Distinct Asthma Phenotypes Research Articles

Neutrophilic inflammation in sputum or blood does not define a clinically distinct asthma phenotype in ATLANTIS

IntroductionNeutrophilic asthma has been suggested to be a clinically distinct phenotype characterized by more severe airflow obstruction and higher exacerbation risk. However, this has only been assessed in few and smaller studies, using different cut-offs to define neutrophilia, and with conflicting results.We used data from ATLANTIS, an observational longitudinal study including a large number of patients with asthma and healthy controls.AimTo examine if neutrophilic inflammation, either in sputum or blood, is more prevalent in asthma and whether it correlates with disease severity.MethodsATLANTIS included 773 asthma patients, with blood collected from 767 (99%) and sputum from 228 patients (30%). Data were available from 244 healthy controls, all providing blood and 126 (52%) providing sputum. Asthma patients were characterized including parameters of large and small airways disease at baseline and after 6- and 12-months follow-up. Sputum and blood neutrophilia were defined as values exceeding the upper quartile in asthma patients.ResultsThe prevalence of sputum neutrophilia did not differ between asthma patients and healthy controls. Asthma patients with sputum neutrophilia did not display more severe symptoms, large or small airways disease, or more frequent exacerbations. Blood neutrophilia was more common in asthma and associated with higher BMI, female sex, current smoking and systemic corticosteroid use. Patients with blood neutrophilia had a statistically significant, but small, increase in RV/TLC. Blood neutrophilia was not associated with large or small airways disease, or exacerbation risk.ConclusionSputum and blood neutrophilia do not define a distinct clinical phenotype in asthma.

Genetic evidence on the causality between gut microbiota and various asthma phenotypes: a two-sample Mendelian randomization study.

Asthma is a multifarious disease that manifests in various phenotypes. Among the various factors that contribute to the development of asthma, the gut microbiota has recently emerged as a compelling area of investigation. This study aims to investigate the causal relationships between gut microbiota and distinct asthma phenotypes. The genome-wide association study (GWAS) summary statistics for 211 gut microbial taxa were used as study exposure. Five traits pertaining to various asthma phenotypes (asthma, allergic asthma, childhood asthma, suggestive for eosinophilic asthma and obesity-related asthma) were included as study outcome. We conducted Mendelian randomization (MR) analysis and sensitivity analysis for each bacterial taxa and asthma phenotypes. We discovered a total of 58 associations that exhibited evidence of causality. Out of these, 4 associations remained significant even after applying multiple correction. An increased risk of asthma was causally associated with higher abundance of genus Holdemanella (OR = 1.11; CI: 1.05-1.17; p = 0.027), genus Oxalobacter (OR = 1.09; CI: 1.04-1.15; p = 0.025) and genus Butyricimonas (OR = 1.14; CI: 1.06-1.22; p = 0.027). Order NB1n was causally linked with an increased risk of obesity-related asthma (OR = 1.17; CI: 1.07-1.29; p = 0.015). There was limited overlap among the taxa that exhibited potential causal relationships with distinct asthma phenotypes. Our research has provided genetic evidence that establishes multiple causal relationships between the gut microbiota and distinct asthma phenotypes, supporting the role of the gut microbiota in various asthma phenotypes. It is possible that different taxa play a role in the development of distinct asthma phenotypes. The causal relationships identified in this study require further investigation.

Complex interplay of gut microbiota between obesity and asthma in children.

Obesity is an important risk factor and common comorbidity of childhood asthma. Simultaneously, obesity-related asthma, a distinct asthma phenotype, has attracted significant attention owing to its association with more severe clinical manifestations, poorer disease control, and reduced quality of life. The establishment of the gut microbiota during early life is essential for maintaining metabolic balance and fostering the development of the immune system in children. Microbial dysbiosis influences host lipid metabolism, triggers chronic low-grade inflammation, and affects immune responses. It is intimately linked to the susceptibility to childhood obesity and asthma and plays a potentially crucial transitional role in the progression of obesity-related asthma. This review article summarizes the latest research on the interplay between asthma and obesity, with a particular focus on the mediating role of gut microbiota in the pathogenesis of obesity-related asthma. This study aims to provide valuable insight to enhance our understanding of this condition and offer preliminary evidence to support the development of therapeutic interventions.

