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Background Sensitisation to moulds and Staphylococcus aureus enterotoxins (SEs) is associated with the pathophysiology of both asthma and chronic rhinosinusitis (CRS). The purpose of this study was to clarify the contribution of sensitisation to these allergens to Type 2 inflammation in the blood, nose and the lower airways, and clinical outcomes in CRS patients. Methods We prospectively enrolled 56 CRS patients who underwent endoscopic sinus surgery (ESS) (20 with comorbid asthma) and 28 healthy controls between October 2015 and December 2017. CRS patients were followed up for 12 months after surgery. Type 2 inflammation-related biomarkers were analysed using blood, resected tissue samples and sputum. 10 allergens including Alternaria, Aspergillus and SEs were measured. Type 2 inflammation-related biomarkers and clinical outcomes were compared in the stratification with the presence or absence of allergen sensitisation. Results Sensitisation rate to moulds and SEs in asthmatic patients was increased when changing the cut-off value of specific IgE titre from 0.35 UA·mL−1 to 0.10 UA·mL−1 (1.7- and 4.5-fold, respectively). Moulds and SEs affected the prevalence of asthma and eosinophilic CRS by interacting with each other. All Type 2 inflammation-related biomarkers except for eosinophils in sinus tissue were significantly higher in patients with mould or SE (mould/SE) sensitisation (≥0.10 UA·mL−1) (n=19) than in those without (n=37) and healthy subjects (all p, Alternaria, Aspergillus and S. aureus enterotoxins are important allergens affecting Type 2 inflammation and clinical outcomes in CRS patients. Sensitisation to moulds/SEs (≥0.10 UA·mL−1) would be meaningful in the pathophysiology of CRS. https://bit.ly/3bUG8ZT

Background: Periostin is an extracellular matrix protein that reflects airway epithelial injury. In asthma, periostin is considered to be useful as a biomarker of type 2 inflammation. In addition, it has been reported that periostin associates with respiratory diseases such as idiopathic pulmonary fibrosis. However, it is unknown that the relationship between periostin and other biomarkers in chronic obstructive pulmonary disease (COPD). Objective: We investigated the relationship between serum periostin levels and other biomarkers including serum markers and pulmonary function. Methods: Ninety-three COPD patients were enrolled, and we reviewed associations among serum periostin, other serum biomarkers and clinical features. Results: Fractional exhaled nitric oxide (FeNO), IgE, and age showed correlations with serum periostin levels respectively, whereas blood eosinophils and stages of COPD showed no correlations. Conclusion: Periostin may be a useful biomarker of type 2 inflammation in COPD.

Background: In severe asthma, the presence of airway eosinophilia is a key “treatable trait”. Airway eosinophilia may be proximal or distal, however work on predictors of airway eosinophilia have focussed on the proximal compartment which is less invasive to sample. The Wessex Severe Asthma Cohort (WSAC) included 342 severe asthmatics for detailed phenotyping, including bronchoalveolar lavage (BAL) and sputum induction in some participants. We aimed to use data from WSAC to determine the most accurate non-invasive predictor of eosinophilia in participants with severe asthma. Method: Severe asthmatics in WSAC were included if they underwent BAL or successful sputum induction. The value of Fraction of Exhaled Nitric Oxide (FeNO), blood eosinophil count and periostin in predicting sputum or BAL eosinophilia (3% or 1% respectively) were assessed using Receiver Operating Characteristic (ROC) curves. Results: All three measures were more accurate at predicting BAL than sputum eosinophilia. FeNO demonstrated a higher predictive value than the other measures in both compartments. Optimal thresholds were similar across compartments for FeNO but more divergent for periostin and blood. Conclusion: Within this cohort, FeNO was the strongest predictor of sputum or BAL eosinophilia. All factors assessed were stronger at predicting BAL eosinophilia than sputum.

Background: Clustering of asthma patients represent attempts to group within a continuum of disease rather than clear-cut entities. Aim: Evaluate an unbiased, multidimensional approach with multiple biomarkers. Methods: We used topological data analysis to characterize 100 adult asthmatic patients based on 21 clinical, pathophysiologic, and inflammatory parameters. In order to provide further dimensions to the clusters parameters were tested for association to particular clusters Results: Six clusters were visualized according to severity (GINA) and blood eosinophilia (Figure 1). For mild asthma, there are no specific biomarkers, besides mild eosinophilia. For moderate and severe asthma, there was a clear separation between type 2 and non-type 2 asthma. Moderate eosinophilic asthma differs by the intensity of systemic type 2 biomarkers (IL-13, IL-5, eosinophil-derived neurotoxin, periostin, blood eosinophilia) and this impacts on outcomes such as corticosteroid resistance and lung function decline. For severe asthma, we observed a non-eosinophilic cluster with increased serum eotaxin and IL-8, and a mild eosinophilic cluster characterized by low dipeptidyl-peptidase 4 inhibitor, increased exacerbation rate and late-onset asthma. Conclusion: The investigation of multiple clinical and biological biomarkers demonstrates new subendotypes and extensive subgrouping within type 2 and non-type 2 asthma

