Long-term efficacy of house dust mite sublingual immunotherapy on clinical and pulmonary function in patients with asthma and allergic rhinitis.

Background: A previous study reported that house dust mite (HDM) sublingual immunotherapy (SLIT) for 48 weeks was effective as add-on treatment for allergic asthma; however, data regarding its long-term efficacy are scarce. Objective: We sought to evaluate the effect of HDM SLIT on asthma control, pulmonary function, and airway inflammation and remodeling throughout the 5-year treatment period. Methods: A total of 140 patients with asthma and allergic rhinitis sensitized to HDM were randomized to receive either drugs alone or drugs plus SLIT for 5 years. The 5-item Asthma Control Questionnaire (ACQ-5), Asthma Quality of Life Questionnaire (AQLQ), Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), spirometry, quantitative computed tomography, and type 2 biomarkers were assessed. Results: An improvement in the ACQ-5, AQLQ, and RQLQ scores was observed in the SLIT group compared with the control group. HDM SLIT increased lung function and reduced the percentage of airway wall area. The levels of fractional exhaled nitric oxide (Feno), blood eosinophil, serum specific IgE for HDM, and total IgE decreased and were sustained during the 5 years. The change in type 2 biomarkers correlated with change in the AQLQ score. On the basis of receiver-operating characteristic analysis for predicting responders, the area under the receiver-operating characteristic curve in FEV1% predicted, airway wall area, Feno, and specific IgE was high. Multivariate regression analysis showed that the strongest predictor of responders was Feno. Conclusions: HDM SLIT continued to provide sustained efficacy, improve lung function, and prevent progression of airway inflammation and remodeling in asthma throughout the 5-year treatment period.

Efficacy of a house dust mite sublingual immunotherapy tablet as add-on dupilumab in asthma with rhinitis.

BACKGROUND: HDM SLIT is one of the disease-modifying treatment for allergic asthma, and has demonstrated efficacy in clinical trials. Dupilumab, blocks IL-4 and IL-13 signaling, key drivers of type 2 inflammation, and is approved for patients with uncontrolled, moderate-to-severe asthma. The aim of this study was to evaluate outcomes after HDM SLIT initiation in asthma with rhinitis not optimally controlled with dupilumab in a real-world setting. METHODS: At baseline and 48 weeks after treatment, asthma control questionnaire (ACQ)-5, asthma quality of life questionnaire (AQLQ) and rhinoconjunctivitis quality of life questionnaire (RQLQ) were assessed. Spirometry, type 2 inflammatory biomarkers and quantitative computed tomographic parameters of airway remodeling were also collected. RESULTS: Of 47 patients received HDM SLIT and 41 completed the study. Combined HDM SLIT and dupilumab improved ACQ-5 (p < 0.05), AQLQ (p < 0.05), RQLQ (p < 0.05), and increased lung function and reduced FeNO (p < 0.05) and airway percentage wall area, and wall thickness (each, p < 0.05). The change in ACQ-5 and AQLQ score correlated with both changes in FeNO and FEV1 percent predicted. Multiple regression analysis showed that the change in FEV1 percent predicted was independent factor for improvement of AQLQ (r2 = 0.510, p = 0.012). Based on ROC analysis for predicting SLIT responders, the baseline area under the curves in serum HDM specific-IgE, total IgE and FEV1 percent predicted were high (>0.8). CONCLUSIONS: These results support the benefits of adding HDM SLIT to pharmacotherapy plus dupilumab in uncontrolled asthma with rhinitis.

Serum Periostin as a Biomarker for Predicting Clinical Response to House Dust Mite Sublingual Immunotherapy in Allergic Rhinitis.