Whispers of change in preschool asthma phenotypes: Findings in the French ELFE cohort

RationaleEarly life asthma phenotyping remains an unmet need in pediatric asthma. In France, severe pediatric asthma phenotyping has been done extensively; however, phenotypes in the general population remain underexplored. Based on the course and severity of respiratory/allergic symptoms, we aimed to identify and characterize early life wheeze profiles and asthma phenotypes in the general population. MethodsELFE is a general population based birth cohort; which recruited 18,329 newborns in 2011, from 320 maternity units nationwide. Data was collected using parental responses to modified versions of ISAAC questionnaire on eczema, rhinitis, food allergy, cough, wheezing, dyspnoea and sleep disturbance due to wheezing at 3 time points: post-natal (2 months), infancy (age 1) and pre-school (age 5). We built a supervised trajectory for wheeze profiles and an unsupervised approach was used for asthma phenotypes. Chi squared (χ2) test or fisher's exact test was used as appropriate (p < 0.05). ResultsWheeze profiles and asthma phenotypes were ascertained at age 5. Supervised wheeze trajectory of 9161 children resulted in 4 wheeze profiles: Persistent (0.8%), Transient (12.1%), Incident wheezers at age 5 (13.3%) and Non wheezers (73.9%). While 9517 children in unsupervised clusters displayed 4 distinct asthma phenotypes: Mildly symptomatic (70%), Post-natal bronchiolitis with persistent rhinitis (10.2%), Severe early asthma (16.9%) and Early persistent atopy with late onset severe wheeze (2.9%). ConclusionWe successfully determined early life wheeze profiles and asthma phenotypes in the general population of France.

Role of adiponectin, resistin and monocyte chemo-attractant protein-1 in overweight/obese asthma phenotype in children

BackgroundAsthma is a chronic inflammatory disorder of the airways with diverse overlapping pathologies and phenotypes contributing to a significant heterogeneity in clinical manifestations. Obesity may modify asthma risk, phenotype, and prognosis. A suggested mechanism linking obesity and asthma is through systemic inflammation. Adipokines secreted by adipose tissue were suggested to provide a link between obesity and asthma.ObjectiveTo have an understanding for the contribution of adiponectin, resistin and MCP-1 to development of distinct asthma phenotype in overweight/obese children through assessment of their serum level and correlation to pulmonary function tests.Subjects and methodsThe study included 29 normal weight asthmatics, 23 overweight/obese asthmatic children and 30 controls. All cases were subjected to detailed history taking, thorough examination and pulmonary function tests. Serum adiponectin, resistin, MCP-1 and IgE were assessed to all recruited subjects.ResultsAdiponectin level was significantly higher in overweight/obese asthmatics (24900 ± 1600 ng/ml) compared to normal weight asthmatics (21700 ± 1700 ng/ml) and control (23000 ± 3200 ng/ml), (p < 0.001 & 0.051 respectively). Normal weight asthmatics had significantly lower adiponectin level than control, (p = 0.039). A significant low level of MCP-1 in overweight/obese asthmatics (149.5 (20—545) ng/L) compared to control (175 (28 -1123.5) ng/L), p = 0.037. No significant difference was found regarding resistin. Normal weight asthmatics had significantly lower FEV1% and FVC% compared to overweight/obese asthmatics (p = 0.036, 0.016 respectively). A significant positive correlation was found between (FEV1%, FVC) and BMI in normal weight asthmatics (P = 0.01, < 0.01 respectively) and a significant negative correlation between PEF and BMI (-0.42, p = 0.05) in obese/overweight asthmatics. Resistin/adiponectin ratio was not affected by sex, degree of asthma severity or level of asthma control in either normal weight or overweight/obese asthmatic.ConclusionThis work could suggest that adiponectin may play a role in overweight/obese asthma phenotype where it is possible to have a dual action (pro & anti- inflammatory). It seems that resistin had no role in asthma pathogenesis.

