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.

Aspirin-exacerbated respiratory disease (AERD): Current understanding of AERD.

The characteristics in AERD are severe adult-onset asthma, eosinophilic rhinosinusitis with nasal polyposis, and CysLT overproduction. The cause of AERD have remained unclear, however the decrease in the production of PGE2 caused by the reduction in COX-2 activity is considered to main pathological mechanism of AERD. The mast cell activation and the interaction between platelets and granulocytes are lead to the CysLT overproduction and severe eosinophilic inflammation. The ongoing activation of mast cells is important key pathogenesis in not only stable AERD but exacerbated AERD by aspirin and NSAIDs. In recent years, type 2 inflammation caused by ILC2 activation in patients with AERD have been attracting attention. Omalizumab is effective option for AERD via suppression of mast cell activation and CysLT overproduction. Dupilumab improves sinus symptoms especially in patients with AERD. In near future, anti-platelet drug, CRTH2 antagonist, and anti-TSLP antibody may be useful candidates of therapeutic options in patients with AERD.

Smoking Cessation as a Possible Risk Factor for the Development of Aspirin-Exacerbated Respiratory Disease in Smokers.

BACKGROUND: The pathogenesis of aspirin-exacerbated respiratory disease (AERD) is characterized by the low expression of cyclooxygenase-2 (COX-2) in airway epithelia, which decreases the production of prostaglandin E2 (PGE2). Conversely, cigarette smoke stimulates COX-2 expression in airway epithelia. Therefore, it was hypothesized that the development of AERD would be suppressed by elevated PGE2 levels in smokers, and smoking cessation might increase susceptibility to AERD. OBJECTIVE: The objective of this study was to evaluate the relationship between smoking and the risk of AERD development. METHODS: The smoking status of patients with AERD (n = 114) was compared with 2 control groups with aspirin-tolerant asthma (ATA), patients diagnosed by a systemic aspirin provocation test (ATA-1, n = 83) and outpatients randomly selected from a large-scale dataset (ATA-2, n = 914), as well as a healthy control group (HC, n = 2313). RESULTS: At the age of asthma onset, there was a low frequency of current smokers (9.7%), but a high frequency of past smokers (20.2%) in the AERD group compared with the ATA-1 (20.5% and 12.0% for current and past smokers, respectively), ATA-2 (24.5% and 10.3%, respectively), and HC group (26.2% and 12.6%, respectively). After adjustment for confounding variables, AERD was positively associated with smoking cessation between 1 and 4 years before disease onset compared with the ATA-2 group (adjusted odds ratio [aOR] 4.63, 95% confidence interval [CI]: 2.16-9.93) and the HC group (aOR 4.09, 95% CI: 2.07-8.05), implying that smoking cessation was followed by the development of AERD. CONCLUSION: Smoking cessation may be a risk factor for the development of AERD.

Platelet activation markers overexpressed specifically in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by respiratory reactions on ingestion of COX-1 inhibitors and cysteinyl leukotriene overproduction. The hypersensitivity reaction is induced by low doses of aspirin that inhibit COX-1 in platelets. OBJECTIVE: We sought to explore the role of platelets in the pathogenesis of AERD in patients under stable conditions and during an aspirin challenge test. METHODS: Stable patients with AERD (n = 30), aspirin-tolerant asthma (ATA; n = 21), or idiopathic chronic eosinophilic pneumonia (n = 10) were enrolled. Platelet activation was estimated based on expression levels of P-selectin (CD62P), CD63, CD69, and GPIIb/IIIa (PAC-1) in peripheral platelets; percentages of circulating platelet-adherent leukocytes; and plasma levels of soluble P-selectin (sP-selectin) and soluble CD40 ligand (sCD40L). RESULTS: In the stable condition, expression of all surface markers on platelets, the percentage of platelet-adherent eosinophils, and the plasma levels of sP-selectin and sCD40L were significantly higher in patients with AERD compared with those in patients with ATA. P-selectin and CD63 expression on platelets and plasma sP-selectin and sCD40L levels were positively correlated with the percentage of platelet-adherent eosinophils. Among these markers, P-selectin expression and plasma sP-selectin levels positively correlated with urinary concentrations of leukotriene E4. Additionally, plasma sP-selectin and sCD40L levels were negatively correlated with lung function. In contrast, platelet activation markers in patients with AERD did not change during the aspirin challenge test. CONCLUSION: Peripheral platelets were activated more in patients with stable AERD compared with those in patients with stable ATA, patients with idiopathic chronic eosinophilic pneumonia, and control subjects. Platelet activation was involved in cysteinyl leukotriene overproduction and persistent airflow limitations in patients with AERD.

Advances in aspirin-exacerbated respiratory disease (AERD).

Aspirin-exacerbated respiratory disease (AERD) is characterized by the triad of asthma, eosinophilic nasal polyposis and a hypersensitivity to all medications that inhibit the cyclo- oxygenase (COX) -1 enzyme. Clinical history and observed aspirin provocation test remains gold standard for diagnosis of AERD. AERD patients typically have more severe asthma with airflow limitation and greater requirement for high-dose corticosteroid therapies. Over- production of cysteinyl-leukotrienes (CysLTs) and prostaglandin D2 (PGD2) correlate with the pathogenetic features of AERD, suggesting the possible involvement of mast cell activation with innate type 2 immune response. Next breakthroughs in diagnosis and treatment have been expected in the nearest futures.

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.