BACKGROUND: House dust mite (HDM) sublingual immunotherapy (SLIT) has proven to be effective for allergic rhinitis (AR), but its efficacy varies among patients. No candidate biomarkers for prediction of response to SLIT are available. Periostin, a matricellular protein, is involved in pathophysiology of AR, and its serum levels reflect airway allergic inflammation. OBJECTIVE: To evaluate the relationship between serum periostin levels and current rhinitis control before and after standardized quality (SQ)-HDM SLIT, and to investigate the role of periostin in predicting clinical response. METHODS: One hundred eleven subjects with HDM-induced AR were randomized to receive either SLIT plus pharmacotherapy or pharmacotherapy alone, for 48 weeks. At enrollment and the end of study, clinical characteristics and biomarkers that included serum periostin, serum HDM-specific IgE (s-IgE), total IgE, blood eosinophil counts, and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) were measured. The association between clinical indices or biomarkers and clinical response to SLIT was analyzed. RESULTS: A response to SLIT was recorded in 64% (32 of 50) patients. High serum periostin levels (>30.2 ng/mL) were associated with an effective response to SLIT, and the magnitude of RQLQ improvement was correlated with the level of serum periostin. The sensitivity and specificity based on receiver operating characteristic analysis for periostin were higher than those of s-IgE. Multivariate regression analysis showed that serum periostin was an independent factor for SLIT responders. CONCLUSIONS: Serum periostin appears to be a useful biomarker for predicting the response to SQ-HDM SLIT in patients with AR.

Association between biomarkers and house dust mite sublingual immunotherapy in allergic asthma.

BACKGROUND: House dust mite (HDM) sublingual immunotherapy (SLIT) has demonstrated efficacy in clinical trials of patients with asthma. Airway inflammation is a characteristic of respiratory allergy, but its relationship to SLIT remains unclear. OBJECTIVE: We evaluate the association between clinical outcomes with pulmonary function and biomarkers in before and after HDM SLIT (UMIN Number 000022390). METHODS: One hundred twelve patients with asthma sensitized to HDM were randomized to add-on 6 standardized quality (SQ)-HDM SLIT to pharmacotherapy or pharmacotherapy alone for 48 weeks. At baseline and end of study, biomarkers, blood eosinophils, serum IgE, serum periostin, fractional exhaled nitric oxide (FeNO), and spirometry and clinical symptoms were measured. Association between biomarkers and an increase in FEV1 of 120 mL or greater were analysed. RESULTS: Sublingual immunotherapy (SLIT) demonstrated a significant reduction of serum periostin (P < .001), FeNO (P < .01), and increase in HDM-specific IgE (P < .05), FEV1 (P < .001) and improvement of clinical symptom scores, when compared to pharmacotherapy. The change in FEV1 correlated with the changes in serum periostin (r = .696, P < .001) and the changes in FeNO (r = .682, P < .001). The independent predictor of improvement in airflow limitation was changed in serum periostin (r2  = .753, P = .013) and FeNO (P = .038). Based on cut-off values derived by receiver operating characteristic analysis (periostin 30.9 ng/mL, FeNO 28.0 ppb), patients were distinguished responders from non-responders, but with no predictive value for blood eosinophils or total IgE. The proportion of patients with both high periostin and FeNO levels was significantly higher in responder than in non-responder (P = .026). CONCLUSIONS AND CLINICAL RELEVANCE: Adding HDM SLIT to pharmacotherapy resulted in reduced serum periostin and FeNO, and improved pulmonary function. Serum periostin and FeNO may be useful biomarkers for prediction of SLIT.

Effect of Sublingual Immunotherapy on Airway Inflammation and Airway Wall Thickness in Allergic Asthma.

