Non-eosinophilic Asthma Research Articles

Both fractional exhaled nitric oxide and sputum eosinophil were associated with uncontrolled asthma.

BackgroundSputum eosinophil and fractional exhaled nitric oxide (FeNO), noninvasive biomarkers of local eosinophilic airway inflammation, can be used to assess asthma outcome. Nevertheless, the clinical application of the association between FeNO and sputum eosinophil is controversial. The aim of the study was to investigate the predictive relationship between FeNO and sputum eosinophil in uncontrolled asthmatic patients and the correlation between sputum eosinophil and FeNO in bronchial reversibility and bronchial hyperresponsiveness (BHR).MethodsA total of 69 uncontrolled asthmatic patients were included in the study. All patients underwent a clinical assessment on the same day as follows: FeNO, spirometry with BHR or bronchodilator reversibility test and induced sputum in turn. Eosinophilic airway inflammation was defined as sputum eosinophil percentage (≥2.5%)/FeNO level (≥32 parts per billion [ppb]).ResultsFeNO level and sputum neutrophilic percentage were higher in the sputum eosinophilia group compared to those without (49 versus 27, p=0.011; 71.12 versus 87.67, p=0.012, respectively). Sputum eosinophil percentage was higher with raised FeNO level compared to those without (10.3% versus 2.75%, p=0.03). A significant correlation was observed between sputum eosinophil percentage and FeNO level (r=0.4016; p=0.0006). There were no significant relationships between sputum eosinophilic percentage and provocative dose (PD20)/ΔFEV1 (improvement in a forced expiratory volume in 1 second [FEV1] after 400μg of salbutamol), FeNO levels and PD20/ΔFEV1. The FeNO level of 35.5 ppb was effective in assessing sputum eosinophilia, with a receiver operating characteristic area under curve (AUC) of 0.707 (p=0.011; 95% confidence interval [CI] 0.573–0.841), and 4.36% was the best diagnostic cutoff value of sputum eosinophil percentage for the FeNO level of 32 ppb (AUC 0.721; 95% CI 0.59–0.852).ConclusionFeNO level can accurately detect eosinophilic asthma but has limited value to assess noneosinophilic asthma in uncontrolled stage. Further studies are required to validate the use of FeNO level to determine an optimal cutoff for sputum eosinophilia that could be used in clinical practice.

Effects of treatment changes on asthma phenotype prevalence and airway neutrophil function

BackgroundAsthma inflammatory phenotypes are often defined by relative cell counts of airway eosinophils/neutrophils. However, the importance of neutrophilia remains unclear, as does the effect of ICS treatment on asthma phenotypes and airway neutrophil function. The purpose of this study was to assess asthma phenotype prevalence/characteristics in a community setting, and, in a nested preliminary study, determine how treatment changes affect phenotype stability and inflammation, with particular focus on airway neutrophils.MethodsFifty adult asthmatics and 39 non-asthmatics were assessed using questionnaires, skin prick tests, spirometry, exhaled nitric oxide (FENO) measurement, and sputum induction. Twenty-one asthmatics underwent further assessment following treatment optimisation (n = 11) or sub-optimisation (n = 10).ResultsForty percent (20/50) had eosinophilic asthma (EA) and 8% had neutrophilic asthma. EA was associated with increased FENO, bronchodilator reversibility (BDR) and reduced lung function (p < 0.05). Following optimisation/sub-optimisation, the EA/NEA (non-eosinophilic asthma) phenotype changed in 11/21 (52%) asthmatics. In particular, fewer subjects had EA post treatment optimisation, but this was not statistically significant. However, a significant (p < 0.05) reduction in FENO, ACQ7 score, and BDR was observed after treatment optimisation, as well as an increase in FEV1-% predicted (p < 0.05). It was also associated with reduced eosinophils (p < 0.05) and enhanced neutrophil phagocytosis (p < 0.05) in EA only, and enhanced neutrophil oxidative burst in both EA and NEA (p < 0.05).ConclusionsIn this community based population, non-eosinophilic asthma was common, less severe than EA, and at baseline most asthmatics showed no evidence of inflammation. In the nested change in treatment study, treatment optimisation was associated with reduced sputum eosinophils, improved symptoms and lung function, and enhanced neutrophil function, but a significant reduction in EA could not be demonstrated.Trial registrationThe nested change in treatment component of this study is registered at the Australia and New Zealand Clinical Trial Registry (www.ANZCTR.org.au) ACTRN12617001356358. Registration date 27/09/2017. Retrospectively registered.