Mechanistic Links Between Obesity and Airway Pathobiology Inform Therapies for Obesity-Related Asthma.

Obesity-related asthma is associated with a high disease burden and a poor response to existent asthma therapies, suggesting that it is a distinct asthma phenotype. The proposed mechanisms that contribute to obesity-related asthma include the effects of the mechanical load of obesity, adipokine perturbations, and immune dysregulation. Each of these influences airway smooth muscle function. Mechanical fat load alters airway smooth muscle stretch affecting airway wall geometry, airway smooth muscle contractility, and agonist delivery; weight loss strategies, including medically induced weight loss, counter these effects. Among the metabolic disturbances, insulin resistance and free fatty acid receptor activation influence distinct signaling pathways in the airway smooth muscle downstream of both the M2 muscarinic receptor and the β2 adrenergic receptor, such as phospholipase C and the extracellular signal-regulated kinase signaling cascade. Medications that decrease insulin resistance and dyslipidemia are associated with a lower asthma disease burden. Leptin resistance is best understood to modulate muscarinic receptors via the neural pathways but there are no specific therapies for leptin resistance. From the immune perspective, monocytes and T helper cells are involved in systemic pro-inflammatory profiles driven by obesity, notably associated with elevated levels of interleukin-6. Clinical trials on tocilizumab, an anti-interleukin antibody, are ongoing for obesity-related asthma. This armamentarium of therapies is distinct from standard asthma medications, and once investigated for its efficacy and safety among children, will serve as a novel therapeutic intervention for pediatric obesity-related asthma. Irrespective of the directionality of the association between asthma and obesity, airway-specific mechanistic studies are needed to identify additional novel therapeutic targets for obesity-related asthma.

Allergic Asthma in the Era of Personalized Medicine.

Allergic asthma is the most common asthma phenotype and is characterized by IgE sensitization to airborne allergens and subsequent typical asthmatic symptoms after exposure. A form of type 2 (T2) airway inflammation underlies allergic asthma. It usually arises in childhood and is accompanied by multimorbidity presenting with the occurrence of other atopic diseases, such as atopic dermatitis and allergic rhinitis. Diagnosis of the allergic endotype is based on in vivo (skin prick tests) and/or in vitro (allergen-specific IgE levels, component-resolved diagnosis (CRD)) documentation of allergic sensitization. Biomarkers identifying patients with allergic asthma include total immunoglobulin E (IgE) levels, fractional exhaled nitric oxide (FeNO) and serum eosinophil counts. The treatment of allergic asthma is a complex procedure and requires a patient-tailored approach. Besides environmental control involving allergen avoidance measurements and cornerstone pharmacological interventions based on inhaled drugs, allergen-specific immunotherapy (AIT) and biologics are now at the forefront when it comes to personalized management of asthma. The current review aims to shed light on the distinct phenotype of allergic asthma, ranging over its current definition, clinical characteristics, pathophysiology and biomarkers, as well as its treatment options in the era of precision medicine.

Role of Obesity in Inflammation and Remodeling of Asthmatic Airway.

Obesity is considered as an important risk factor for the onset of asthma and plays a key role in enhancing the disease’s severity. Obese asthmatic individuals represent a distinct phenotype of asthma that is associated with additional symptoms, more severe exacerbation, decreased response to standard medication, and poor quality of life. Obesity impairs the function of the lung airway in asthmatic individuals, leading to increased inflammation and severe remodeling of the bronchus; however, the molecular events that trigger such changes are not completely understood. In this manuscript, we review the current findings from studies that focused on understanding the role of obesity in modulating the functions of airway cells, including lung immune cells, epithelial cells, smooth muscle cells, and fibroblasts, leading to airway inflammation and remodeling. Finally, the review sheds light on the current knowledge of different therapeutic approaches for treating obese asthmatic individuals. Given the fact that the prevalence of asthma and obesity has been increasing rapidly in recent years, it is necessary to understand the molecular mechanisms that play a role in the disease pathophysiology of obese asthmatic individuals for developing novel therapies.

Immunotherapy for Asthma.