BACKGROUND: The efficacy of the standardized quality (SQ) house dust mite (HDM) sublingual immunotherapy (SLIT) has been demonstrated for respiratory allergic disease. However, the effects of SLIT on inflammation and structural changes of the airways are still unknown. OBJECTIVE: The aim of this study was to assess the effects of the 6 SQ-HDM SLIT on airway inflammation and airway geometry in allergic asthma and rhinitis. METHODS: One hundred two asthmatic patients with rhinitis sensitized to HDM were randomized to receive either SLIT plus pharmacotherapy or standard pharmacotherapy alone, for 48 weeks. Fractional exhaled nitric oxide (FeNO), pulmonary function, quantitative computed tomography, and clinical symptoms were performed at baseline and end of the study. RESULTS: Compared with pharmacotherapy, SLIT demonstrated a significant reduction of FeNO (P < .01), airway wall area/body surface area (WA/BSA, P < .001), wall thickness (T/√BSA, P < .001), percentage wall area (WA/Ao, P < .01), increase in luminal area (Ai/BSA, P < .05), improvement of airflow limitation (P < .001), and clinical symptom scores (P < .05). The change in forced expiratory volume in 1 second (FEV1) was correlated with both changes in FeNO and airway dimensions. Multiple regression analysis showed that the change in FeNO was independently associated with an increase in FEV1 in the SLIT group (r2 = 0.623, P = .037). CONCLUSIONS: Adding 6 SQ-HDM SLIT to standard asthma therapy provides a significant improvement in symptoms and pulmonary function compared with pharmacotherapy. Improvement of airflow limitation with SLIT was associated with the decrease in eosinophilic airway inflammation.

Comparison between montelukast and tiotropium as add-on therapy to inhaled corticosteroids plus a long-acting ß2-agonist in for patients with asthma.

Objective: Asthma often remains uncontrolled despite treatment with inhaled corticosteroids (ICS) alone or with ICS plus a long-acting ß2-agonist (LABA). The recommended alternative is the addition of either montelukast or tiotropium. The aim of this study was to compare the effects of montelukast and tiotropium on airway inflammation and remodeling in persistent asthma. Methods: Eighty-seven patients with asthma were treated with budesonide and formoterol (640/18 µg); then, the patients were randomly allocated to three groups to receive oral montelukast (10 mg/day), inhaled tiotropium (5 µg/day), or no add-on to the maintenance therapy for 48 weeks. Fractional exhaled nitric oxide (FeNO) and pulmonary function were measured, and quantitative computed tomography was performed. Results: Compared to the maintenance therapy, add-on montelukast significantly decreased FeNO (p < 0.05) and improved airflow obstruction (p < 0.05), whereas airway dimensions remained unchanged. Changes in FeNO were significantly correlated with changes in FEV1 (r = -0.71, p < 0.001). In contrast, the addition of tiotropium significantly decreased airway wall area corrected for body surface area (WA/BSA) (p < 0.05), decreased wall thickness (T/√BSA) (p < 0.05) and improved airflow obstruction (p < 0.05) with no change in FeNO. Changes in WA/BSA and T/√BSA were significantly correlated with the change in percentage predicted FEV1 (r = -0.84, p < 0.001 and r = -0.59, p < 0.01, respectively). Conclusions:Adding either montelukast or tiotropium to ICS/LABA may provide additive benefits with respect to the pulmonary function and airway inflammation or remodeling in patients with asthma.

Effects of the addition of tiotropium on airway dimensions in symptomatic asthma.

BACKGROUND: Tiotropium, a once-daily, long-acting anticholinergic bronchodilator, has shown efficacy and safety as an add-on to maintenance therapy in patients with symptomatic asthma. OBJECTIVE: The aim of the present study was to assess the effect of tiotropium on airway geometry and airway inflammation in patients with asthma who were symptomatic despite treatment with inhaled corticosteroid (ICS) plus a long-acting beta 2agonist (LABA). METHODS: In total, 53 patients with symptomatic asthma who received ICS plus LABA and who had a prebronchodilator forced expiratory volume in 1 second of 6090% of the predicted value were randomized to the addition of tiotropium 5 g once daily (n = 25) or no add-on (n = 28) to maintenance therapy for 48 weeks. Quantitative computed tomography, fractional exhaled nitric oxide, and pulmonary function were measured. RESULTS: Compared with maintenance therapy, the addition of tiotropium significantly decreased airway wall area (WA) corrected for body surface area (BSA) (WA/BSA) (p 0.05) and wall thickness (T) (T/BSA, p 0.05), and improved airflow obstruction. No significant difference in the change of fractional exhaled nitric oxide was observed between the two treatment groups. Changes in WA/BSA and T/BSA were significantly correlated with the change in predicted forced expiratory volume in 1 second (r = 0.87, p 0.001, and r = 0.82, p 0.001, respectively). CONCLUSION: The addition of once-daily tiotropium to maintenance therapy improved airflow limitation and reduced airway T. A triple combination of tiotropium and ICS plus LABA may have additive protective effects of bronchodilation and remodeling.