Sputum TWEAK expression correlates with severity and degree of control in non-eosinophilic childhood asthma.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to play a role in the pathogenesis of various inflammatory diseases. However, no study has been performed on childhood asthma. Ninety-five children with asthma and 78 controls aged 5-18years were included. Sputum induction, pulmonary function test (PFT), and methacholine challenge test were performed. The subjects were divided into the eosinophilic airway (EA) and non-EA (NEA) groups based on sputum analysis and into the high and low TWEAK groups according to the TWEAK cutoff level (263.0pg/mL). TWEAK in induced sputum supernatant was measured through enzyme-linked immunosorbent assay. Children with asthma had higher TWEAK levels than healthy controls (493.0 [157.1-904.3] vs 118.2 (67.5-345.5) pg/mL, P<.001). Sputum TWEAK levels were significantly correlated with PFT parameters reflecting airway obstruction. This association was particularly prominent in subjects with NEA inflammation. Significant differences in FEF25-75 (maximum mid-expiratory flow, % predicted; P=.017), AX (reactance area; P<.001), R5-R20 (difference between resistance at 5 and 20Hz; P=.025), and X5 (reactance at 5Hz, % predicted; P<.001) were noted between the high and low TWEAK groups within the NEA group. Sputum TWEAK level also showed significant positive correlations with asthma severity (r=.358, P=.001) and control status (r=.470, P<.001), distinctively in subjects with NEA inflammation. Airway TWEAK may play a role in small airway inflammation especially in children with non-eosinophilic asthma.

Effectiveness of inhaled corticosteroids in real life on clinical outcomes, sputum cells and systemic inflammation in asthmatics: a retrospective cohort study in a secondary care centre

ObjectivesThe impact of inhaled corticosteroids (ICS) on eosinophilic inflammation in asthma is well established, but their effect in a real-life setting has not been extensively studied. Our purpose was to...

Differential effects of obesity on eosinophilic vs. non-eosinophilic asthma subtypes

ABSTRACTObjective: Asthma is a heterogeneous disease composed of multiple disease subtypes. Obesity may worsen asthma, although the mechanism is poorly understood and its effects on different subtypes are not well characterized. We sought to determine whether obesity affects eosinophilic asthma differently from non-eosinophilic asthma. Methods: Charts of 196 persistent asthmatics were reviewed. Subjects were categorized according to BMI (obese ≥ 30 kg/m2) and blood eosinophilia based on two different cutoffs (≥200 or ≥400 cells/µl): eosinophilic, non-obese (E-NO), eosinophilic, obese (E-O), non-eosinophilic, non-obese (NE-NO), and non-eosinophilic, obese (NE-O). We analyzed clinical parameters across these groups to determine associations with obesity and/or eosinophilia. Results: Obesity was highly prevalent in our population (50.5%, 99/196). The majority of asthmatics were female (75.5%), though the ratio was lower in the E-NO group (56%). The NE-NO group was associated with lowest asthma severity, lower atopy, and less medication use. Regardless of eosinophilia, obesity was associated with higher inhaled corticosteroid doses and lower FVC% predicted than their non-obese counterparts. Obesity was associated with reduced FEV1% only in the non-eosinophilic group. Eosinophilia was also associated with reduced FEV1% in the non-obese subjects, but FEV1% was not further reduced in the E-O group compared to the E-NO and NE-O groups. Similar findings were observed regardless of whether the blood eosinophil cutoff was 200 or 400 cells/ µl. Conclusion: Multiple clinical features of asthma are adversely affected by obesity, which may affect eosinophilic and non-eosinophilic subtypes differently.

Sputum microbiota in severe asthma patients: Relationship to eosinophilic inflammation.

