Specific Asthma Phenotypes Research Articles

Contribution of Gestational Weight Gain to Childhood Asthma Phenotypes: A Prospective Cohort Study

BackgroundThe contribution of prenatal anthropometric measures to the development of specific childhood asthma phenotypes is not known. ObjectiveWe aimed to evaluate associations between prepregnancy body mass index (BMI) and gestational weight gain (GWG) with allergic and non-allergic asthma phenotypes in childhood. MethodsOur study population included term, healthy infants in the middle Tennessee region of the United States. Prepregnancy BMI and GWG were ascertained from questionnaires administered during early infancy and categorized based on World Health Organization (WHO) and Institute of Medicine (IOM) recommendations, respectively. Allergic asthma was defined as 5-year current asthma and a positive skin test or specific IgE to aeroallergen(s). We used multivariable logistic regression models for asthma and multinomial logistic regression models for non-asthma, allergic asthma, and non-allergic asthma. ResultsA total of 1,266 children were included. At the 5-year follow-up, 194 (15.3%) had asthma; among them, 102 (52.6%) had allergic asthma. Both inadequate and excessive GWG, compared to adequate GWG, were associated with increased odds of asthma (inadequate: aOR 1.76 [95% CI: 1.03–2.98]; excessive: aOR 1.70 [95% CI: 1.12–2.57]) and increased odds of allergic asthma compared to no asthma (inadequate: aOR 3.49 [95% CI: 1.66–7.32]; excessive: aOR 2.55 [95% CI: 1.34–4.85]). Prepregnancy BMI was not associated with asthma nor with asthma phenotypes. ConclusionBoth inadequate and excessive GWG were associated with allergic asthma risk. These results support the benefits of optimal GWG during pregnancy on child health outcomes.

Unraveling the Link between Ιnsulin Resistance and Bronchial Asthma.

Evidence from large epidemiological studies has shown that obesity may predispose to increased Th2 inflammation and increase the odds of developing asthma. On the other hand, there is growing evidence suggesting that metabolic dysregulation that occurs with obesity, and more specifically hyperglycemia and insulin resistance, may modify immune cell function and in some degree systemic inflammation. Insulin resistance seldom occurs on its own, and in most cases constitutes a clinical component of metabolic syndrome, along with central obesity and dyslipidemia. Despite that, in some cases, hyperinsulinemia associated with insulin resistance has proven to be a stronger risk factor than body mass in developing asthma. This finding has been supported by recent experimental studies showing that insulin resistance may contribute to airway remodeling, promotion of airway smooth muscle (ASM) contractility and proliferation, increase of airway hyper-responsiveness and release of pro-inflammatory mediators from adipose tissue. All these effects indicate the potential impact of hyperinsulinemia on airway structure and function, suggesting the presence of a specific asthma phenotype with insulin resistance. Epidemiologic studies have found that individuals with severe and uncontrolled asthma have a higher prevalence of glycemic dysfunction, whereas longitudinal studies have linked glycemic dysfunction to an increased risk of asthma exacerbations. Since the components of metabolic syndrome interact with one another so much, it is challenging to identify each one's specific role in asthma. This is why, over the last decade, additional studies have been conducted to determine whether treatment of type 2 diabetes mellitus affects comorbid asthma as shown by the incidence of asthma, asthma control and asthma-related exacerbations. The purpose of this review is to present the mechanism of action, and existing preclinical and clinical data, regarding the effect of insulin resistance in asthma.

Effects of biological therapies on patients with Type-2 high asthma and comorbid obesity.

Over 20 million adults and 6 million children in the United States (US) have asthma, a chronic respiratory disease characterized by airway inflammation, bronchoconstriction, and mucus hypersecretion. Obesity, another highly prevalent disease in the US, is a major risk factor for asthma and a significant cause of diminished asthma control, increased submucosal eosinophilia, and reduced quality of life. A large subgroup of these patients experiences severe symptoms and recurrent exacerbations despite maximal dosage of standard asthma therapies. In the past two decades, the development of biological therapies has revolutionized the field and advanced our understanding of type 2 inflammatory biomarkers. However, patients with obesity and comorbid asthma are not principally considered in clinical trials of biologics. Large landmark cluster analyses of patients with asthma have consistently identified specific asthma phenotypes that associate with obesity but may be differentiated by age of asthma onset and inflammatory cell profiles in sputum. These patterns suggest that biologic processes driving asthma pathology are heterogenous among patients with obesity. The biological mechanisms driving pathology in patients with asthma and comorbid obesity are not well understood and likely multifactorial. Future research needs to be done to elicit the cellular and metabolic functions in the relationship of obesity and asthma to yield the best treatment options for this multiplex condition. In this review, we explore the key features of type 2 inflammation in asthma and discuss the effectiveness, safety profile, and research gaps regarding the currently approved biological therapies in asthma patients with obesity.