Asthma represents one of the biggest global health concerns with increasing prevalence and influence on global health. Several distinct asthma phenotypes have been identified with one of the most common, earliest recognized, and described being the allergic asthma phenotype, in which allergens trigger asthma through mechanisms involving allergen-specific immunoglobulin E (IgE). Allergen-specific immunotherapy (AIT), in the forms of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), has been used for many decades as a tool for reducing IgE-mediated sensitization and controlling symptoms of allergic disease, most commonly for allergic rhinitis, and it remains the only currently available disease modifying therapy in atopic patients. AIT has been studied for use in mild to moderate allergic asthma. While the data are often inconsistent, and utilize a multitude of different methods, antigens, and outcome measures, in general, AIT may have several beneficial effects on asthma disease control, quality of life, and requirement for medication. These benefits are notable when immunotherapy is used as an adjunct to pharmacologic treatment in carefully selected and monitored patients with mild to moderate persistent asthma. Patients with severe asthma are excluded from these trials. Importantly, patients with asthma, and in particular severe asthma, may have a higher rate of systemic adverse reactions to SCIT, including anaphylaxis; however, these events are overall rare. Future research in the area is needed to definitively assess the benefit of SCIT and SLIT for patients with asthma, comparing outcomes with different methods, addressing the role of AIT in severe asthma, significance of multiallergen AIT in allergic asthma, and safety concerns in asthma.

Phenotyping older adults with asthma by means of cluster analysis

Whereas a number of publications have identified asthma phenotypes in adults, 1 Haldar P Pavord ID Shaw DE Berry MA Thomas M Brightling CE et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008; 178: 218-224 Crossref PubMed Scopus (1492) Google Scholar few have focused only on older adults. 2 Hanania NA King MJ Braman SS Saltoun C Wise RA Enright P et al. Asthma in the elderly: current understanding and future research needs–a report of a National Institute on Aging (NIA) workshop. J Allergy Clin Immunol. 2011; 128: S4-24 Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar ,3 Baptist AP Hao W Karamched KR Kaur B Carpenter L Song PX. Distinct asthma phenotypes among older adults with asthma. J Allergy Clin Immunol Prac. 2018; 6: 244-249 Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar As a component of a randomized controlled trial of older adults (≥50 years old) with persistent asthma, Baptist et al, 3 Baptist AP Hao W Karamched KR Kaur B Carpenter L Song PX. Distinct asthma phenotypes among older adults with asthma. J Allergy Clin Immunol Prac. 2018; 6: 244-249 Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar identified 4 phenotypic clusters. The purpose of this study was to compare findings from the Baptist et al 3 Baptist AP Hao W Karamched KR Kaur B Carpenter L Song PX. Distinct asthma phenotypes among older adults with asthma. J Allergy Clin Immunol Prac. 2018; 6: 244-249 Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar study with cluster analysis findings from a cohort of older adults with asthma participating in a longitudinal observational study.

Stable and exacerbation period serum cytokine and periostin levels of the five distinct phenotypes of severe asthma.

The differences in molecular mechanisms during a stable period and the changes in the inflammatory responses during exacerbations between distinct severe asthma phenotypes remain unclear. In this study, we aimed to characterize stable and exacerbation period serum cytokine and periostin levels of 5 different predefined severe asthma phenotypes with real-life data. Changes in the viral infection-induced exacerbations were also analyzed. Serum levels of 8 cytokines and periostin were measured from the sera obtained from the adult patients with five different severe asthma phenotypes based on the presence/absence of aeroallergen sensitivity, peripheral eosinophilia and chronic rhinosinusitis with nasal polyposis (CRSwNP) during stable and exacerbation periods, and from the matched controls. Serum IL-13, IL-25, TSLP, and periostin levels were similar between the patient and the control groups during stable and exacerbation periods. Serum IL-25 and TSLP levels, and peripheral eosinophil count and periostin level showed a strong correlation. Stable period periostin levels were significantly higher in eosinophilic patients, and eosinophilic patients without long-term systemic steroid therapy had higher IL-13 levels. Compared to stable period, exacerbation period serum periostin levels found significantly lower [5853 (2309-8427) pg/mL vs. 4479 (2766-6495) pg/mL; p = 0.05] and periostin levels were much lower in viral infection-induced exacerbations [2913 (893-4770) pg/mL vs. 7094 (4782-9596) pg/mL; p = 0.022]. Our study showed that serum periostin levels were decreased in viral infection-induced exacerbations and increased in the presence of eosinophilia independent from atopy and it can help to differentiate eosinophilia even if the patient is under long-term systemic steroid therapy. Also, serum IL-13 levels may reflect peripheral eosinophilia in patients without long-term systemic steroid use.

