Fuyumi Nishihara

Omalizumab Attenuates Airway Inflammation and Interleukin-5 Production by Mononuclear Cells in Patients with Severe Allergic Asthma

Background: Omalizumab, an anti-immunoglobulin E monoclonal antibody, has shown an inhibitory effect on airway inflammation, which may be associated with clinical improvement of severe asthma. This study evaluated changes in airway inflammation and cytokine release by the peripheral blood mononuclear cells (PBMCs) of Japanese patients with severe asthma after administration of omalizumab. Methods: Sixteen Japanese patients with severe asthma who were allergic to house-dust mites were enrolled in this study. Eight received omalizumab every 2 or 4 weeks for 16 weeks, and 8 control subjects were treated with conventional drug treatment. Changes in clinical scores for sputum eosinophils and levels of fraction of exhaled nitric oxide (FeNO) were measured at the time of enrollment and at week 16. Cytokines from PBMCs stimulated by house-dust mite (Dermatophagoides farinae) or ionomycin/phorbol myristate acetate (PMA) were measured at baseline and at week 16. Results: In the omalizumab-treated group, decreases in sputum eosinophils and FeNO were observed following treatment. Furthermore, the ex vivo production of interleukin (IL)-5 by PBMCs in response to both mite allergen and ionomycin/PMA decreased significantly. In contrast, interferon (IFN)-γ production was unchanged. There were no changes in any of the parameters observed in the control group. Conclusion: Omalizumab exerts inhibitory effects on airway inflammation in Japanese patients with severe allergic asthma. This treatment attenuates production of IL-5 by PBMCs stimulated with both a specific allergen and a nonspecific activator. Reduction of the Th2 inflammatory cascade likely contributes to clinical benefits; however, further studies are required to clarify these results due to the small sample size in this study.

Effect of Formoterol on Eosinophil Trans-Basement Membrane Migration Induced by Interleukin-8-Stimulated Neutrophils

Background: Neutrophils are often increased in the airways of either chronic severe asthma or acute exacerbations. Neutrophils that have migrated in response to interleukin-8 (IL-8) may lead eosinophils to accumulate in the airways of patients with asthma and possibly aggravate the disease. In this study, we investigated whether formoterol modified the trans-basement membrane migration (TBM) of eosinophils stimulated with neutrophils and IL-8. Methods: Neutrophils and eosinophils were isolated from peripheral blood obtained from healthy donors. Eosinophil TBM was examined using a modified Boydens chamber technique. Neutrophils were preincubated with or without formoterol (0.1 μM) at 37°C for 30 min. Eosinophils were added to the upper compartment of a chamber with a Matrigel-coated transwell insert. Medium containing preincubated neutrophils and IL-8 was added to the lower compartment of the chamber. After a 90-minute incubation, the eosinophils that had migrated into the lower chamber were calculated using eosinophil peroxidase assays. Results: A combination of neutrophils and IL-8 significantly induced the eosinophil TBM; formoterol alone had no effect. However, formoterol modestly but significantly attenuated the TBM of eosinophils stimulated with neutrophils and IL-8. Conclusion: These results suggest that formoterol may act as a therapeutic agent on enhanced eosinophilic inflammation in acute exacerbation or persistent, severe asthma. The effect of formoterol likely involves the inhibition of neutrophil activation.

Trans-basement membrane migration of eosinophils induced by LPS-stimulated neutrophils from human peripheral blood in vitro

In the airways of severe asthmatics, an increase of neutrophils and eosinophils is often observed despite high-dose corticosteroid therapy. We previously reported that interleukin-8-stimulated neutrophils induced trans-basement membrane migration (TBM) of eosinophils, suggesting the link between neutrophils and eosinophils. Concentrations of lipopolysaccharide (LPS) in the airway increase in severe asthma. As neutrophils express Toll-like receptor (TLR)4 and can release chemoattractants for eosinophils, we investigated whether LPS-stimulated neutrophils modify eosinophil TBM. Neutrophils and eosinophils were isolated from peripheral blood of healthy volunteers and severe asthmatics. Eosinophil TBM was examined using a modified Boydens chamber technique. Eosinophils were added to the upper compartment, and neutrophils and LPS were added to the lower compartment. Migrated eosinophils were measured by eosinophil peroxidase assays. LPS-stimulated neutrophils induced eosinophil TBM (about 10-fold increase), although LPS or neutrophils alone did not. A leukotriene B4 receptor antagonist, a platelet-activating factor receptor antagonist or an anti-TLR4 antibody decreased eosinophil TBM enhanced by LPS-stimulated neutrophils by almost half. Neutrophils from severe asthmatics induced eosinophil TBM and lower concentrations of LPS augmented neutrophil-induced eosinophil TBM. These results suggest that the combination of neutrophils and LPS leads eosinophils to accumulate in the airways, possibly involved the pathogenesis of severe asthma. LPS-stimulated neutrophils induced eosinophil TBM, which may be involved in the pathogenesis of severe asthma http://ow.ly/UR4jP