Evaluation of serum levels of interferon beta and nucleotide binding and oligomerization domain 2 gene polymorphism in children with cough asthma phenotype: a case–control study

BackgroundIndividuals with asthma are thought to suffer from a variety of distinct disorders, or phenotypes, each of which is characterized by a unique combination of genetic and environmental factors. Syndromes that are exacerbated by allergens, non-allergic factors, and aspirin, as well as syndromes that are best differentiated by pathologic findings, response to therapy, and natural history, fall into this category. The best course of treatment for an individual patient with asthma can be determined by first determining his or her specific asthma phenotype and its underlying pathophysiology.Aim of the workExplore clinical characteristics, serum INF-β in cough asthma phenotype and allergic march asthmatic children. Also, to assess the association of NOD2 (rs2066845) gene polymorphism among those asthma phenotypes in Egyptian asthmatic children.Patients and methodsThe study included 64 cough phenotypic asthmatic children and 60 allergic march phenotypic asthmatic children in addition to 39 healthy controls (control group). The included children were subjected to full clinical history taking, full clinical examination, assessment of (total serum IgE, CBC for peripheral eosinophil percentage, cytokine profile (serum levels of INF-B), and genetic analysis: SNPs of NOD2 (rs2066845).ResultsThere was a significant increase in G allele frequency, in both homozygous (GG) and heterozygous (GC) states, among asthmatic children of cough and allergic march phenotypes compared to healthy controls, with no significant difference between the two phenotypes. In addition, serum INF-β was significantly lower in cough and allergic march phenotypic asthmatics with GG genotypes versus healthy controls of the same genotype.ConclusionsNOD2 (rs2066845) gene polymorphism is associated with both cough and allergic march asthma phenotypes in Egyptian asthmatic children. It was also shown that G allele may be implicated in asthma pathophysiology.

Association of eosinophil-derived neurotoxin levels with asthma control status in patients with aspirin-exacerbated respiratory disease.

The long-term goals of asthma treatment are to achieve well control of symptoms and to minimize the future risk of asthma exacerbation. Identifying biomarkers for uncontrolled asthma is important for improving the asthma outcome. This study aimed to investigate the association of the levels of eosinophil-derived neurotoxin (EDN) with asthma control status in specific asthma phenotype, aspirin-exacerbated respiratory disease (AERD), and aspirin-tolerant asthma (ATA). A total of 136 adult asthmatics, including 47 asthmatics with AERD and 89 asthmatics with ATA, were enrolled. Plasma, sputum, and urine were collected at enrollment and the levels of EDN were measured by the K-EDN ELISA kit. Urinary leukotriene E4 (LTE4 ) level was measured using liquid chromatography-mass spectrometry (LC-MS)/MS methods. Asthma control status was evaluated according to the GINA guideline, asthma control test and asthma control questionnaire scores. In the total study subjects, sputum levels of EDN as well as of urine and plasma EDN showed significantly higher levels in patients with uncontrolled asthma than in those with well-controlled or partly-controlled asthma (ANOVA, p<0.001); in patients with AERD, the sputum EDN levels showed significant correlations with ACT, ACQ, and AQLQ scores (p=0.010, r=-0.536, p=0.001, r=0.665, and p<0.001, r=-0.691, respectively), while no differences were noted in patients with ATA. Sputum EDN level was the only significant factor for ACT, ACQ, and AQLQ scores in patients with AERD (p=0.001, p<0.001, and p<0.001, respectively) in the multivariate analysis adjusting for age, sex, peripheral eosinophil count, and urine LTE4 . The ROC curve analysis demonstrated that sputum EDN can predict uncontrolled asthma with 80% sensitivity and 88.2% specificity for ACT≤19 (area under the ROC curve [AUC]=0.824, p=0.019); 71.4% sensitivity and 86.7% specificity for ACQ≥1.5 (AUC=0.752, p=0.049) only in AERD patients. The level of sputum EDN may be a potential biomarker for identifying the asthma control status in patients with AERD.