Inhaled corticosteroid response in smoker versus non-smoker asthmatic patients: a cross-sectional study

BackgroundAsthmatic smokers are a distinct phenotype of asthma. There is a lack of specific information about the treatment of asthma in smokers. The purpose of this study was to compare the effects of inhaled corticosteroid (ICS) on asthmatic smokers and non-smokers.ResultsThe present observational, cross-sectional study was conducted at the Chest Department in Assiut University Hospital, during the period from August 2018 to January 2020. Hundred and seventeen asthmatic patients (42 smokers, 30 ex-smokers, and 45 non-smokers) were assessed using an asthma control questionnaire (ACQ), spirometry, sputum cytology, and serum periostin and eotaxin-2 to compare between a patient on inhaled corticosteroid for at least 3 months and patients who do not receive any form of corticosteroid. Asthmatic smokers had poor response to ICS and had insignificant improvement as regard all parameters. However, asthmatic ex-smokers had a partial response to ICS. They had higher post-bronchodilator FEV1 in comparison to those who did not receive ICS. Asthmatic non-smokers on ICS showed the best response as they were well controlled as regard ACQ. Moreover, they had higher post-bronchodilator FEV1/FVC, post-bronchodilator FEV1, and post-bronchodilator FEF25-75, and lower sputum eosinophils and neutrophils.ConclusionSmoking adversely affects the course and response to ICS therapy in asthma.Trial registrationInterrelation between bronchial asthma and smoking: ClinicalTrials.gov ID: NCT03207620. Registered 27 June 2017.

IL-25R+ circulating fibrocytes are increased in asthma and correlate with fixed airflow limitation.

Interleukin (IL)-25 is a T helper (Th) type-2 cytokine implicated in the pathogenesis of asthma. Fibrocytes are progenitor cells that can migrate into circulation and inflamed bronchial epithelium. We aim to test the hypothesis that circulating fibrocytes may be the novel cellular targets of IL-25 and the recruitment of IL-25R+ circulating fibrocytes may correlate with asthmatic airway obstruction. By using flow cytometry analysis, IL-25R+ fibrocytes (i.e., IL-17RB+ fibrocytes) in the freshly isolated peripheral blood mononuclear cells (PBMCs) from 15 control subjects and 35 patients with asthma were enumerated and compared. Enzyme-linked immunosorbent assay (ELISA) was used to detect the plasma levels of IL-25. We found the percentage of total and IL-25R+ (IL-17RB+ ) fibrocytes in PBMCs was significantly increased in patients with asthma when compared with control subjects. Subgroup analysis further showed that the percentage of circulating total and IL-25R+ fibrocytes in PBMCs was markedly increased in asthma patients with severe-to-very severe fixed airflow limitation. Furthermore, IL-25R+ circulating fibrocytes in asthma patients were shown to significantly correlate with forced expiratory volume in 1s/forced vital capacity (FEV1 /FVC), FEV1 % predicted, blood eosinophils, serum IgE and plasma IL-25 levels. We concluded that circulating fibrocytes are the novel potential cellular targets of IL-25. IL-25R+ fibrocytes are increased in asthma patients. Increased proportions of IL-25R+ fibrocytes predict a distinct asthma phenotype with fixed airflow limitation. Biological therapy-targeting IL-25-fibrocytes axis may offer great promise for the control of asthma patients with severe airway remodelling and obstruction.