Changes in Airway Inflammation and Hyperresponsiveness after Inhaled Corticosteroid Cessation in Allergic Asthma

Background: Most patients with asthma are currently controlled by pharmacotherapeutic means such as inhaled corticosteroid (ICS). However, whether ICS actually induces remission of asthma remains unknown. The present study evaluates changes in airway inflammation and hyperresponsiveness in adult patients with asthma after stopping ICS. Methods: We enrolled 11 patients with allergic asthma (7 males and 4 females; mean age, 52.3 years) who had been asymptomatic and had no exacerbation by low-dose ICS. Airway hyperresponsiveness (AHR) was assessed using methacholine challenge, and induced sputum was evaluated before and every 3 months after ICS cessation during the 1-year follow-up. Results: Among the 11 asthmatics, AHR increased in 10 (90.9%) and asthma clinically relapsed in 4 (36.4%) within 1 year of ICS cessation. AHR increased in all 7 asthmatics that were sensitized to Dermatophagoides farinae and asthma clinically relapsed in 4 (57.1%) of them. Furthermore, eosinophil numbers and IL-4 concentrations in the sputum significantly increased after ICS cessation. Conclusions: Remission with normal airway response to methacholine (no AHR) might be rare in adult patients with allergic asthma, and sensitization to house dust mites appears to play an important role in relapse. Therefore, ICS cessation should be carefully considered in patients sensitive to house dust mites. Serial determination of eosinophil counts or IL-4 concentrations in sputum might be appropriate for monitoring and preventing asthma relapse in adults.

Eosinophil transendothelial migration induced by the bronchoalveolar lavage fluid of acute eosinophilic pneumonia

Acute eosinophilic pneumonia (AEP) is characterized by a massive pulmonary infiltration of eosinophils. Mechanisms regulating the selective accumulation of eosinophils in AEP have not been fully established. The objective of this study was to evaluate the mechanisms of eosinophil accumulation in alveolar spaces through examination of bronchoalveolar lavage fluid (BALF) from AEP patients (AEP‐BALF).

Mycobacterium gordonae-induced humidifier lung

BackgroundNontuberculous mycobacteria are well known to be a cause of hot tub lung, however, to our knowledge, there exists no case report of humidifier lung induced by mycobacteria.Case presentationA case of a nonimmunocompromised female patient with Mycobacterium gordonae-induced humidifier lung is described. She spontaneously recovered after discontinuing ultrasonic humidifier use. When subjected to a provocation test, she demonstrated acute respiratory distress with signs and symptoms, consistent with hypersensitivity pneumonitis. Before and after the provocation test, water in the humidifier reservoir revealed only Mycobacterium gordonae by the microbiologic analyses.ConclusionTo our knowledge, this is the first report of humidifier lung induced by nontuberculous mycobacteria. Although nontuberculous mycobacteria are well-known to be agents of hot tub lung or metal working fluid lung, physicians should also consider the pathogen as a cause of hypersensitivity lung reaction associated with humidifier use.