Asthma-associated bacterial infections: Are they protective or deleterious?

Eosinophilic, noneosinophilic, or mixed granulocytic inflammations are the hallmarks of asthma heterogeneity. Depending on the priming of lung immune and structural cells, subjects with asthma might generate immune responses that are TH2-prone or TH17-prone immune response. Bacterial infections caused by Haemophilus, Moraxella, or Streptococcus spp. induce the secretion of IL-17, which in turn recruit neutrophils into the airways. Clinical studies and experimental models of asthma indicated that neutrophil infiltration induces a specific phenotype of asthma, characterized by an impaired response to corticosteroid treatment. The understanding of pathways that regulate the TH17-neutrophils axis is critical to delineate and develop host-directed therapies that might control asthma and its exacerbation episodes that course with infectious comorbidities. In this review, we outline clinical and experimental studies on the role of airway epithelial cells, S100A9, and high mobility group box 1, which act in concert with the IL-17-neutrophil axis activated by bacterial infections, and are related with asthma that is difficult to treat. Furthermore, we report critically our view in the light of these findings in an attempt to stimulate further investigations and development of immunotherapies for the control of severe asthma.

Dyslipidemia Is Associated With Worse Asthma Clinical Outcomes: A Prospective Cohort Study

Dyslipidemia has been widely documented to be associated with cardiovascular disease, and recent studies have found an association with asthma prevalence. However, longitudinal studies investigating the relationships between dyslipidemia, asthma phenotypes, and future asthma exacerbations (AEs) are lacking. To investigate the relationships between dyslipidemia, asthma phenotypes, and AEs. This study used an observational cohort study design with a 12-month follow-up. All subjects underwent serum lipid measurement, and they were then classified into 2 groups: the normal-lipidemia group and the dyslipidemia group. Demographic and clinical information and details regarding pulmonary function and asthma phenotypes at baseline were collected. All patients were followed up regularly to assess AEs. Associations of dyslipidemia with airway obstruction and asthma phenotypes were assessed at baseline, whereas dyslipidemia and AEs were assessed longitudinally. A total of 477 patients with asthma were consecutively enrolled in this study. At baseline, the dyslipidemia group (n= 218) had a higher proportion of uncontrolled asthma, defined by the 6-item Asthma Control Questionnaire score (≥1.5). Furthermore, dyslipidemia was associated with severe asthma, nonallergic asthma, asthma with fixed airflow limitation, and older adult asthma phenotypes at baseline. In addition, dyslipidemia was associated with increased frequencies of severe AEs and moderate to severe AEs during the 12-month follow-up. In sensitivity analyses, after excluding the patients who were receiving statins, results did not differ significantly from those of the main analysis. We identified the clinical relevance of dyslipidemia, which is associated with specific asthma phenotypes and increased AEs, independent of other components of metabolic syndrome. These findings highlight the importance of considering dyslipidemia as an "extrapulmonary trait" in asthma management.

Heterogeneity of asthma with nasal polyposis phenotypes: Acluster analysis.

Chronic rhinosinusitis with nasal polyposis (CRSwNP) affects a significant number of asthmatic patients and is notably associated with a more difficult-to-control asthma and marked inflammation. We need more studies on this specific asthma phenotype and its possible subphenotypes, in order to better individualize treatments. The aim of this study is to identify and characterize subphenotypes of asthma patients with CRSwNP using clinical, physiological and inflammatory variables. K-means cluster analysis was performed on 17 clinical, physiological, and inflammatory variables from 1263 patients of all asthma severity and on a subpopulation of patients with asthma and CRSwNP. Study was registered on ClinicalTrials.gov (NCT03694847). On the overall population, three groups were identified. Cluster T1 (n=708) are young, have a short asthma duration and a low prevalence of CRSwNP. Cluster T2 (n=263) have the longest asthma duration and Cluster T3 (n=292) are older with the shortest asthma duration. Patients in Clusters T2 and T3 have similar prevalences of CRSwNP. On the subpopulation of asthma with CRSwNP, three clusters were also identified. Cluster S1 (n=83) have mild-to-moderate asthma with normal lung function. Clusters S2 (N=53) and S3 (N=42) include patients with severe asthma and decreased lung function, but those in Cluster S2 have a longer asthma duration, whereas those Cluster S3 have late-onset asthma. Despite coexistence of asthma and CRSwNP, not all patients have the same evolution of their asthma. Different phenotypes of asthma with CRSwNP can be identified and exploration of the characteristics of these subgroups could lead to a better individualized, targeted management.

