Non-eosinophilic Phenotype Research Articles

The Determinants of Eosinophilia in Patients With Severe Asthma.

Asthma is defined by the Global Initiative for Asthma (GINA) as a heterogeneous disease characterized by chronic airway inflammation. The pathogenesis of the disease is better understood with the comprehension of immunological pathways. These pathways differ by the type of recruited cells and released interleukin (IL). Thus, asthma can be classified into subtypes based on the underlying immune mechanism: eosinophilic asthma (EA) and non-eosinophilic asthma (NEA). Patients with EA tend to respond better to inhaled corticosteroid as compared to those with NEA. The distinction of EA is very important in the light of emergent type 2 inflammation targeted therapies. We performed a 1-year (2018) retrospective cohort analysis of the Nationwide Inpatient Database (NIS). We included all adult patients presenting with severe asthma. Patients were stratified into two groups: eosinophilic severe asthma and non-eosinophilic severe asthma. The primary outcomes measures were the prevalence of chronic steroid use, status asthmaticus, family history of asthma, food, drug and environmental allergies, presence of nasal polyps, allergic rhinitis, allergic dermatitis, need for mechanical ventilation, need for oxygen supplementation, gastroesophageal reflux disease, in-hospital mortality, and length of stay. We performed descriptive statistics. Continuous parametric variables were reported using a mean and standard deviation. Continuous nonparametric variables were reported using a median and interquartile range. To compare the characteristics of the two groups, we used the independent t-test for continuous parametric variables and the Mann-Whitney U test for continuous nonparametric variables. The Chi-square test was used to assess differences in categorical variables. A total of 2,646 patients were included, out of which 882 belonged to the eosinophilic group and 1,764 were in the non-eosinophilic group. Comparing EA versus NEA, we have found that eosinophilic group was characterized by higher percentage of steroid use (18.3% vs. 9.5%, P < 0.001). This group also had higher rates of status asthmaticus and positive family history (P = 0.009 and 0.004, respectively). The presence of allergies, allergic rhinitis, nasal polyps, and allergic dermatitis was higher among patients with eosinophilia. The need for mechanical ventilation and supplemental oxygen was also higher among this group (P < 0.001 for both); however, there was no significant difference in mortality rate (P = 0.347) and the length of hospital stay was similar in both groups (P < 0.001). We showed herein that the eosinophilic subtype of asthma differs widely from the non-eosinophilic phenotype. Clinically, patients with eosinophilia might exhibit different symptomatology, more atopy, and concomitant comorbidities. However, this group might have better response to steroid therapy and might benefit from the new emergent T2 immune targeted therapy. The identification of EA is crucial for better disease control.

Asthma Prevalence and Phenotyping in the General Population: The LEAD (Lung, hEart, sociAl, boDy) Study.

Asthma is a chronic heterogeneous respiratory disease involving differential pathophysiological pathways and consequently distinct asthma phenotypes. In the LEAD Study, a general population cohort (n=11.423) in Vienna ranging from 6-82 years of age, we addressed the prevalence of asthma and explored inflammatory asthma phenotypes that included allergic and non-allergic asthma, and within these phenotypes, an eosinophilic (eosinophils ≥300 cells/µL, or ≥150 cells/µL in the presence of ICS medication) or non-eosinophilic (eosinophils <300 cells/µL, or <150 cells/µL in the presence of ICS) phenotype. In addition, we compared various factors related to biomarkers, body composition, lung function, and symptoms in control subjects versus subjects with current asthma (current doctor's diagnosis of asthma). An overall prevalence of 4.6% was observed for current asthma. Furthermore, an age-dependent shift from allergic to non-allergic asthma was found. The non-eosinophilic phenotype was more prominent. Obesity was a prevalent condition, and body composition including visceral adipose tissue (VAT), is affected in current asthma versus controls. This broad-aged and large general population cohort identified differential patterns of inflammatory asthma phenotypes that were age-dependent. The presence of eosinophilia was associated with worse asthma control, increased asthma medication, increased VAT, and lower lung function, the opposite was found for the presence of an allergic asthma.