Phénotypage de l’asthme professionnel par la réalisation d’expectoration induite après test d’exposition spécifique

RationaleAlthough the non-invasive assessment of airway inflammation through the induced sputum (IS) technique identified distinct asthma phenotypes, there is few information on the determinants of airway inflammatory pattern in sensitizer-induced occupational asthma (OA). AimTo investigate whether the pattern of airway inflammation in IS is associated with distinct clinical phenotypes of OA. MethodsThis retrospective multicentric study was conducted among 372 patients with OA confirmed by a positive specific inhalation challenge (SIC) who were recruited in the European network for the Phenotyping of OCupational Asthma cohort (2006–2018). Each patient underwent an analysis of IS before and 24 hours after the SIC. Sputum eosinophilia and neutrophilia were defined by the presence of≥3% eosinophils and≥76% neutrophils in sputum samples collected after the SIC. ResultsIn total, 268 (72%) and 42 patients (11%) exhibited sputum eosinophilia and neutrophilia, respectively. Multivariate logistic regression analysis revealed that eosinophilia was associated with exposure to a high molecular weight agent (odds ratio [OR], 1.89; 95% CI, 1.18–3.04), moderate asthma (OR, 3.17; 95% CI, 1,43–7.0) and severe asthma (OR, 2.39; 95% CI, 1.06–5.43). Sputum neutrophilia was associated with age (OR for each additional year, 1.04; 95% CI, 1.01–1.08), male gender (OR, 2.74; 95% CI, 1,21–6.8), mild asthma (OR, 3.26; 95% CI, 1.24–8.88), and dysphonia (OR, 2.83; 95% CI, 1.14–6.87). ConclusionsSputum eosinophilia post-SIC was predominant in OA patients. Sputum eosinophilia and neutrophilia were associated with distinct clinical phenotypes of OA, especially in terms of causal agents and asthma severity.

Stable and exacerbation period serum cytokine and periostin levels of the five distinct phenotypes of severe asthma.

The differences in molecular mechanisms during stable period and the changes in the inflammatory responses during exacerbations between distinct severe asthma phenotypes remain unclear. In this study, we aimed to characterize stable and exacerbation period serum cytokine and periostin levels of 5 different pre-defined severe asthma phenotypes with real-life data. Changes in the viral infection-induced exacerbations were also analyzed. Serum levels of 8 cytokines and periostin were measured from the sera obtained from the adult patients with five different severe asthma phenotypes based on the presence/absence of aeroallergen sensitivity, peripheral eosinophilia and chronic rhinosinusitis with nasal polyposis (CRSwNP) during stable and exacerbation periods, and from the matched controls. Serum IL-13, IL-25, TSLP and periostin levels were similar between the patient and the control groups during stable and exacerbation periods. Serum IL-25 and TSLP levels, and peripheral eosinophil count and periostin level showed a strong correlation. Stable period periostin levels were significantly higher in eosinophilic patients and eosinophilic patients without long-term systemic steroid therapy had higher IL-13 levels. Compared to stable period, exacerbation period serum periostin levels found significantly lower [5853 (2309-8427) pg/mL vs. 4479 (2766-6495) pg/mL; p=0.05] and periostin levels were much more lower in viral infection-induced exacerbations [2913 (893-4770) pg/mL vs. 7094 (4782-9596) pg/mL; p=0.022]. Our study showed that serum periostin levels were decreased in viral infection-induced exacerbations and increased in the presence of eosinophilia independent from atopy and it can help to differentiate eosinophilia even if the patient is under long-term systemic steroid therapy. Also, serum IL-13 levels may reflect peripheral eosinophilia in patients without long term systemic steroid use.