Altered composition of airway microbiota has been reported in subjects suffering from asthma but its relation to eosinophilic phenotype is unclear. To examine the relationship between sputum microbiota, asthma severity and inflammatory type in asthmatic subjects from Guangzhou, China. Induced sputum samples were obtained from 49 non-smoking asthma patients, 25 severe and 24 non-severe, and 15 healthy subjects. Total DNA was amplified using primers specific for the V3-V5 hypervariable region of bacterial 16s rRNA and sequenced using the 454GS FLX sequencer. Sequences were assigned to bacterial taxa by comparing them with 16s rRNA sequences in the Ribosomal Database Project. Sputum eosinophil counts were higher and FEV1 (% predicted) was lower in severe compared to non-severe asthmatics. There were no significant differences in operational taxonomic unit (OTU) numbers at the phylum level and in diversity scores between non-severe asthmatics and severe asthmatics, and healthy subjects. At the family level, Porphyromonadaceae was most abundant in healthy subjects whereas Pseudomonadaceae and Enterobacteriaceae were higher in severe asthmatics compared to non-severe asthmatics (p<0.05). Actinomycetaceae was particularly abundant in eosinophilic asthma patients compared to non-eosinophilic asthma (p=0.011). Bacteroidaceae was positively correlated with FEV1 in all subjects (r=0.335, p<0.01), whereas body mass index was negatively associated with the number of species observed (r=-0.3, p<0.05). Principal component analysis confirmed the positive association of Actinomycetaceae and Enterobacteriaceae abundance with eosinophilic asthma. Patients with asthma have an altered airway microbiota, with specific bacteria associated with severe asthma and the eosinophilic inflammatory phenotype.

Non-eosinophilic occupational asthma due to exposure of merbau and bangkirai wood.

Objectives: To evaluate association between wood dust exposure and occupational asthma, and investigate immunopathogenesis behind the disease by examining IgE, CD4, and eosinophil level.Methods: Subjects diagnosed with occupational asthma using Work Related Asthma Questionnaire and PEFR variability for two weeks. Wood dust exposure measured by personal dust sampler for two days during working time.Results: Among 104 samples, 17 % diagnosed with occupational asthma. Analysis showed that there were correlation between wood dust exposure and occupational asthma ( r) = 0,384; p = 0,000). ROC methods revealed that wood dust exposure 70,5 mg/m3/year associated with greater risk of occupational asthma, with sensitivity of 87,5 % and specificity 75 %. Wood dust exposure was significantly correlated with serum CD4 level, r 0,455, p 0,000. Eosinophil level did not correlate with CD4 level nor wood dust exposure.Conclusion: Merbau and bangkirai wood dust exposure is one of risk factor of occupational asthma. Occupational asthma due to these wood exposure is a non eosinophilic mechanism, and associated with elevated of CD4 serum level.

Asthma management: A new phenotype-based approach using presence of eosinophilia and allergy.

Asthma is a heterogeneous disease. The Czech Pneumology and Allergology Societies commissioned 10 experts to review the literature and create joint national guidelines for managing asthma, reflecting this heterogeneity. The aim was to develop an easy-to-use diagnostic strategy as a rational approach to the widening opportunities for the use of phenotype-targeted therapy. The guidelines were presented on websites for public comments by members of both the societies. The reviewers' comments contributed to creating the final version of the guidelines. The key hallmark of the diagnostic approach is the pragmatic concept, which assesses the presence of allergy and eosinophilia in each asthmatic patient. The guidelines define three clinically relevant asthma phenotypes: eosinophilic allergic asthma, eosinophilic nonallergic asthma and noneosinophilic nonallergic asthma. The resulting multifunctional classification describing the severity, level of control and phenotype is the starting point for a comprehensive treatment strategy. The level of control is constantly confronted with the intensity of the common stepwise pharmacotherapy, and the concurrently included phenotyping is essential for phenotype-specific therapy. The concept of the asthma approach with assessing the presence of eosinophilia and allergy provides a way for more precise diagnosis, which is a prerequisite for using widening options of personalized therapy.