Differences in Survival of Patients With COPD According to the New GesEPOC 2021 Classification of Phenotypes

IntroductionChronic obstructive pulmonary disease (COPD) is a respiratory pathology with high prevalence, morbidity and mortality. The Spanish COPD guideline (GesEPOC) recommends individualizing treatment according to phenotypes. The phenotype classification was updated in 2021. This study aimed to determine the survival of patients by this new classification and compare the predictive capacity of mortality compared to the previous version. MethodsThis observational study of COPD patients involved prospective follow-up for 6 years. Demographic and clinical data were collected at the beginning and evolutionary data at the end of the study. Patients were classified according to GesEPOC 2017 and GesEPOC 2021. Univariate survival analysis and multivariate analysis identified mortality risk factors. ResultsOf the 273 patients, 243 (89.0%) were male. Ninety-three patients (34.1%) died during follow-up. Regarding phenotypes, 190 patients (69.6%) were non-exacerbators, 69 (25.3%) belonged to the non-eosinophilic exacerbator phenotype and 14 (5.1%) were of the eosinophilic exacerbator phenotype. Compared with non-exacerbator patients, those with the non-eosinophilic exacerbator phenotype had lower survival (p=0.009). Risk factors independently associated with mortality were older age (p<0.001), non-eosinophilic exacerbator phenotype (p=0.017) and a high Charlson index score (p<0.001). The new classification presented a worse ability to predict mortality than the previous version (area under the curve 0.632 vs 0.566, p=0.018). ConclusionPatients with the non-eosinophilic exacerbator phenotype had worse prognoses. This phenotype, advanced age and high comorbidity were mortality risk factors. The GesEPOC 2021 classification predicts mortality worse than the 2017 version. These data must be considered for more individualized management of COPD patients.

Different Airway Inflammatory Phenotypes Correlate with Specific Fungal and Bacterial Microbiota in Asthma and Chronic Obstructive Pulmonary Disease.

Background Studies of chronic airway inflammatory diseases have increasingly focused on airway microbiota. However, the microbiota characteristics of asthma and chronic obstructive pulmonary disease (COPD) patients with different airway inflammatory phenotypes remain unclear. Objective We aimed to reveal the differences of fungal and bacterial microbiota between eosinophilic asthma (EA) and noneosinophilic asthma (NEA) patients and between eosinophilic COPD (EC) and noneosinophilic COPD (NEC) patients. Further, explore whether similarities exist in the airway microbiota of patients with the same phenotype. Methods Induced sputum samples were collected from 45 asthma subjects and 39 COPD subjects. The airway microbiota of the subjects was profiled by nearly full-length 16S rRNA and internal transcribed space (ITS) sequencing. Results Subjects with eosinophilic phenotype (EA and EC) showed significant differences in both fungal and bacterial microbiota compared to the corresponding subjects with noneosinophilic phenotype (NEA and NEC). In addition, no differences were observed between the fungal microbiota of subjects with the same phenotype (EA vs. EC, NEA vs. NEC). In bacterial microbiota, the greater relative abundance of Streptococcus thermophilus was observed in EA and EC subjects, while Ochrobactrum was enriched in NEA and NEC subjects. In fungal microbiota, the EA and EC subjects showed higher relative abundances of Aspergillus and Bjerkandera, while the NEA and NEC subjects were enriched in Rhodotorula and Papiliotrema. Conclusions Different airway inflammatory phenotypes were related to specific fungal and bacterial microbiota in both asthma and COPD, while the same airway inflammatory phenotype revealed a degree of similarity in airway microbiota, particularly in fungal microbiota.

Dupilumab and tezepelumab in severe refractory asthma: new opportunities.

Bronchial asthma is a chronic inflammatory condition with increasing prevalence worldwide that may present as heterogeneous phenotypes defined by the T2-mediated pattern of airway inflammation T2-high and T2-low asthma. Severe refractory asthma includes a subset of asthmatic patients who fail to control their disease despite maximal therapy and represent a group of patients needing marked resource utilization and hence may be eligible to add-on biological therapies. Among the new biologics, we focused our attention on two monoclonal antibodies: dupilumab, exerting a dual blockade of cytokine (interleukin (IL)-4 and IL-13) signaling; and tezepelumab, acting at a higher level preventing the binding of thymic stromal lymphopoietin (TSLP) to its receptor, thus blocking TSLP, IL-25, and IL-33 signaling, hence modulating airway T2 immune responses. With their different mechanisms of action, these two biologics represent important options to provide an enhanced personalized treatment regimen. Several clinical trials have been conducted testing the efficacy and safety of dupilumab in severe refractory asthmatic patients showing improvements in lung function, asthma control, and reducing exacerbations. Similar results were reported with tezepelumab that, differently from dupilumab, acts irrespectively on eosinophilic or non-eosinophilic phenotype. In this review, we provide an overview of the most important highlights regarding dupilumab and tezepelumab characteristics and mechanism of action with a critical review of the principal results of clinical (Phase II and III) studies concluded and those still in progress.