Predictors of Low and High Exhaled Nitric Oxide Values in Asthma: A Real-World Study

Background: In asthma, exhaled nitric oxide (F_ENO) is a clinically established biomarker of airway T2 inflammation and an indicator for anti-inflammatory therapy. Objectives: The aim of the study was to identify, in an observational real-world cross-sectional study, the main characteristics of patients with asthma as classified by their F_ENO level. Method: We stratified 398 patients with stable mild-to-severe asthma according to F_ENO level as low (≤25 ppb) versus elevated (>25 ppb), subdividing the latter into two subgroups: moderately elevated (26–50 ppb) versus very high F_ENO (>50 ppb). Clinical, functional, and blood parameters were extrapolated from patients’ chart data and compared with the F_ENO stratification. Predictors of low and elevated F_ENO asthma were detected by logistic regression model. Results: Low BMI, higher blood eosinophilia, allergen poly-sensitization, the severest airflow obstruction (FEV₁/FVC), and anti-leukotriene use are predictors of elevated F_ENO values in asthma, as well as persistent rhinitis and chronic rhinosinusitis with or without nasal polyps. Beyond these, younger age, more than 2 asthma exacerbations/year, higher airflow reversibility (post-bronchodilator ∆FEV₁), and oral corticosteroid dependence are predictors of very high F_ENO values. In contrast, obesity, obstructive sleep apnoea syndrome, gastroesophageal reflux disease, arterial hypertension, and myocardial infarction are predictors of low F_ENO asthma. In our population, F_ENO correlated with blood eosinophils, airflow obstruction, and reversibility and negatively correlated with age and BMI. Conclusions: Stratifying patients by F_ENO level can identify specific asthma phenotypes with distinct clinical features and predictors useful in clinical practice to tailor treatment and improve asthmatic patients’ outcomes.

Genome-wide study of early and severe childhood asthma identifies interaction between CDHR3 and GSDMB

Asthma with severe exacerbation is one of the most common causes of hospitalization among young children. Exacerbations are typically triggered by respiratory infections, but the host factors causing recurrent infections and exacerbations in some children are poorly understood. As a result, current treatment options and preventive measures are inadequate. We sought to identify genetic interaction associated with the development of childhood asthma. We performed an exhaustive search for pairwise interaction between genetic single nucleotide polymorphisms using 1204 cases of a specific phenotype of early childhood asthma with severe exacerbations in patients aged 2 to 6 years combined with 5328 nonasthmatic controls. Replication was attempted in 3 independent populations, and potential underlying immune mechanisms were investigated in the COPSAC2010 and COPSAC2000 birth cohorts. We found evidence of interaction, including replication in independent populations, between the known childhood asthma loci CDHR3 and GSDMB. The effect of CDHR3 was dependent on the GSDMB genotype, and this interaction was more pronounced for severe and early onset of disease. Blood immune analyses suggested a mechanism related to increased IL-17A production after viral stimulation. We found evidence of interaction between CDHR3 and GSDMB in development of early childhood asthma, possibly related to increased IL-17A response to viral infections. This study demonstrates the importance of focusing on specific disease subtypes for understanding the genetic mechanisms of asthma.

Suhuang Antitussive Capsule Ameliorates Corticosteroid Insensitivity in Cough Variant Asthma Guinea Pigs by Inhibiting p38 MAPK Signal Pathway.