Phenotypes of bronchial asthma

It is increasingly recognized that the bronchial asthma is a heterogeneous entity, encompassing a variety of different phenotypes. The identification of specific phenotypes is the key to develop more effective personalised treatment. The earliest attempt to phenotype asthma was proposed classifying into extrinsic and intrinsic subtypes. Clinical asthma is mainly divided into allergic (atopic) and non-allergic (non-atopic) asthma. Other phenotypes are based on trigger factors. Later the phenotyping based on the predominant cellular nature of inflammation: It can be divided into eosinophilic and non-eosinohilic. The non-eosinophilic asthma may be neutrophilic, combined, and paucigranulocytic. The discovery of Ig E represented a major breakthrough in asthma research. Ig E is an immunglobulin that plays a central role in pathomechanisms. Later identify with novel immune phenotypes: T-helper-2 high and T-helper-2 low subtypes. Neutrophilic asthma is mostly dependent of T-helper-17 cell induced mechanisms. The cluster analysis have been used increasingly to identify phenotypes. New data have been identified molecular pathways. However phenotyping of asthma is complex because of the overlap of the various phenotypes. The limitations of the studies need future research. Biomarkers e.g. levels of eosinophils in blood and sputum, exhaled nitric oxide fraction, serum immunglobulin E, serum periostin identify different asthma phenotypes. Orv. Hetil., 2017, 158(13), 491-498.

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.

Dupilumab for the treatment of asthma

ABSTRACTIntroduction: Dupilumab (REGN668/SAR231893), produced by a collaboration between Regeneron and Sanofi, is a monoclonal antibody currently in phase III for moderate-to-severe asthma. Dupilumab is directed against the α-subunit of the interleukin (IL)-4 receptor and blocks the IL-4 and IL-13 signal transduction.Areas covered: Pathophysiological role of IL-4 and IL-13 in asthma; mechanism of action of dupilumab; pharmacology of IL-4 receptor; phase I and phase II studies with dupilumab; regulatory affairs.Expert opinion: Patients with severe asthma who are not sufficiently controlled with standard-of-care represent the target asthma population for dupilumab. If confirmed, efficacy of dupilumab in both eosinophilic and non-eosinophilic severe asthma phenotype might represent an advantage over approved biologics for asthma, including omalizumab, mepolizumab, and reslizumab. Head-to-head studies to compare dupilumab versus other biologics with different mechanism of action are required. Pediatric studies with dupilumab are currently lacking and should be undertaken to assess efficacy and safety of this drug in children with severe asthma. The lack of preclinical data and published results of the completed four phase I studies precludes a complete assessment of the pharmacological profile of dupilumab. Dupilumab seems to be generally well tolerated, but large studies are required to establish its long-term safety and tolerability.

Clinical Characteristics of Exacerbation-Prone Adult Asthmatics Identified by Cluster Analysis.

PurposeAsthma is a heterogeneous disease characterized by various types of airway inflammation and obstruction. Therefore, it is classified into several subphenotypes, such as early-onset atopic, obese non-eosinophilic, benign, and eosinophilic asthma, using cluster analysis. A number of asthmatics frequently experience exacerbation over a long-term follow-up period, but the exacerbation-prone subphenotype has rarely been evaluated by cluster analysis. This prompted us to identify clusters reflecting asthma exacerbation.MethodsA uniform cluster analysis method was applied to 259 adult asthmatics who were regularly followed-up for over 1 year using 12 variables, selected on the basis of their contribution to asthma phenotypes. After clustering, clinical profiles and exacerbation rates during follow-up were compared among the clusters.ResultsFour subphenotypes were identified: cluster 1 was comprised of patients with early-onset atopic asthma with preserved lung function, cluster 2 late-onset non-atopic asthma with impaired lung function, cluster 3 early-onset atopic asthma with severely impaired lung function, and cluster 4 late-onset non-atopic asthma with well-preserved lung function. The patients in clusters 2 and 3 were identified as exacerbation-prone asthmatics, showing a higher risk of asthma exacerbation.ConclusionsTwo different phenotypes of exacerbation-prone asthma were identified among Korean asthmatics using cluster analysis; both were characterized by impaired lung function, but the age at asthma onset and atopic status were different between the two.