EFFICACY OF TEZEPELUMAB IN PATIENTS WITH SEVERE, UNCONTROLLED ASTHMA GROUPED BY BASELINE BMI IN THE NAVIGATOR STUDY

EFFICACY OF TEZEPELUMAB IN PATIENTS WITH SEVERE, UNCONTROLLED ASTHMA GROUPED BY BASELINE BMI IN THE NAVIGATOR STUDY

Asthma Phenotyping in Primary Care: Applying the International Severe Asthma Registry Eosinophil Phenotype Algorithm Across All Asthma Severities

We developed an eosinophil phenotype gradient algorithm and applied it to a large severe asthma cohort (International Severe Asthma Registry). We sought to reapply this algorithm in a UK primary care asthma cohort, quantify the eosinophilic phenotype, and assess the relationship between the likelihood of an eosinophilic phenotype and asthma severity/health care resource use (HCRU). Patients age 13 years and older with active asthmaand blood eosinophil count or 1 or greater, who were included from the Optimum Patient Care Research Databaseand the Clinical Practice Research Datalink, were categorized according to the likelihood of eosinophilic phenotype using the International Severe Asthma Registry gradient eosinophilic algorithm. Patient demographic, clinicaland HCRU characteristics were described for each phenotype. Of 241,006 patients, 50.3%, 22.2%, and 21.9% most likely (grade 3), likely (grade 2), and least likely (grade 1), respectively, had an eosinophilic phenotype, and 5.6% had a noneosinophilic phenotype (grade 0). Compared with patients with noneosinophilic asthma, those most likely to have an eosinophilic phenotype tended to have more comorbidities (percentage with Charlson comorbidity index of ≥2: 28.2% vs 6.9%) and experienced more asthma attacks (percentage with one or more attack: 24.8% vs 15.3%). These patients were also more likely to have asthma that was difficult to treat (31.1% vs 18.3%), to receive more intensive treatment (percentage on Global Initiative for Asthma 2020 step 4 or 5: 44.2% vs 27.5%), and greater HCRU (eg, 10.8 vs 7.9 general practitioner all-cause consultations per year). The eosinophilic asthma phenotype predominates in primary care and is associated with greater asthma severity and HCRU. These patients may benefit from earlier and targeted asthma therapy.

Less airway inflammation and goblet cell metaplasia in an IL-33-induced asthma model of leptin-deficient obese mice

BackgroundObesity-associated asthma is a phenotype of severe asthma. Late-onset, non-eosinophilic and female-dominant phenotype is highly symptomatic and difficult to treat. Leptin, an adipokine, exerts an immunomodulatory effect. IL-33 associated with innate immunity induces type 2 inflammation and is present in adipose tissue. The purpose of this study was to elucidate the pathogenesis of obesity-associated asthma by focusing on the interaction between leptin and IL-33.MethodsIn leptin-deficient obese (ob/ob) and wild-type mice, IL-33 was instilled intranasally on three consecutive days. In part of the mice, leptin was injected intraperitoneally prior to IL-33 treatment. The mice were challenged with methacholine, and airway hyperresponsiveness (AHR) was assessed by resistance (Rrs) and elastance (Ers) of the respiratory system using the forced oscillation technique. Cell differentiation, IL-5, IL-13, eotaxin, keratinocyte-derived chemokine (KC) in bronchoalveolar lavage fluid (BALF) and histology of the lung were analyzed. For the in vitro study, NCI-H292 cells were stimulated with IL-33 in the presence or absence of leptin. Mucin-5AC (MUC5AC) levels were measured using an enzyme-linked immunosorbent assay.ResultsOb/ob mice showed greater Rrs and Ers than wild-type mice. IL-33 with leptin, but not IL-33 alone, enhanced Ers rather than Rrs challenged with methacholine in ob/ob mice, whereas it enhanced Rrs alone in wild-type mice. IL-33-induced eosinophil numbers, cytokine levels in BALF, eosinophilic infiltration around the bronchi, and goblet cell metaplasia were less in ob/ob mice than in wild-type mice. However, leptin pretreatment attenuated these changes in ob/ob mice. MUC5AC levels were increased by co-stimulation with IL-33 and leptin in vitro.ConclusionsOb/ob mice show innate AHR. IL-33 with leptin, but not IL-33 alone, induces airway inflammation and goblet cell metaplasia and enhances AHR involving peripheral airway closure. This is presumably accelerated by mucus in ob/ob mice. These results may explain some aspects of the pathogenesis of obesity-associated asthma.