Background: Previously we showed that air-flow limitation, GG genotype of IL4RA rs8832, and A allele of ADAM33 T_2 rs2280090 were independent risks of adult asthma patients with both exacerbations and type 2-high endotype (Sunadome, et al. ATS2016). Meanwhile, little is known about risks of asthma exacerbations in type 2-low patients. Aims: To determine clinical and genetic risks that may contribute to exacerbations in asthma patients with type 2-low endotype. Methods: This is a follow-up study of asthmatics on inhaled corticosteroids treatment who were enrolled in the Kinki Hokuriku Airway disease Conference multicenter study. Associations between asthma exacerbations requiring systemic corticosteroids during the 2 years of follow-up and clinical and genetic factors were examined in patients with type 2-low endotype. Type 2-low endotype was defined as serum periostin of ORMDL3 rs7216389, IL4RA rs8832 and CDHR3 rs6967330 were assessed. Results: Among 134 type 2-low patients (106 females, average age 61.6 years), 33 had one or more exacerbations during subsequent 2 years. Multivariate analysis showed that female [Odds ratio (95% confidence interval); 7.9 (1.6-66.7), p = 0.02], body mass index [1.2 (1.1-1.5), p = 0.008], recent exacerbations [10.5 (2.5-56.0), p = 0.003], ORMDL3 rs7216389 TT genotype [3.5 (1.2-11.5), p = 0.03] and IL4RA rs8832 GG genotype [0.03 (0.001-0.024), p = 0.007] were associated with exacerbations in patients with type 2-low endotype. CDHR3 rs6967330 was unrelated to exacerbations in type 2-low patients. Conclusions: Clinical and genetic risks of asthma exacerbations may be different between type 2-high and type 2-low patients.

Background: The roles of periostin in patients with severe obstructive sleep apnea (OSA) remain unclear. Aims and objectives Serum periostin is a marker of type-2 inflammation and tends to increase in non-obese patients with asthma. Meanwhile‚ several in vitro studies suggest that impaired glycolipid metabolism, mechanical stress and hypoxia upregulate expression of periostin. Here‚ we aimed to clarify roles of periostin in patients with OSA‚ who are often obese but accompanied by these conditions. Methods: In patients diagnosed as having OSA‚ we examined associations between serum periostin levels and clinical indices‚ such as severity of OSA‚ body mass index (BMI)‚ and blood glucose and lipids. Assessments were done at baseline and after 3 months of continuous positive airway pressure (CPAP) treatment. Results: In 96 patients with OSA‚ serum periostin levels positively correlated with age and blood glucose and tended to correlate with BMI negatively (p = 0.055). When adjusted for BMI‚ severe OSA (apnea hypopnea index ≥ 30) tended to associate with elevated serum periostin (p = 0.07). Among 53 patients with severe OSA‚ patients with high serum periostin levels (highest quartile‚ ≥ 85ng⁄mL, n = 13) showed higher free fatty acid‚ fasting blood glucose and frequency of micro⁄overt albuminuria than those with severe OSA alone. In patients with severe OSA and high serum periostin‚ serum periostin and urinary albumin levels were significantly decreased after 3 months of CPAP treatment. Conclusions Serum periostin levels tend to increase in severe OSA‚ when adjusted for BMI. Elevated serum periostin in patients with severe OSA may indicate the risk of albuminuria‚ which could be reduced with CPAP treatment.

Background Serum periostin is a useful biomarker for asthma stratification. Automated periostin assays that can be applied to clinical chemistry auto-analyzers are urgently needed for routine diagnosis and to determine stepwise treatment strategies for asthma. Methods Our new automated assay utilizes latex agglutination method with anti-human periostin monoclonal antibodies. The assay was designed for use on open-platform chemistry analyzers. The reaction requires ≤10 μL of serum and can be completed in 10 min. The analytical performance of the assay and compatibility with the results obtained with a commercially available ELISA kit (Shino-Test) were assessed in 140 healthy controls, 143 asthma patients and 40 subjects of unknown clinical background. Results The dynamic range of the new latex assay was 22-1000 ng/mL. Intra-assay variations ranged from 0.8-2.1% C.V. at various concentrations. Using 6 periostin-depleted serum samples, LOB, LOD and LOQ were determined to be 2, 10 and 22 ng/mL, respectively. The median periostin level was significantly higher in asthma patients (111 ng/mL; range 38-329) than in healthy controls (93 ng/mL; range 39-217). The 40 subjects showed a strong correlation between the ELISA results and those of the new method (r=0.90, p Conclusions We report herein for the first time a newly-developed quantitative automated periostin assay for open-platform clinical chemistry analyzers. This assay is accurate and precise, simple to use, and the results correlate well with those of the conventional ELISA kit of known reliability. This method is anticipated to facilitate the diagnosis and management of asthma treatment.