Noneosinophilic Severe Asthma

Asthma could be a type-I allergic airway illness characterized by Th2 cells and immunoglobulin. Episodes of cartilaginous tube inflammation, white corpuscle in nature and promoting bronchoconstriction, could become chronic and result in persistent metabolism symptoms and irreversible structural airway changes. Representative largely of delicate to moderate bronchial asthma, this clinical definition fails to account for the atypical and infrequently additional severe makeup found during a tidy proportion of asthmatics United Nations agency have augmented white blood cell counts within the airways as a characteristic attribute. Neutrophilic inflammation could be a hallmark of another sort of allergic airway pathology, hypersensitivity redness. Thought-about as associate degree immune counterpart of bronchial asthma, hypersensitivity redness could be a prototypic type-III allergic inflammatory reaction involving the alveoli and respiratory organ interstitium, steered by Th1 cells and immune serum globulin and, in its chronic type, among pathology. Though pathologically terribly completely different and ordinarily approached as separate disorders, as mentioned during this review, clinical studies also as information from animal models reveal simple parallels between each airway diseases. Danger communication induced by the matter agent or by incidental to microorganism patterns emerges as vital in facultative immune sensitization and in deciding the sort of sensitization and succeeding allergic illness. On this basis, we have a tendency to propose that allergens cause severe noneosinophilic asthma attributable to sensitization within the presence of hypersensitivity pneumonitispromoting danger communication.

Eosinophilic airway inflammation in asthmatic patients is associated with an altered airway microbiome

Asthmatic patients have higher microbiome diversity and an altered composition, with more Proteobacteria and less Bacteroidetes compared with healthy control subjects. Studies comparing airway inflammation and the airway microbiome are sparse, especially in subjects not receiving anti-inflammatory treatment. We sought to describe the relationship between the airway microbiome and patterns of airway inflammation in steroid-free patients with asthma and healthy control subjects. Bronchoalveolar lavage fluid was collected from 23 steroid-free nonsmoking patients with asthma and 10 healthy control subjects. Bacterial DNA was extracted from and subjected to Illumina MiSeq sequencing of the 16S rDNA V4 region. Eosinophils and neutrophils in the submucosa were quantified by means of immunohistochemical identification and computerized image analysis. Induced sputum was obtained, and airway hyperresponsiveness to mannitol and fraction of exhaled nitric oxide values were measured. Relationships between airway microbial diversity and composition and inflammatory profiles were analyzed. In asthmatic patients airway microbial composition was associated with airway eosinophilia and AHR to mannitol but not airway neutrophilia. The overall composition of the airway microbiome of asthmatic patients with the lowest levels of eosinophils but not asthmatic patients with the highest levels of eosinophils deviated significantly from that of healthy subjects. Asthmatic patients with the lowest levels of eosinophils had an altered bacterial abundance profile, with more Neisseria, Bacteroides, and Rothia species and less Sphingomonas, Halomonas, and Aeribacillus species compared with asthmatic patients with more eosinophils and healthy control subjects. The level of eosinophilic airway inflammation correlates with variations in the microbiome across asthmatic patients, whereas neutrophilic airway inflammation does not. This warrants further investigation on molecular pathways involved in both patients with eosinophilic and those with noneosinophilic asthma.

Targeted Therapy for Older Patients with Uncontrolled Severe Asthma: Current and Future Prospects

Severe asthma in the elderly places a high burden on affected individuals and society. Emerging therapies target specific phenotypes of the asthma disease spectrum, and can be beneficial for older asthmatics, albeit their response might be altered due to age-related characteristics. Paradoxically, these characteristics are often ground for exclusion from clinical trials. The question thus arises how the senior asthmatic population can successfully enter the era of targeted therapy. Therefore, we highlight characteristics of this population relevant to effective treatment, and review the evidence for targeted therapy in elderly patients. For targeted therapy it is important to account for aging, as this affects the distribution of phenotypes (e.g. late-onset asthma, non-eosinophilic asthma) and may alter biomarkers and drug metabolism. Elderly asthmatics suffer from age-related comorbidities and subsequent polypharmacy. A systematic search into targeted asthma therapy yielded no randomized clinical trials dedicated to older asthmatics. Post hoc analyses of the anti-immunoglobulinE agent omalizumab indicate similar efficacy in both younger and older adults. Conference abstracts on anti-interleukin-5 and anti-interleukin-13 therapy suggest even more pronounced effects of targeted treatments in late-onset disease and in asthmatic patients 65 years or older, but full reports are lacking. For non-eosinophilic asthma in the elderly, there is not yet high-level evidence for targeted therapy, but macrolides may offer a viable option. In conclusion, there is a gap in knowledge regarding the effect of older age on the safety and efficacy of targeted asthma therapy. Further investigations in the elderly are needed, with special emphasis on both late-onset asthma and therapeutics for non-eosinophilic asthma.