Eosinophilic and Noneosinophilic Asthma: An Expert Consensus Framework to Characterize Phenotypes in a Global Real-Life Severe Asthma Cohort

Phenotypic characteristics of patients with eosinophilic and noneosinophilic asthma are not well characterized in global, real-life severe asthma cohorts. What is the prevalence of eosinophilic and noneosinophilic phenotypes in the population with severe asthma, and can these phenotypes be differentiated by clinical and biomarker variables? This was an historical registry study. Adult patients with severe asthma and available blood eosinophil count (BEC) from 11 countries enrolled in the International Severe Asthma Registry (January 1, 2015-September 30, 2019) were categorized according to likelihood of eosinophilic phenotype using a predefined gradient eosinophilic algorithm based on highest BEC, long-term oral corticosteroid use, elevated fractional exhaled nitric oxide, nasal polyps, and adult-onset asthma. Demographic and clinical characteristics were defined at baseline (ie, 1 year before or closest to date of BEC). One thousand seven hundred sixteen patients with prospective data were included; 83.8%were identified as most likely (grade 3), 8.3%were identified as likely (grade 2), and 6.3%identified as least likely (grade 1) to have an eosinophilic phenotype, and 1.6%of patients showed a noneosinophilic phenotype (grade 0). Eosinophilic phenotype patients (ie, grades 2 or 3) showed later asthma onset (29.1 years vs6.7 years; P< .001) and worse lung function (postbronchodilator %predicted FEV1, 76.1%vs89.3%; P= .027) than those with a noneosinophilic phenotype. Patients with noneosinophilic phenotypes were more likely to be women (81.5%vs62.9%; P= .047), to have eczema (20.8%vs8.5%; P= .003), and to use anti-IgE (32.1%vs13.4%; P= .004) and leukotriene receptor antagonists (50.0%vs28.0%; P= .011) add-on therapy. According to this multicomponent, consensus-driven, and evidence-based eosinophil gradient algorithm (using variables readily accessible in real life), the severe asthma eosinophilic phenotype was more prevalent than previously identified and was phenotypically distinct. This pragmatic gradient algorithm uses variables readily accessible in primary and specialist care, addressing inherent issues of phenotype heterogeneity and phenotype instability. Identification of treatable traits across phenotypes should improve therapeutic precision.

CASCADE: a phase 2, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the effect of tezepelumab on airway inflammation in patients with uncontrolled asthma

