Background: Combining a fraction of exhaled nitric oxide (FeNO) and blood eosinophil count (B-EOS) may be a useful strategy for administration of biologics such as anti-IgE or anti-IL-5 to patients with type 2 inflammatory-predominant severe asthma and is important to be elucidated considering the increasing use of biologics.Methods: This cross-sectional study analyzed the clinical data from 114 adult patients with severe asthma, who were treated at Saitama Medical University Hospital. The eligible patients were stratified into four subgroups defined by thresholds of FeNO and blood eosinophil (B-EOS) counts to detect sputum eosinophilia, using the receiver operating characteristic curve analysis. A total of 75 patients with optimal samples were stratified into four subtypes defined by thresholds of sputum eosinophilia and neutrophilia. Clinical characteristics, pattern of biologics, and distribution of sputum subtypes were analyzed in the stratified subclasses according to the FeNO and B-EOS thresholds. The asthma exacerbation (AE)-free time of the FeNO/B-EOS subgroups and any biologics treatment including anti-IgE or anti-IL-5 use were examined using the Kaplan–Meier method. The hazard ratios (HRs) for AE-free time were examined using the Cox proportional hazard model.Results: The optimal cutoff values for prediction of sputum eosinophilia were defined as ≥2.7% wherein for FeNO as ≥27 ppb and B-EOS as ≥265/µL were considered. The high-FeNO subgroups showed significant high total IgE, compared with the low FeNO. The high-FeNO/high-B-EOS and the high-FeNO/low-B-EOS subgroups showed the largest prevalence of mepolizumab and benralizumab use among the other FeNO/B-EOS, respectively. The high-FeNO/low-B-EOS showed the largest frequency of AEs, high HR, and the shortest AE-free time, among the other FeNO/B-EOS. The sputum eosinophil-predominant subtype was the great majority in the high FeNO/high B-EOS. A diverse distribution of sputum leukocyte-predominant subtype was observed in the other FeNO/B-EOS. The subsequent AE-free time and its HR were comparable among the biologics use groups.Conclusion: The strategy of classifying severe asthma based on the combination of FeNO and B-EOS proposes particular refractory type 2 severe asthma and underlying airway inflammation as a feasible trait for optimal biologics use.

Allergen immunotherapy (AIT) is a treatment in which clinically corresponding allergens are administered to patients with allergic diseases, either by subcutaneous immunotherapy (SCIT) or sublingual immunotherapy (SLIT), or by oral immunotherapy (OIT) in the case of food allergy. Since etiological allergens are administered to patients, AIT is presumed to modify mainly allergen-specific immune responses. In bronchial asthma, AIT with house dust mites (HDM) alleviates clinical symptoms, suppresses airway hyperresponsiveness, and reduces medication doses of HDM-sensitive asthmatics. Moreover, AIT can suppress the symptoms of other allergic diseases associated with asthma including allergic rhinitis. However, AIT sometimes reduces allergic symptoms not induced by the responsible allergens, such as non-targeted allergens, in clinical settings. Furthermore, AIT can suppress the spread of sensitization to new allergens that are not targeted allergens by AIT, suggesting the suppression of allergic immune responses in an allergen-nonspecific manner. In this review, the nonspecific suppression of allergic immune responses by AIT is discussed. AIT has been reported to increase regulatory T cells that produce IL-10, transforming growth factor-β, and IL-35, IL-10-producing regulatory B cells, and IL-10-producing innate lymphoid cells. These cells can suppress type-2 mediated immune responses mainly through the production of anti-inflammatory cytokines or a cell–cell contact mechanism, which may be involved in the nonspecific suppression of allergic immune responses by AIT.

A 66‐year‐old woman was admitted to our hospital with a 2‐month history of dry cough and exertional dyspnea. She had worked as a mushroom farmer and had been exposed to mushroom for more than 40 years. The patient showed elevated levels of KL‐6 (2966 U/mL) and surfactant protein D (410 ng/mL), and computed tomography of the chest revealed ground‐glass opacities and fine nodular shadows in both lungs, suggesting mushroom‐induced hypersensitivity pneumonitis. Pulmonary function testing revealed decreases in forced vital capacity (78% of predicted) and carbon monoxide diffusing capacity (67% of predicted). The inhalational provocation test was positive for bunashimeji mushrooms. Precipitating antibody was only identified for spores or bodies of bunashimeji mushrooms, and lymphocyte stimulation testing with spores or bodies of bunashimeji mushrooms also yielded positive results. Bunashimeji mushroom‐induced hypersensitivity pneumonitis was therefore diagnosed. Radiological findings and pulmonary function were improved by corticosteroid therapy and the patient has since remained healthy with allergen avoidance.

RATIONALE: The underlying molecular pathways involved in fluid extravasation and cardiovascular collapse in severe food allergy (FA) are not yet fully elucidated. METHODS: We employed BALB/c wild-type (WT), intestinal IL-9Tg and VE-specific Abl1 kinase-deficient (Cdh5 Cre Abl1 fl/fl) mice and pharmacologic inhibitors (Imatinib) and models of anaphylaxis to determine the requirement of Abl1 kinase in IgE-mediated reactions. Involvement of Abl1 kinase in histamine and IL-4-induced VE dysfunction we examined by electrophysiologic and permeability analyses on a human VE cell line (EA.hy926) following Abl1 kinase shRNA-lentiviral knockdown. RESULTS: In vitro genetic ablation of Abl1 activity revealed that histamine induced barrier dysfunction of EA.hy926 cells was dependent on Abl1 (TER (U/cm 2) : 90.2 6 11.0 WT ; 114.5 6 11.8 shRNA-Abl1; p < 0.005). Imatinib pretreatment of ovalbumin (OVA)-sensitized and orally challenged mice protected the mice from anaphylaxis as the level of hypothermia (Temperature loss (8C):-3.1 6 0.88 vehicle vs.-0.8 6 0.4 imatinib; p < 0.001); hypovolemic shock (hematocrit %: 65.9 6 9.6 vehicle; 52.21 6 2.5 imatinib; p < _ 0.01); and diarrhea (# mice with diarrhea: 8/8 vehicle vs. 3/8 imatinib; p < _ 0.05). IgE-MC activation in iIL-9Tg VED Abl1 (Tie2 Cre Abl1 fl/fl mice) revealed that loss of VE-restricted Abl1 expression attenuated the development of anaphylactic symptoms (maximum temperature loss:-2.6 6 0.76 8C iIL-9Tg VE WT ;-4.5 6 1.64 8C VED Abl1 ; p < _ 0.05). CONCLUSIONS: IgE-mediated fluid extravasation in mice is mediated by a histamine-induced VE Abl1-dependent mechanism. These studies identify a new pathway for therapeutic intervention and prevention of severe FA.