CT-assessed large airway involvement and lung function decline in eosinophilic asthma: The association between induced sputum eosinophil differential counts and airway remodeling

Objectives: Eosinophilic asthma (EA) is a distinct clinical phenotype characterized by eosinophilic airway inflammation and airway remodeling. Few studies have used computed tomography (CT) scanning to assess the association between sputum eosinophil differential counts and airway involvement. We aimed to investigate the clinical characteristics and airway involvement of EA, and to examine the correlation between induced sputum eosinophil differential counts and CT-assessed airway remodeling. Methods: We retrospectively divided 63 patients with stable asthma receiving inhaled corticosteroids into 2 groups: 26 patients with EA (sputum eosinophil >3%) and 37 patients with non-eosinophilic asthma (NEA). Clinical measurements such as spirometry, fractional exhaled nitric oxide levels (FeNO), and CT-assessed indices of airway involvement were compared between the groups. Multivariate analysis was performed to identify determinants of the percentage of wall area (WA%). Results: The EA group had significantly longer asthma duration, lower pulmonary function, and higher FeNO than the NEA group. Also, the EA group had higher WA% and smaller airway luminal area than the NEA group. Sputum eosinophil differential counts and WA% were positively correlated. The multivariate linear regression analysis showed that the factors associated with WA% included sputum eosinophil differential counts, age, and body mass index. However, asthma duration was not associated with WA%. Our CT-assessed findings demonstrated large airway involvement in EA, and we observed a positive association between induced sputum eosinophil differential counts and WA%. Conclusions: The findings indicate that induced sputum eosinophil differential counts may be associated with airway remodeling in patients with stable asthma.

Periostin levels and eosinophilic inflammation in poorly-controlled asthma.

BackgroundPeriostin levels are associated with airway eosinophilia and are suppressed by corticosteroid treatment in asthma. This study sought to determine the relationship between serum and sputum periostin, airway inflammatory phenotype and asthma control.MethodsAdults with poorly-controlled asthma (n = 83) underwent a clinical assessment, sputum induction and blood sampling. Dispersed sputum was used for a differential cell count and periostin assessment (ELISA). Serum periostin was determined by the Elecsys® immunoassay.ResultsPeriostin levels were significantly higher in serum (median (IQR) of 51.6 (41.8, 62.6) ng/mL) than in sputum (1.1 (0.5, 2.0) ng/mL) (p < 0.001). Serum and sputum periostin were significantly higher in patients with eosinophilic asthma (n = 37) compared with non-eosinophilic asthma. Both serum and sputum periostin levels were significantly associated with proportion of sputum eosinophils (r = 0.422, p < 0.001 and r = 0.364, p = 0.005 respectively) but were not associated with asthma control. In receiver operator characteristic curve analysis, the area under the curve (AUC) for serum periostin (n = 83) was 0.679, p = 0.007. Peripheral blood eosinophils assessed in 67 matched samples, had a numerically greater AUC of 0.820 compared with serum periostin, p = 0.086 for the detection of eosinophilic asthma.ConclusionIn poorly-controlled asthma, sputum and serum periostin levels are significantly related to sputum eosinophil proportions while their ability to predict the presence of eosinophilic asthma is modest.Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-016-0230-4) contains supplementary material, which is available to authorized users.

Epithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsiveness.