BackgroundPatients with severe, uncontrolled asthma, particularly those with a non-eosinophilic phenotype, have a great unmet need for new treatments that act on a broad range of inflammatory pathways in the airway. Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, an epithelial cytokine. In the PATHWAY phase 2b study (NCT02054130), tezepelumab reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, irrespective of baseline eosinophilic inflammatory status. This article reports the design and objectives of the phase 2 CASCADE study.MethodsCASCADE is an ongoing exploratory, phase 2, randomized, double-blind, placebo-controlled, parallel-group study aiming to assess the anti-inflammatory effects of tezepelumab 210 mg administered subcutaneously every 4 weeks for 28 weeks in adults aged 18–75 years with uncontrolled, moderate-to-severe asthma. The primary endpoint is the change from baseline to week 28 in airway submucosal inflammatory cells (eosinophils, neutrophils, T cells and mast cells) from bronchoscopic biopsies. Epithelial molecular phenotyping, comprising the three-gene-mean technique, will be used to assess participants’ type 2 (T2) status to enable evaluation of the anti-inflammatory effect of tezepelumab across the continuum of T2 activation. Other exploratory analyses include assessments of the impact of tezepelumab on airway remodelling, including reticular basement membrane thickening and airway epithelial integrity. At the onset of the COVID-19 pandemic, the protocol was amended to address the possibility that site visits would be limited. The amendment allowed for: at-home dosing of study drug by a healthcare professional, extension of the treatment period by up to 6 months so patients are able to attend an onsite visit to undergo the end-of-treatment bronchoscopy, and replacement of final follow-up visits with a virtual or telephone visit.DiscussionCASCADE aims to determine the mechanisms by which tezepelumab improves clinical asthma outcomes by evaluating the effect of tezepelumab on airway inflammatory cells and remodelling in patients with moderate-to-severe, uncontrolled asthma. An important aspect of this study is the evaluation of the anti-inflammatory effect of tezepelumab across patients with differing levels of eosinophilic and T2 inflammation.Trial registrationNCT03688074 (ClinicalTrials.gov). Registered 28 September 2018.

Neutrophil Extracellular Trapping Network Promotes the Pathogenesis of Neutrophil-associated Asthma through Macrophages

ABSTRACT Asthma is a complex airway inflammatory disease that can be roughly classified into eosinophilic phenotype and non-eosinophilic phenotype. Most of the latter manifested as airway inflammation dominated by neutrophil infiltration, namely neutrophil-dominated asthma (NA). Neutrophil extracellular trapping (NETs) is a newly discovered antimicrobial mechanism of neutrophils; however, NETs can not only resist killing pathogenic microorganisms, but also promote tissue damage and autoimmune response. In the present study, we successfully established NA model in C57BL/6 mice and observed the increased formation of NETs. In NA mice, the free DNA abundance, the airway resistance, the cell numbers (total cell number, macrophage number, and neutrophil number), and inflammatory cytokine levels were significantly increased while the lung dynamic compliance was significantly reduced. After DNase I treatment, the above indexes in NA mice were all improved. In NA mice, either treatment with macrophage scavenger or IL-1β neutralizing antibody also improved the above-described indexes. In vitro, in human peripheral blood-derived neutrophils, PMA treatment significantly increased the formation of NETs. Furthermore, in macrophages differentiated from THP-1 monocytes, LPS or isolated NETs both significantly increased the levels of cytokines. In conclusion, NETs can stimulate macrophages to secrete IL-1β, which promotes neutrophils infiltration in the airway; infiltrated neutrophils, in turn, generates NETs, which can amplify the tissue damage caused by NETs and macrophages, inducing and aggravating NA.

Asthma phenotypes and their impact on treatment

Patients with asthma can have varying characteristics, and therefore they need different treatments. Knowing asthma phenotypes can aid practice nurses to better understand how to best manage their patients' condition, as Aleksandra Gawlik-Lipinski describes Asthma is characterised by the presence of a wheeze, a cough, breathlessness, tightness in the chest and various levels of airway obstruction ( Chapman et al, 2014 , British Thoracic Society and Scottish Intercollegiate Guidelines Network, 2016 ). There is diversity among asthma patients and it was in the final decade of twentieth century that asthma was categorised into phenotypes ( Wenzel, 2012a ). A phenotype is an observable manifestation of the interaction between an individual's genotype and their environment ( Marieb and Hoehn, 2012 ). Traditionally, phenotypes are based on clinical, molecular and individual characteristics, designed to recognise different treatment requirements among asthma patients and deliver targeted therapy ( Chung et al, 2014 ). Apart from inhaled corticosteroids, eosinophilic, early- and late-onset asthma phenotypes benefit from leukotriene receptor antagonists (LTRAs) and monoclonal anti-immunoglobin E therapy; obesity-related, non-eosinophilic phenotype from weight management; and allergic bronchopulmonary mycoses from antifungal treatment ( Haldar et al, 2008 ; Moore et al, 2010 ; Wenzel, 2012b ). The treatments of early-onset, non-eosinophilic phenotype with LTRAs ( Bacci et al, 2006 ; Paggiaro and Bacci, 2011 ) and the neutrophilic phenotype solely with macrolide antibiotics ( Wenzel, 2012b ) continue to be debated.

