 - 9 days) from the COVID-19 team to the otolaryngologist. The duration from tracheal intubation to tracheostomy ranged from 14 to 27 days (average, 20 days). The average time of tracheostomy was 27 min (range, 17 - 39 min), and post-wound bleeding occurred in only one patient. No significant differences in hemoglobin (Hb) levels were found between the pre- and postoperative periods (mean: 10.2 vs. 10.2 g/dl, p = 0.93). Similarly, no difference was found in white blood cell (WBC) count (mean: 12,200 vs. 9,900 cells /µl, p = 0.25). After the tracheostomy, there was no occupational infection among the HCWs who assisted the tracheostomy patients during the perioperative period. CONCLUSION: We proposed a modified weaning protocol and surgical indications of tracheostomy for COVID-19 patients and recommend that an optimal timing for tracheostomy in COVID-19 patients of 2 - 3 weeks after tracheal intubation, from our early experiences in Japan. An experienced multi-disciplinary tracheostomy team is essential to perform a safe tracheostomy in patients with COVID-19 and to minimize the risk of occupational infection in HCWs.

CERS6 required for cell migration and metastasis in lung cancer.

Sphingolipids constitute a class of bio-reactive molecules that transmit signals and exhibit a variety of physical properties in various cell types, though their functions in cancer pathogenesis have yet to be elucidated. Analyses of gene expression profiles of clinical specimens and a panel of cell lines revealed that the ceramide synthase gene CERS6 was overexpressed in non-small-cell lung cancer (NSCLC) tissues, while elevated expression was shown to be associated with poor prognosis and lymph node metastasis. NSCLC profile and in vitro luciferase analysis results suggested that CERS6 overexpression is promoted, at least in part, by reduced miR-101 expression. Under a reduced CERS6 expression condition, the ceramide profile became altered, which was determined to be associated with decreased cell migration and invasion activities in vitro. Furthermore, CERS6 knockdown suppressed RAC1-positive lamellipodia/ruffling formation and attenuated lung metastasis efficiency in mice, while forced expression of CERS6 resulted in an opposite phenotype in examined cell lines. Based on these findings, we consider that ceramide synthesis by CERS6 has important roles in lung cancer migration and metastasis.

Bronchial wall thickening is associated with severity of chronic rhinosinusitis.

BACKGROUND: Though the relationship between chronic rhinosinusitis (CRS) and lower airway diseases is well recognized, the impact of CRS on bronchial wall structure has not been elucidated. Here, we evaluated the bronchial wall structure of CRS patients with or without diagnosed airway diseases by three-dimensional computed tomography (3D-CT). METHODS: Subjects who underwent both chest CT and sinus CT within a year were recruited from consecutive medical records. CRS was defined as a Lund-Mackay score (LMS) of over 5 points. Airway dimensions were measured using validated software. Standard blood tests and pulmonary function tests were performed, and their correlation with airway thickness was examined. RESULTS: One-hundred-seventy-two patients were recruited (93 CRS subjects and 79 non-CRS subjects). The bronchial walls of CRS subjects were significantly thicker than those of non-CRS subjects. CRS and asthma were related to bronchial wall thickening by multivariate linear regression analysis adjusted for age, smoking status, and chest symptoms. In addition, LMS was significantly correlated with bronchial wall thickening. CONCLUSION: Airway walls in CRS subjects were thicker than those in non-CRS subjects and associated with the severity of CRS. These data indicate strong relationship between upper and lower airways regardless of chest symptoms or diagnosed airway diseases.

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.