Association of airway wall thickness with serum periostin in steroid-naive asthma.

BACKGROUND: Periostin may be a useful biomarker of T-helper type 2 eosinophilic airway inflammation and has been linked to remodeling in asthma. However, the association between serum periostin and the magnitude of airway wall thickness remains unclear. OBJECTIVE: We examined the relationship between serum periostin and airway geometry in asthma. METHODS: Twenty-six patients with steroid-naive asthma, 30 patients with asthma treated with inhaled corticosteroids, and 46 aged-matched healthy controls were studied. Serum periostin levels, lung function, and inflammatory cell counts in sputum were measured. The following parameters of airway dimension were assessed by computed tomography: lumen area, wall area (WA), WA to total area ratio, and wall thickness. RESULTS: Serum periostin levels were significantly elevated in patients with steroid-naive asthma compared with the controls (p < 0.01) and patients with asthma who were treated with steroids (p < 0.01). In patients who were steroid naive, serum periostin was correlated with air flow limitation (r = -0.62, p < 0.01) and the WA to body surface area (r = 0.71, p < 0.01), and sputum eosinophil percentage (r = 0.60, p < 0.01). Multivariate analysis showed that the percentage of predicted forced expiratory volume in 1 second, WA to body surface area, and sputum eosinophils were independent factors for high serum periostin. CONCLUSION: Serum periostin may be a candidate for a novel biomarker for not only eosinophilic inflammation but as a marker for airway remodeling in asthma.

Effect of treatment with inhaled corticosteroid on serum periostin levels in asthma.

BACKGROUND AND OBJECTIVE: Periostin is a biomarker of eosinophilic airway inflammation and may contribute to airway remodeling in asthma. The anti-inflammatory activity of inhaled corticosteroids (ICS) for asthma control is widely recognized. The aim of this study was to assess the effects of ICS on serum periostin levels and its relationships to inflammation and airway geometry. METHODS: Forty-two healthy controls and 20 patients with steroid-naïve asthma before and after treatment with fluticasone propionate (800 µg/day for 16 weeks) were examined. Serum periostin, lung function and inflammatory cell counts in sputum were measured. Airway dimensions were determined by quantitative computed tomography (total area of the airway (Ao), wall area (WA), wall thickness (T) and percentage wall area (WA%) ). RESULTS: Serum periostin concentrations were significantly higher in patients with asthma than in controls. Periostin levels were correlated with airway wall thickness and sputum eosinophilia and inversely correlated with airflow limitation in asthma. ICS significantly decreased serum periostin (P < 0.01), decreased WA corrected for body surface area (WA/BSA, P < 0.05), T/√BSA (P < 0.01) and WA% (P < 0.01), reduced the percentage of sputum eosinophils (P < 0.01) and improved airflow limitation. The decrease in serum periostin levels was associated with an increased per cent predicted forced expiratory volume in 1 s (r = -0.64, P < 0.01), decreased WA/BSA (r = 0.46, P < 0.05) and decreased sputum eosinophils (r = 0.71, P < 0.01). CONCLUSION: Serum periostin levels respond partially to ICS and may reflect a reduction in airway inflammation and wall thickening in asthma.

Comparison of airway dimensions with once daily tiotropium plus indacaterol versus twice daily Advair(®) in chronic obstructive pulmonary disease.