Pattern of inflammatory phenotypes using sputum cytology among patients with asthma in a tertiary care centre, Kerala –A prospective cohort study

Background: Asthma is a chronic inflammatory airway disease in which various inflammatory cells play a pivotal role in pathogenesis. Based on the inflammatory cells count in the sputum, various inflammatory phenotypes are identified. The identification of asthma phenotypes has potential clinical significance, as natural history and treatment response differ according to phenotype. Objectives: To find out pattern of inflammatory phenotypes of asthma patients and to compare the level of asthma control after 3 months of optimized treatment in different phenotypes. Methods: We did a hospital based prospective cohort study in the Department of Pulmonary Medicine, Medical College, Thiruvananthapuram, Kerala, over a period of one year. 138 consecutive non-smoker, asthma patients were included. Sputum was examined for differential count. The phenotype was considered eosinophilic if eosinophil count was ≥3% and noneosinophilic if eosinophil count < 3%. Each patient was reassessed after 3 months of optimized treatment and level of asthma control was assessed according to GINA guidelines. Results: 53.6% of study population were in the eosinophilic and 46.4% were in the noneosinophilic phenotype. Mean age of eosinophilic phenotype was 38.4 ± 11.7 years and that of noneosinophilic was 48.8 ± 10.6 years (p<0.001). Mean BMI of eosinophilic asthma patient was 23.3 ± 2.4 and that of noneosinophilic was 24.9 ± 2.3 (p <0.001). Atopic symptoms were present in 73% of the eosinophilic phenotype and 25% of the noneosinophilic phenotype (p<0.001). There was no statistically significant difference between the two phenotypes with regard to the gender, duration of illness, family history of asthma, or initial severity of the disease. After 3 months of optimized treatment, in eosinophilic phenotype 73% of patients became controlled or partially controlled. In noneosinophilic group only 46.9% became controlled or partially controlled (p= 0.002).Conclusion: Noneosinophilic asthma occured in older, obese patients, were usually non atopic and had poor asthma control after three months optimized treatment, compared to eosinophilic phenotype. Thus phenotypic classification could help to guide clinical decisions in personalized medicine approach.

Race is associated with differences in airway inflammation in patients with asthma

African American subjects have a greater burden from asthma compared with white subjects. Whether the pattern of airway inflammation differs between African American and white subjects is unclear. We sought to compare sputum airway inflammatory phenotypes of African American and white subjects treated or not with inhaled corticosteroids (ICSs; ICS+ and ICS-, respectively). We performed a secondary analysis of self-identified African American and white subjects with asthma enrolled in clinical trials conducted by the National Heart, Lung, and Blood Institute-sponsored Asthma Clinical Research Network and AsthmaNet. Demographics, clinical characteristics, and sputum cytology after sputum induction were examined. We used a sputum eosinophil 2% cut point to define subjects with either an eosinophilic (≥2%) or noneosinophilic (<2%) inflammatory phenotype. Among 1018 participants, African American subjects (n=264) had a lower FEV1 percent predicted (80% vs 85%, P<.01), greater total IgE levels (197 vs 120 IU/mL,P<.01), and a greater proportion with uncontrolled asthma (43% vs 28%, P<.01) compared with white subjects (n=754). There were 922 subjects in the ICS+group (248 African American and 674 white subjects) and 298 subjects in the ICS- group (49 African American and 249 white subjects). Eosinophilic airway inflammation was not significantly different between African American and white subjects in either group (percentage with eosinophilic phenotype: ICS+group: 19% vs 16%, P=.28; ICS- group: 39% vs 35%, P=.65; respectively). However, when adjusted for confounding factors, African American subjects were more likely to exhibit eosinophilic airway inflammation than white subjects in the ICS+group (odds ratio, 1.58; 95% CI, 1.01-2.48; P=.046) but not in the ICS-group (P=.984). African American subjects exhibit greater eosinophilic airway inflammation, which might explain the greater asthma burden in this population.

Exacerbation risk in severe asthma is stratified by inflammatory phenotype using longitudinal measures of sputum eosinophils.

