Omalizumab reduces cysteinyl leukotriene and 9a,11b-prostaglandin F 2 overproduction in aspirinexacerbated respiratory disease

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 E 4 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 E 4 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 E 4 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 E 4 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.

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SummaryBackgroundDistinguishing 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.ObjectiveTo establish the usefulness of molecular‐based allergy diagnostics using allergen components from Af in distinguishing ABPA from Af‐sensitized asthma without ABPA.MethodsSera from Japanese patients with ABPA (n = 53) and Af‐sensitized asthma without ABPA (n = 253) were studied. The levels of IgE and IgG antibodies to allergen components from Af and IgE antibodies to different fugal allergen extracts were measured by ImmunoCAP. Comorbid atopic dermatitis (AD) was taken into consideration in the sensitization profile analysis.ResultsPatients with ABPA possessed significantly higher levels of IgE antibodies to Asp f 1, and Asp f 2 than asthmatic patients without ABPA. The areas under the receiver operating characteristic curves for the levels of IgE to Asp f 1 and Asp f 2 as diagnostic markers of ABPA were 0.75 and 0.78, respectively. The presence of IgE positivity to Asp f 1 and/or Asp f 2 resulted in increased sensitivity while losing little specificity. Comorbid AD was associated with higher levels of IgE to Asp f 6 (manganese superoxide dismutase from Af, a ubiquitous pan‐allergen in fungi) and low but positive levels of IgE to other Af‐components, which hampered the serological discrimination of ABPA.Conclusions and Clinical RelevanceThe levels of IgE to Asp f 1 and/or Asp f 2 can effectively differentiate ABPA from Af‐sensitized asthma, suggesting that the amounts of IgE specific for these molecules are markers for genuine Af‐sensitization in ABPA. However, comorbid AD must be taken into consideration in the interpretation of high IgE to Asp f 6. Establishing of IgE‐sensitization profiles using panel of Af‐allergen components provides valuable information for distinguishing genuine vs. cross‐reactive sensitization in Af‐sensitized patients.