Longitudinal Outcomes of Severe Asthma: Real-World Evidence of Multidimensional Analyses

There have been few studies assessing long-term outcomes of asthma based on regular follow-up data. We aimed to demonstrate clinical outcomes of asthma by multidimensional analyses of a long-term real-world database and a prediction model of severe asthma using machine learning. The database included 567 severe and 1337 nonsevere adult asthmatics, who had been monitored during a follow-up of up to 10 years. We evaluated longitudinal changes in eosinophilic inflammation, lung function, and the annual number of asthma exacerbations (AEs) using a linear mixed effects model. Least absolute shrinkage and selection operator logistic regression was used to develop a prediction model for severe asthma. Model performance was evaluated and validated. Severe asthmatics had higher blood eosinophil (P= .02) and neutrophil (P < .001) counts at baseline than nonsevere asthmatics; blood eosinophil counts showed significantly slower declines in severe asthmatics than nonsevere asthmatics throughout the follow-up (P= .009). Severe asthmatics had a lower level of forced expiratory volume in 1 second (P < .001), which declined faster than nonsevere asthmatics (P= .033). Severe asthmatics showed a higher annual number of severe AEs than nonsevere asthmatics. The prediction model for severe asthma consisted of 17 variables, including novel biomarkers. Severe asthma is a distinct phenotype of asthma with persistent eosinophilia, progressive lung function decline, and frequent severe AEs even on regular asthma medication. We suggest a useful prediction model of severe asthma for research and clinical purposes.

Airway Epithelium Gene Expression Endotyping of Asthma and Airway Obstruction in Urban Children

Measurements of gene transcription in airway epithelium can provide mechanistic insights into the development of distinct asthma phenotypes. Clinical characteristics were collected prospectively from 456 children in the URECA (Urban Environment and Childhood Asthma) birth cohort through age 10 years. Children were then classified into one of six respiratory health phenotypes based upon longitudinal analysis of wheezing illnesses, aeroallergen sensitization, and lung function. Nasal epithelial brushings were obtained at age 11 years; cell differentials were assessed by cytology and nasal gene expression by RNA-sequencing. Differential gene expression was assessed by modular analysis and linear mixed-effects modeling. Through 10 years of age, 12% (56/456) of children had frequent wheezing, high levels of allergic sensitization, and evidence of airway obstruction and small airway dysfunction. Compared to the other 5 phenotypes, transcriptomic analysis of the nasal epithelium of this high-wheeze/high-atopy/low-lung-function group showed significantly elevated expression of multiple molecular modules including MUC5AC hypersecretion, leukotriene metabolism, and epithelial IL-13 response (fold changes [FC]s 1.3-2; FDRs<0.001). Another 17% (76/456) of children had moderate wheezing, but low or no allergic sensitization; this medium-wheeze/low-atopy group showed significantly decreased expression of a module of epithelial integrity and leukocyte migration genes (FC=0.9, FDR<0.001) and elevated expression of a module of epithelial injury response genes (FC=1.1, FDR<0.001). Our results demonstrate specific molecular modules are differentially expressed in the airways of children with distinct respiratory phenotypes, including allergic and non-allergic asthma. Notably, MUC5AC hypersecretion and IL-13 response over-expression are associated with a distinct respiratory phenotype that includes significant airflow obstruction.

Subphenotypes of nonsteroidal antiinflammatory disease-exacerbated respiratory disease identified by latent class analysis.

BackgroundInduced sputum (IS) allows to measure mediators of asthmatic inflammation in bronchial secretions. NSAID‐exacerbated respiratory disease (NERD) is recognized as a distinct asthma phenotype, usually with a severe course, eosinophilic airway inflammation, and increased production of pro‐inflammatory eicosanoids. A more insightful analysis of NERD patients has shown this phenotype to be nonhomogeneous.ObjectiveWe aimed to identify possible subphenotypes in a cohort of NERD patients with the means of latent class analysis (LCA).MethodsA total of 95 asthma patients with aspirin hypersensitivity underwent sputum induction. High‐performance liquid chromatography or gas chromatography coupled with mass spectrometry was used to profile eicosanoids in induced sputum supernatant (ISS). Sixteen variables covering clinical characteristics, IS inflammatory cells, and eicosanoids were considered in the LCA.ResultsThree classes (subphenotypes) were distinguished within the NERD cohort. Class 1 subjects had mild‐to‐moderate asthma, an almost equal distribution of inflammatory cell patterns, the lowest concentrations of eicosanoids, and logLTE4/logPGE2 ratio. Class 2 represented severe asthma with impaired lung function despite high doses of steroids. High sputum eosinophilia was in line with higher pro‐inflammatory LTE4 in ISS and the highest logLTE4/logPGE2 ratio. Class 3 subjects had mild‐to‐moderate asthma and were also characterized by eosinophilic airway inflammation, yet increased production of pro‐ (LTE4, PGD2 and 11‐dehydro‐TBX2) was balanced by anti‐inflammatory PGE2. The value of logLTE4/logPGE2 was between values calculated for classes 1 and 3, similarly to disease control and severity.ConclusionsLCA revealed three distinct NERD subphenotypes. Our results support a more complex pathobiology of aspirin hypersensitivity. Considering NERD heterogeneity, the relationship between inflammatory pathways and clinical manifestations of asthma may lead to more individualized treatment in difficult to treat patients in the future.