Background: Periostin is a matricellular protein that is involved in the pathophysiology of upper airway diseases [UADs, primarily allergic rhinitis and chronic rhinosinusitis (CRS)] and asthma. Although serum periostin has been utilized as a therapeutic target in severe asthma, its implication in UADs in asthmatics remains unclear. We aimed to investigate the utility of serum periostin as a diagnostic biomarker in UADs in patients with asthma. M ethods: We prospectively enrolled 65 patients with stable asthma {20 without UADs, 22 with rhinitis, 21 with CRS [10 with nasal polyps (NPs), 11 without] and 2 with NPs} between July 2014 and December 2015. Serum periostin and other biomarkers were measured and compared between UAD subtypes. We evaluated the utility of each biomarker in detecting UADs, associations among each biomarker, severity of rhinitis and CRS as measured by the Lund–Mackay score (LMS) for sinus computed tomography. Results: Serum periostin levels correlated with fractional exhaled nitric oxide (FeNO) and blood/sputum eosinophil counts (r = 0.36, 0.35, and 0.44). Serum periostin levels were higher in asthmatic patients with CRS (119.8±49.1 ng/ml) than those without UADs (86.3±22.9 ng/ml) (p=0.04). Serum periostin levels in asthmatic patients with CRS with nasal polyps (NP) were significantly higher (143.3±47.6 ng/ml) than those without NP (94.0±37.7 ng/ml) (p=0.01). Serum periostin level correlated with LMS in patients with CRS (r = 0.51, p = 0.02). Conclusions: Serum periostin is a valuable biomarker of comorbid CRS detection in patients with asthma and reflecting its severity.

The importance of different markers of type-2 inflammation with regard to asthma morbidity has recently been highlighted. For example, eosinophilic inflammation has been related to reduced lung function in adults with asthma. Our aim was to analyse the relation between periostin, a novel marker of systemic type-2 inflammation, eosinophil inflammation and lung function. Measurements of serum periostin, urinary eosinophil-derived neurotoxin (U-EDN), serum eosinophil cationic protein (S-ECP) and exhaled nitric oxide (FeNO) were done in 340 adults with asthma from the Swedish GA2LEN study (see also James et al. ERS 2016 for determinants of periostin in the Swedish GA2LEN study). High biomarker levels were defined as >80 ng/mL for periostin, >77 µg/mmol creatinine (upper quartile among asthmatics) for U-EDN, >20 ng/mL for S-ECP, and >25 ppb for FeNO. Having increased periostin related to having FEV1 The results suggest that simultaneous elevation of two type-2 biomarkers, periostin and U-EDN, bring additive information in relation to reduced lung function in adult asthmatics.

Introduction: In a pivotal phase 2b trial (NCT01854047), adult patients (pts) with uncontrolled persistent asthma using ICS+LABA were randomized to 24 weeks (wks) of add-on therapy with dupilumab (DPL; an anti-IL-4Rα antibody), 200 or 300 mg every 2 weeks (q2w) or q4w, or placebo (PBO). DPL significantly reduced the rate of severe exacerbation when administered q2w. Most common adverse events (DPL vs PBO) were upper respiratory tract infections (12−15% vs 18%) and injection site erythema (8−22% vs 8%). We aimed to evaluate whether DPL, a dual antagonist of both IL-4 and IL-13, reduced severe exacerbations irrespective of baseline levels of serum periostin (PN; a biomarker of IL-13 activity). Methods: PN was assayed by ELISA (Shino-Test, Tokyo). Annualized rates of severe exacerbation in the 24-wk treatment period are given for “PN-high” and “PN-low” subgroups (≥ and Results: PN levels decreased on DPL vs PBO. Both DPL q2w regimens significantly reduced the rates of severe exacerbation in both PN-high and PN-low subgroups vs PBO. On PBO, the rate of exacerbation was 2-fold higher in PN-high vs PN-low pts. Conclusions : Dupilumab treatment, 200 and 300 mg q2w, reduces serum PN and the risk of severe exacerbation in both the more-frequently exacerbating PN-high and less-frequently exacerbating PN-low asthma pts.