BACKGROUND: Current guidelines recommend combining long-acting bronchodilators with different modes of action in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). We evaluated the effects of airway dimensions and pulmonary function with tiotropium plus indacaterol versus Advair(®). METHODS: Subjects (n = 46) were randomized to receive tiotropium (18 µg once daily) plus indacaterol (150 µg once daily) or Advair(®) (50/250 µg twice daily) for 16 weeks. Airway geometry was determined by quantitative computed tomography (luminal area, Ai; total area of the airway, Ao; wall area, WA; and percentage wall area, WA/Ao and wall thickness, T). Spirometry (forced expiratory volume in 1 s, FEV1; forced vital capacity, FVC and inspiratory capacity, IC) and St. George's Respiratory Questionnaire (SGRQ) were evaluated. RESULTS: Tiotropium plus indacaterol significantly increased CT-indices including Ai corrected for body surface area (Ai/BSA), and decreased WA/BSA, WA/Ao and T/√BSA compared with Advair(®) (p < 0.05, respectively). In physiological parameters, mean difference in IC was significantly higher under treatment with tiotropium plus indacaterol than Advair(®) (p < 0.05). The changes in Ai/BSA, WA/BSA, WA/Ao and T/√BSA were significantly correlated with changes in IC (r = 0.535, p = 0.011; r = -0.688, p < 0.001; r = -0.555, p = 0.002 and r = -0.542, p = 0.007; respectively). There were more significant improvements in SGRQ scores after treatment with tiotropium plus indacaterol than Advair(®). CONCLUSIONS: These findings suggest that dual bronchodilation with tiotropium plus indacaterol is superior in airway geometry and lung function compared with Advair(®) in COPD.

Increased C-reactive protein is associated with airway wall thickness in steroid-naive asthma.

BACKGROUND: Asthma is characterized by chronic airway inflammation and remodeling. Levels of serum high-sensitivity C-reactive protein (hs-CRP) reflect airway eosinophilic inflammation. However, the relation between hs-CRP and the development of airway wall thickening remains unknown. OBJECTIVE: To evaluate whether serum hs-CRP is associated with airway geometry in asthma. METHODS: Forty-eight steroid-naive patients with asthma, 51 patients with asthma treated with inhaled corticosteroids, and 38 aged-matched healthy controls were studied cross-sectionally. Serum hs-CRP levels, lung function, and inflammatory cell counts in sputum were measured. Quantitative computed tomographic analysis of the apical segment of the right upper lobe was performed. RESULTS: Serum hs-CRP levels were significantly elevated in steroid-naive patients with asthma compared with controls and steroid-treated patients with asthma and were associated with airflow limitation. In steroid-naive patients, serum hs-CRP levels were correlated with airway wall thickness (r = 0.88, P < .001) and sputum eosinophil percentage (r = 0.75, P < .001). Multivariate analysis showed a significant association between hs-cRP levels and forced expiratory volume in 1 second (percentage predicted; R(2) = 0.65, P = .001). CONCLUSION: Serum hs-CRP may be a useful systemic biomarker of airway eosinophilia in steroid-naive asthma and has potential utility as a marker for the development of airway wall thickening. TRIAL REGISTRATION: University Hospital Medical Information Network (www.umin.ac.jp/ctr/index/htm); identifier, UMIN000006724.

Investigation of plasmonic gold-silica core-shell nanoparticle stability in dye-sensitized solar cell applications.

Plasmonic core-shell Au@SiO2 nanoparticles have previously been shown to enhance the performance of dye-sensitized solar cells (DSSCs). A thin silica coating can provide a better stability during thermal processing and chemical stability to survive the corrosive electrolyte used in DSSCs. However, the thickness and completeness of the silica shell has proven crucial for the performance of the plasmonic particles and is largely controlled by the linking chemistry between the gold core and silica shell. We have evaluated four different silica coating procedures of ∼15 nm gold nanoparticles for usage in DSSCs. The chemical stability of these core-shell nanoparticles was assessed by dispersing the particles in iodide/triiodide electrolyte solution and the thermal stability by heating the particles up to 500°C. In order to maintain stable gold cores a complete silica coating was required, which was best obtained by using a mercaptosilane as a linker. In situ TEM characterization indicated that the heating process only had minor effects on the core-shell particles. The final step was to evaluate how the stable Au@SiO2 nanoparticles were influencing a real DSSC device when mixed into the TiO2 photoanode. The plasmon-incorporated DSSCs showed a ∼10% increase in efficiency compared to devices without core-shell nanoparticles.