Combination therapy with carboplatin and paclitaxel for small cell lung cancer

BACKGROUND Although small cell lung cancer (SCLC) is an aggressive cancer, few useful treatment options exist after relapse. Information concerning the efficacy and safety of carboplatin plus paclitaxel in patients with SCLC is limited. METHODS From April 2007 to October 2016, 318 patients with SCLC received chemotherapy at our institution. The medical records of patients treated with carboplatin and paclitaxel after first-line chemotherapy with platinum plus etoposide or irinotecan were retrospectively analyzed. The objectives were to investigate the frequency at which a carboplatin and paclitaxel regimen was administered to patients with SCLC in clinical practice, and to determine the response rate, progression-free survival (PFS), and tolerability of such agents. RESULTS A total of 24 (7.5%) patients (male, n = 21; female, n = 3; median age, 67 years; performance status, 0-1/≥2, 15/8 patients; limited/extensive disease, 6/15 patients; sensitive/refractory relapse, 3/21 patients) were treated with carboplatin plus paclitaxel. This regimen was chosen due to interstitial lung disease (ILD) (n = 17), radiation pneumonitis (n = 3), combination with palliative radiation therapy (n = 2), and the presence of other cancers (n = 2). The response rate was 33.3%, and the disease control rate was 62.5%. The median PFS and overall survival were 4.1 and 8.7 months, respectively. Grade 3/4 hematologic toxicities observed included neutropenia (54.2%), anemia (4.2%), and thrombocytopenia (8.3%). With the exception of grade 3 neuropathies (n = 2), non-hematologic toxicities were mild. No patients experienced an acute exacerbation of ILD. CONCLUSION A combination of carboplatin plus paclitaxel as second-line chemotherapy is effective and feasible in patients with SCLC, especially in those with ILD.

155 Omalizumab Improves Asthma but not Nasal Symptoms in Japanese Patients With Severe Allergic Asthma and Rhinitis.

Background There is evidence that humanized monoclonal antibody against IgE (Omalizumab) is effective in severe allergic asthma. In this study, we examined the effectiveness of omalizumab on asthma and nasal symptoms in Japanese patients with severe allergic asthma and rhinitis. Methods An open-label study that enrolled 7 patients with both severe allergic asthma and rhinitis who visited Allergy Center, Saitama Medical University was performed. All patients presented uncontrolled asthma despite medication including high-dose inhalational corticosteroids, long-acting beta2-agonist, leukotriene receptor antagonist, theophylline, and oral predonisolone. Omalizumab was added on their treatments and symptoms score using Asthma Contol Test (ACT), peak expiratory flow rate (PEFR), exhaled nitric oxide (eNO), sputum eosinophils and nasal symptoms were evaluated before and 12 to 16 weeks after omalizumab. Results Omalizumab significantly improved ACT scores especially dose of rescue use of short-acting beta2-agonist (P < 0.05) and PEFR (P < 0.05). Furthermore, omalizumab significantly decreased exhaled both eNO (P < 0.05) and the percentage of eosinophils in induced sputum. On the other hand, nasal symptoms were not change following induction of omalizumab. Conclusions Clinical effectiveness of omalizumab was confirmed in Japanese population of severe allergic asthma, but not rhinitis. The therapeutic potency of omalizumab on asthma likely involves anti-inflammatory properties such as decreasing eNO or airway eosinophilia.

64 Effect of Formoterol on Eosinophil Trans-Basement Migration Induced by Interleukin-8-Stimulated Neutrophils.

Background Neutrophils are often increased in the airways of either chronic severe disease or acute exacerbation of asthma. Neutrophils migrated in response to interleukin-8 (IL-8) may lead eosinophils to accumulate in the airways of asthma and possibly aggravate this disease. In this study, we investigated whether formoterol modify the trans-basement membrane migration (TBM) of eosinophils stimulated with neutrophils and IL-8. Methods Neutrophils and eosinophils were isolated from peripheral blood obtained from healthy donors. The TBM of eosinophils was examined using a modified Boydens chamber technique. Neutrophils were preincubated with or without formoterol (0.1 &mgr;M) at 37°C for 30 minutes. Eosinophils were added to the upper compartment of a chamber with a Matrigel-coated transwell insert. Medium that contained preincubated neutrophils and IL-8 was added to the lower compartment of the chamber. After 90 minute incubation, migrated eosinophils in the lower chamber were calculated using eosinophil peroxidase assays. Results A combination of neutrophils and IL-8 significantly induced TBM of eosinophils. Formoterol by itself did not modify the TBM of eosinophils. However, formoterol significantly attenuated TBM of eosinophils stimulated with neutrophils and IL-8. Conclusions These results suggest that formoterol may act as a therapeutic agent on enhanced eosinophilic inflammation in acute exacerbation or persistent severe disease of asthma. This effect of formoterol likely involves inhibition of activation of neutrophils.