Background Periostin is suggested to be a biomarker of Th2-driven asthma yet large studies examining relationships between circulating periostin and patient characteristics are lacking, and the suitability of periostin as a biomarker remains unclear. Aim To examine periostin levels in controls and well-characterised asthmatic patients from the general population, with and without chronic rhinosinusitis (CRS), in relation to other biomarkers and clinical characteristics. Methods Serum periostin was examined by ELISA in 460 asthmatics with/without CRS, 97 individuals with CRS, and 203 healthy controls from the Swedish GA(2)LEN study (age 17-76). Clinical tests included measurement of lung function, exhaled NO, IgE and urinary EPX (eosinophil protein X). Results In multiple regression analyses, periostin was associated with higher FeNO, urinary EPX and total IgE in subjects both with and without asthma. Increased age and lower BMI related to higher periostin, whereas current smoking related to lower periostin levels. Mean periostin levels were no different between subject groups. See Malinovschi et al . (ERS 2016) for further analyses of periostin and lung function in Swedish GA(2)LEN asthma patients. Conclusion We confirm associations between periostin and markers of type-2 inflammation. The effects of age, BMI and smoking need to be considered when using periostin as a biomarker in asthma.

Introduction: Elevated Th2 biomarkers may predict efficient reduction in exacerbations during the 1 st year of omalizumab treatment. Recent studies of long-term treatment with omalizumab suggest the presence of late responders, of which predictive markers remain unknown. Here we hypothesized that interleukin-18 (IL-18), a cytokine inducing IFN-γ from Th1 cells but also enhancing production of Th2 cytokines, may be a marker of late responders that show gradual reduction in exacerbations. Objectives: In this prospective and observational study, we assessed the association between baseline serum free IL-18 (fIL-18) and late response to omalizumab treatment in allergic patients with severe asthma. Methods: Patients who had completed 2 years of omalizumab treatment were recruited. At baseline, serum fIL-18 levels, in addition to Th2 biomarkers including serum periostin, were determined. Association between serum fIL-18 levels and response to treatment was assessed. Results: We enrolled 27 patients (19 females, average55.7 years old). Baseline serum IgE levels were plotted against serum fIL-18 levels in inverted V-shape. When patients were divided into 3 equal parts according to their serum fIL-18 levels, patients with top third range of serum fIL-18 showed the lowest blood eosinophil counts and serum periostin levels. They had asthma exacerbations during 1 year before and after omalizumab treatment more frequently than the remaining, but showed gradual and significant reduction in number of exacerbations over 2 years of treatment. Conclusions: Baseline serum fIL-18 levels may be associated with late response to omalizumab treatment in allergic patients with severe asthma.

Background: There few biomarkers of asthma which can be easily assessed for clinical use, especially in children. Periostin is an extracellular matrix protein and is upregulated by IL-4 and IL-13 stimulation from airway epithelial cells and other structural cells. Serum periostin is expected as a non-invasive biomarker for asthma diagnosis and management. Purpose: To assess the usefulness of serum periostin levels as a clinical biomarker of pediatric asthma. Method: 29 asthmatic children (BA) and 27 non-asthma control children (Cont) were investigated (6-16 years). Bronchial asthma was diagnosed by ISAAC medical questionnaire, and methacholine challenge test was performed for BA. Comorbid diseases including heart disease, renal disease, skeletal disease and atopic dermatitis were excluded. FeNO, lung function, blood eosinophil counts, serum levels of IgE, periostin were assessed. The diagnostic accuracy of these markers to identify asthma was calculated using receiver operating characteristics area under the curve (ROC AUC). Results: Mean PC20 of methacholine was 1.1 mg/ml. Serum periostin levels in BAwas significantly higher than in Cont (mean ± SD: 138.3 ± 34.9 vs 119.2 ± 35.0 ng/ml,p

Background: Respiratory syncytial virus (RSV)-induced bronchiolitis in infancy is a major risk factor for asthma. Recently, periostin and squamous cell carcinoma antigen (SCCA) have been suggested as non-invasive biomarkers of asthma which can be easily assessed for clinical use. Objective: To clarify the relationship between RSV airway infections with or without an increased risk of asthma and serum periostin/SCCA levels. Method: We measured the serum levels of periostin, SCCA-1 and -2 in 14 cases of RSV-bronchitis with positive modified asthma predictive index (mAPI (+)), 22 cases of RSV-bronchitis with negative mAPI, 18 cases with food allergy with no respiratory symptoms (positive control) and 18 controls. We also compared the data of RSV-bronchitis between acute and recovery phases. Results: The levels of periostin, SCCA in acute phases were significantly elevated than in recovery phases. Especially SCCA1 levels were significantly higher than in other groups. However there were no significant differences of biomarkers between the groups with or without mAPI. Conclusions: Both periostin and SCCA may play some role in the pathogenesis of RSV-induced acute bronchitis. Further research is required to clarify the role of these molecules in the airway with RSV infection, and usefulness as the biomarker in young children with recurrent wheezing or asthma.