Airway inflammatory phenotyping is increasingly applied to subjects with asthma. However, its relationship to clinical outcomes in difficult asthma is incompletely elucidated. The goal of our study was to determine the relationship between exacerbation rates and phenotypes of difficult asthma based on the longitudinal measures of sputum eosinophils and neutrophils. Subjects in the longitudinal observational study from two tertiary care centres that completed 1 year of observation and provided at least three sputum samples were classified by inflammatory phenotypes using previously established thresholds. Kaplan-Meier curves and univariable and multivariable Cox proportional hazard models were used to determine the association between inflammatory phenotypes and exacerbation rate. During the study, 115 exacerbations occurred in 73 severe asthmatic subjects. Subjects with the persistently eosinophilic phenotype had a significantly shorter time to first exacerbation and greater risk of exacerbation over a 1-year period than those with the non-eosinophilic phenotype based on the univariable and multivariable Cox proportional hazard model (hazard ratio [HR], 3.24; 95% confidence interval [CI], 1.35-7.72; adjusted HR, 3.90; 95% CI, 1.34-11.36). No significant differences in time to first exacerbation or exacerbation risk over a 1-year period were observed among the neutrophilic phenotypes. The persistent eosinophilic phenotype is associated with increased exacerbation risk compared with the non-eosinophilic phenotype in severe asthma. No differences in time to first exacerbation or exacerbation risk over a 1-year period were detected among neutrophilic phenotypes.

Malaysian Nasal Polyps: Eosinophil or Neutrophil-Predominant

Eosinophil-type nasal polyp (NP) is common in Western population. This aim of this study was to determine the histology type of NP among different Malaysian ethnic groups. A total of 122 chronic rhinosinusitis with nasal polyposis (CRSwNP) patients were retrospectively enrolled and demographic data was recorded. The histological slides were retrieved. The number of eosinophils and non-eosinophils were counted and average number of inflammatory cells for each high power field was calculated. Eosinophil-predominant was seen in 32.8% of patients and 67.2% was non-eosinophil-predominant. Phenotypes of NP significantly showed an association with ethnicity (x² = 8.322; p < 0.05). A total of 78.9% of Chinese nasal polyps showed non-eosinophil predominant, while Malay and Indian nasal polyps revealed 71.9% and 40.7% of non-eosinophilic phenotype, respectively. Our study showed that Malaysian population had a non-eosinophilic phenotype of nasal polyps. There was a significant association in Malaysian ethnicity with the highest percentage in Chinese population.

Exhaled Hydrogen Sulfide Predicts Airway Inflammation Phenotype in COPD.

The role of exhaled H2S as a marker of airway inflammation and its relationship with COPD severity remain to be determined. Airway inflammation was classified in 77 COPD subjects based on the presence of inflammatory cells in induced sputum. We investigated the association between disease phenotype and exhaled H2S, lung function, and plasma levels of several inflammatory factors, including tumor necrosis factor alpha, interleukin-8, and leukotriene B4. In total, 33.77% of enrolled COPD subjects were diagnosed with eosinophilia. These subjects had a longer disease course, smoked fewer cigarettes, and experienced more frequent exacerbation events before study enrollment. However, they also had worse lung function and larger residual volume, they demonstrated greater changes in FEV1 following bronchodilator inhalation. Although levels of plasma inflammatory factors did not significantly differ between subjects with and without eosinophilia, subjects without eosinophilia had significantly higher levels of exhaled H2S (9.19±2.74 vs 7.24±1.68 parts per billion, P=.01). Furthermore, exhaled H2S levels were negatively correlated with induced sputum eosinophils (r=-0.45, P=.05), and positively correlated with inspiratory capacity in COPD subjects (r=0.51, P=.026), but did not correlate significantly with plasma inflammatory factors. A cut-off value of 7.10 parts per billion of exhaled H2S predicted a non-eosinophilic phenotype with 68.6% sensitivity and 77.9% specificity. Exhaled levels of H2S were lower in subjects with eosinophilia. Increased levels of exhaled H2S predicted a non-eosinophilic phenotype in our study population.