Persistent Asthma from Childhood to Adulthood Presents a Distinct Phenotype of Adult Asthma

In approximately 30% of children with asthma, the condition persists into adulthood. The longer duration of asthma in these patients is a risk factor for poor asthma control. However, the characteristics of adult patients with asthma that has persisted since childhood are not well documented. We sought to compare the clinical characteristics among patients with adult-onset asthma, patients who outgrew childhood asthma but relapsed, and patients with persistent asthma since childhood. We conducted a cross-sectional study of adult patients with asthma who visited our hospital. We classified them into 3 groups: those with adult-onset asthma (adult-onset), those who had remitted childhood asthma that relapsed (relapsed), and those who had asthma that had persisted since childhood (persistent). The clinical characteristics of these groups were compared. A total of 1443 patients were enrolled. The persistent group was younger and included fewer patients with a smoking history. There were statistically significant differences among the 3 groups in the percentages of patients with a family history of asthma and comorbidities of allergic rhinitis and atopic dermatitis. The proportion of patients with severe asthma differed among the 3 groups (31% in the adult-onset group, 34% in the relapsed group, and 40% in the persistent group; P= .015). The values of forced expiratory flow at 75% of vital capacity were lower in the persistent group than the relapsed or adult-onset group. A multivariable logistic regression analysis (dependent variable: severe asthma) in each group revealed that the factors associated with severe asthma differed among the adult-onset, relapsed, and persistent groups. When we established an overall model that included interaction terms of cohort-by-other factors, there was a trend that comorbidity of allergic rhinitis affected the severity of asthma differently in therelapsed group compared with the other groups. The clinical phenotype of asthma that persists from childhood to adulthood seems to be a distinct phenotype of adult asthma.

Distinct asthma phenotypes with low maximal attainment of lung function on cluster analysis

Objective Asthma is a heterogeneous disease with varying clinical presentations, severity and ability to achieve asthma control. The present study aimed to characterize clinical phenotypes of asthma in an Indian cohort of subjects using a cluster analysis approach. Methods Patients with confirmed asthma (N = 100) and at least 6-months of follow-up data, identified by retrospective chart review, were included in this study. Demographics, age at disease onset, disease duration, body mass index, serial spirometry and allergen sensitization were assessed. Asthma control was assessed prospectively using Global Initiative for Asthma and Asthma Control Test. R version 3.4.3 was used for statistical analysis. Ward’s minimum-variance hierarchical clustering method was performed using an agglomerative (bottom-up) approach. To compare differences between clusters, analysis of variance using Kruskal-Wallis test (continuous variables) and chi-square test (categorical variables) was used. Results Cluster analysis of 100 treatment-naive patients with asthma identified four clusters. Cluster 1, (N = 40), childhood onset of disease, normal body weight, equal gender distribution and achieved normal lung function. Cluster 2 (N = 16) included adolescent disease-onset, obese, majority males and had poor attainment of maximum lung functions. Cluster 3 (N = 20) were older, late-onset of disease, obese, majority male and had poor attainment of maximum lung function. Cluster 4 (N = 24) had adult-onset of disease, obese, predominantly female and achieved normal lung function. Conclusions In an Indian cohort of well-characterized patients with asthma, cluster analysis identified four distinct clinical phenotypes of asthma, two of which had poor attainment of maximum lung functions.