Asthma is one of the most common chronic diseases globally and can be divided into presenting with or without an immune response. Current therapies have little effect on nonimmune disease, and the mechanisms that drive this type of asthma are poorly understood. Here, we have shown that loss of the transcription factors forkhead box P1 (Foxp1) and Foxp4, which are critical for lung epithelial development, in the adult airway epithelium evokes a non-Th2 asthma phenotype that is characterized by airway hyperresponsiveness (AHR) without eosinophilic inflammation. Transcriptome analysis revealed that loss of Foxp1 and Foxp4 expression induces ectopic expression of neuropeptide Y (Npy), which has been reported to be present in the airways of asthma patients, but whose importance in disease pathogenesis remains unclear. Treatment of human lung airway explants with recombinant NPY increased airway contractility. Conversely, loss of Npy in Foxp1- and Foxp4-mutant airway epithelium rescued the AHR phenotype. We determined that NPY promotes AHR through the induction of Rho kinase activity and phosphorylation of myosin light chain, which induces airway smooth muscle contraction. Together, these studies highlight the importance of paracrine signals from the airway epithelium to the underlying smooth muscle to induce AHR and suggest that therapies targeting epithelial induction of this phenotype may prove useful in treatment of noneosinophilic asthma.

TCDD-Induced Activation of Aryl Hydrocarbon Receptor Inhibits Th17 Polarization and Regulates Non-Eosinophilic Airway Inflammation in Asthma.

The aryl hydrocarbon receptor (AhR), a transcription factor of the bHLH/PAS family, has recently been demonstrated to regulate T cell differentiation. Whether AhR activation participates in allergic airway inflammation remains unknown. In the current study, using a non-eosinophilic asthma model, we demonstrate that 2, 3, 7, 8-tetrachlorodibenzo-P-dioxin (TCDD), a potent AhR ligand, reduced the airway infiltration of neutrophils, airway hyperresponsiveness and Th17 cytokine expression. Furthermore, stimulation with TCDD promoted Treg differentiation and inhibited Th17 differentiation. However, the maturation of dendritic cells may not be inhibited by AhR activation. This study thus indicates a critical role of TCDD-induced AhR activation in the regulation of non-eosinophilic airway inflammation.

Novel approaches to the management of noneosinophilic asthma.

Noneosinophilic airway inflammation occurs in approximately 50% of patients with asthma. It is subdivided into neutrophilic or paucigranulocytic inflammation, although the proportion of each subtype is uncertain because of variable cut-off points used to define neutrophilia. This article reviews the evidence for noneosinophilic inflammation being a target for therapy in asthma and assesses clinical trials of licensed drugs, novel small molecules and biologics agents in noneosinophilic inflammation. Current symptoms, rate of exacerbations and decline in lung function are generally less in noneosinophilic asthma than eosinophilic asthma. Noneosinophilic inflammation is associated with corticosteroid insensitivity. Neutrophil activation in the airways and systemic inflammation is reported in neutrophilic asthma. Neutrophilia in asthma may be due to corticosteroids, associated chronic pulmonary infection, altered airway microbiome or delayed neutrophil apoptosis. The cause of poorly controlled noneosinophilic asthma may differ between patients and involve several mechanism including neutrophilic inflammation, T helper 2 (Th2)-low or other subtypes of airway inflammation or corticosteroid insensitivity as well as noninflammatory pathways such as airway hyperreactivity and remodelling. Smoking cessation in asthmatic smokers and removal from exposure to some occupational agents reduces neutrophilic inflammation. Preliminary studies of 'off-label' use of licensed drugs suggest that macrolides show efficacy in nonsmokers with noneosinophilic severe asthma and statins, low-dose theophylline and peroxisome proliferator-activated receptor gamma (PPARγ) agonists may benefit asthmatic smokers with noneosinophilic inflammation. Novel small molecules targeting neutrophilic inflammation, such as chemokine (CXC) receptor 2 (CXCR2) antagonists reduce neutrophils, but do not improve clinical outcomes in studies to date. Inhaled phosphodiesterase (PDE)4 inhibitors, dual PDE3 and PDE4 inhibitors, p38MAPK (mitogen-activated protein kinase) inhibitors, tyrosine kinase inhibitors and PI (phosphoinositide) 3kinase inhibitors are under development and these compounds may be of benefit in noneosinophilic inflammation. The results of clinical trials of biological agents targeting mediators associated with noneosinophilic inflammation, such as interleukin (IL)-17 and tumor necrosis factor (TNF)-α are disappointing. Greater understanding of the mechanisms of noneosinophilic inflammation in asthma should lead to improved therapies.