Altered sputum granzyme B and granzyme B/proteinase inhibitor‐9 in patients with non‐eosinophilic asthma

The non-eosinophilic phenotype of asthma (NEA) is associated with chronic airway inflammation and airway neutrophilia. An accumulation of apoptotic airway epithelial cells, if not efficiently cleared by efferocytosis, can undergo secondary necrosis, with the potential for inflammation of surrounding tissues. Apoptosis may occur via the T cell granzyme B pathway. The role of granzyme B in NEA is not known. The aim of this study was to investigate production of granzyme B and its inhibitor proteinase inhibitor (PI)-9 by T cells from induced sputum and compare expression between eosinophilic, NEA and healthy controls. We investigated T cell intracellular granzyme B and its inhibitor, PI-9, in sputum from healthy control subjects (n = 10), and patients with NEA (n = 22) or eosinophilic asthma (EA) (n = 15) using flow cytometry. Granzyme B expression and the ratio of granzyme B to PI-9 positive cells were highest in those with NEA for both CD3+ and CD4+ T cells. The expression of granzyme B was not statistically different between patients with NEA and EA; however, the ratio of granzyme B to PI-9 positive cells for CD3+ T cells was significantly higher in those with NEA compared with EA. Induced sputum provides a non-invasive tool for investigating T cell cytotoxic mediators in the various asthma subtypes. Granzyme B expression is increased in NEA and the contribution of granzyme B to chronic inflammation requires further study.

Work-exacerbated asthma and occupational asthma: Do they really differ?

Although work-exacerbated asthma (WEA) is a prevalent condition likely to have an important societal burden, there are limited data on this condition. The aims of this study were (1) to compare the clinical, functional, and inflammatory characteristics of workers with WEA and occupational asthma (OA) and (2) compare health care use and related costs between workers with WEA and OA, as well as between workers with work-related asthma (WRA; ie, WEA plus OA) and those with non-work-related asthma (NWRA) in a prospective study. We performed a prospective observational study of workers with and without WRA with a 2-year follow-up. The diagnosis of OA and WEA was based on the positivity and negativity of results on specific inhalation challenges, respectively. One hundred fifty-four subjects were enrolled: 53 with WEA, 68 with OA, and 33 control asthmatic subjects (NWRA). WEA was associated with more frequent prescriptions of inhaled corticosteroids (odds ratio [OR], 4.4; 95% CI, 1.4-13.6; P= .009), a noneosinophilic phenotype (OR, 0.3; 95% CI, 0.1-0.9; P= .04), a trend toward a lower FEV1 (OR, 0.9; 95% CI, 0.9-1.0; P= .06), and a higher proportion of smokers (OR, 2.5; 95% CI, 0.96-9.7; P= .06) than the diagnosis of OA. The health care use of WRA and related costs were 10-fold higher than those of NWRA. Workers with WEA appeared to have features of greater asthma severity than workers with OA. In contrast with OA, WEA was associated with a noneosinophilic phenotype. Both OA and WEA were associated with greater health care use and 10-fold higher direct costs than NWRA.

Both allergic and nonallergic asthma are associated with increased FENO levels, but only in never‐smokers

Allergic asthma is consistently associated with increased FE(NO) levels whereas divergence exists regarding the use of exhaled nitric oxide (NO) as marker of inflammation in nonallergic asthma and in asthmatic smokers. The aim of this study is to analyze the effect of having allergic or nonallergic asthma on exhaled nitric oxide levels, with special regard to smoking history. Exhaled NO measurements were performed in 695 subjects from Turin (Italy), Gothenburg and Uppsala (both Sweden). Current asthma was defined as self-reported physician-diagnosed asthma with at least one asthma symptom or attack recorded during the last year. Allergic status was defined by using measurements of specific immunoglobulin E (IgE). Smoking history was questionnaire-assessed. Allergic asthma was associated with 91 (60, 128) % [mean (95% CI)] increase of FE(NO) while no significant association was found for nonallergic asthma [6 (-17, 35) %] in univariate analysis, when compared to nonatopic healthy subjects. In a multivariate analysis for never-smokers, subjects with allergic asthma had 77 (27, 145) % higher FE(NO) levels than atopic healthy subjects while subjects with nonallergic asthma had 97 (46, 166) % higher FE(NO) levels than nonatopic healthy subjects. No significant asthma-related FE(NO) increases were noted for ex- and current smokers in multivariate analysis. Both allergic and nonallergic asthma are related to increased FE(NO) levels, but only in never-smoking subjects. The limited value of FE(NO) to detect subjects with asthma among ex- and current smokers suggests the predominance of a noneosinophilic inflammatory phenotype of asthma among ever-smokers.