Methods The CVA guinea pig model was successfully established by use of ovalbumin (OVA) sensitization and cigarette smoke (CS) exposure. The guinea pigs were divided into 6 groups: a control group, an OVA model group, an OVA + CS model group, a Suhuang treatment group, a BUD treatment group, and a combination (Suhuang and BUD) treatment group. The effects of the treatment were determined by measuring lung function (RI/Cydn) and cough symptoms (coughs number/cough latency) as outcome criteria. The levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were determined by ELISA. Lung tissues were stained by hematoxylin and eosin (H&E). The expressions of GR/total p38 MAPK/p-p38 MAPK were detected by Western blot. The MKP-1 mRNA levels were detected by RT-PCR. Results Combination treatment significantly decreased RI/coughs numbers and increased Cydn/cough latency. Significantly, the results indicated that combination treatment decreased injury to pulmonary tissues. Results also revealed that levels of inflammatory cytokines were reduced in all treatment groups but most markedly in the combination treatment group. Moreover, Suhuang treatment significantly ameliorated corticosteroid insensitivity by improving the expression of glucocorticoid receptors (GR). The expressions of total p38 MAPK and p-p38 MAPK in lung tissue were significantly inhibited in the Suhuang and combination treatment groups. The MKP-1 mRNA levels in Suhuang and combination treatment groups were also increased significantly. Conclusion Suhuang was effective for reversing corticosteroid insensitivity by regulating the p38 MAPK signal pathway, and combining BUD and Suhuang treatment showed synergistic interactions in CVA guinea pigs. Our findings showed that this combination therapy might be a promising therapeutic agent for CVA and also clarified its underlying mechanism of action, providing a theoretical basis for clinical combination treatment with Suhuang and BUD in CVA patients.

The Role of Biologics in the Management of Asthma in the Pediatric Patient.

The management of pediatric patients with asthma continues to be a major health issue. For many patients, traditional therapies have been very effective, but for a large number of patients asthma remains poorly controlled. This leads to significant morbidity and impairment to quality of life. Recently, several new biologics, as well as new dosage forms of combination inhaled drugs, have been made available for use adding to the armamentarium of therapy for specific asthma phenotypes. Biologics have shown promise in the more difficult to manage asthma patient. Approved in children, omalizumab, an anti-immunoglobulin E (anti-IgE) antibody, has been available for several years. New agents, like mepolizumab and benralizumab, directed against interleukin (IL) 5, have indications for children >6 and >12 years of age, respectively. Dupilumab, an IL-4- and IL-13-directed antibody, has been studied as well in eosinophilic asthma, with positive results. A thorough understanding of the clinical data of these agents is key, as they may greatly improve the quality of life in children with difficult-to-manage asthma.

Cross-reactive antibodies against dust mite-derived enolase induce neutrophilic airway inflammation.

Neutrophilic inflammation is a hallmark of some specific asthma phenotypes; its aetiology is not yet fully understood. House dust mite (HDM) is the most common factor in the pathogenesis of airway inflammation. This study aims to elucidate the role of cross-antibodies against HDM-derived factors in the development of neutrophilic inflammation in the airway. Blood samples were collected from asthma patients with chronic neutrophilic asthma for analysis of HDM-specific cross-reactive antibodies. The role of an antibody against HDM-derived enolase (EnoAb) in the impairment of airway epithelial barrier function and induction of airway inflammation was assessed in a cell culture model and an animal model. High similarity (72%) of the enolase gene sequences was identified between HDM and human. Serum EnoAb was detected in patients with chronic neutrophilic asthma. The EnoAb bound to airway epithelial cells to form complexes with enolase, which activated complement, impaired airway epithelial barrier functions and induced neutrophilic inflammation in the airway tissues. HDM-derived enolase can induce specific cross-antibodies in humans, which induce neutrophilic inflammation in the airway.

Use of mepolizumab in adult patients with cystic fibrosis and an eosinophilic phenotype: case series

BackgroundCystic fibrosis (CF) is characterized by inflammation, progressive lung disease, and respiratory failure. Although the relationship is not well understood, patients with CF are thought to have a higher prevalence of asthma than the general population. CF Foundation (CFF) annual registry data in 2017 reported a prevalence of asthma in CF of 32%. It is difficult to differentiate asthma from CF given similarities in symptoms and reversible obstructive lung function in both diseases. However, a specific asthma phenotype (type 2 inflammatory signature), is often identified in CF patients and this would suggest potential responsiveness to biologics targeting this asthma phenotype. A type 2 inflammatory condition is defined by the presence of an interleukin (IL)-4high, IL-5high, IL-13high state and is suggested by the presence of an elevated total IgE, specific IgE sensitization, or an elevated absolute eosinophil count (AEC). In this manuscript we report the effects of using mepolizumab in patients with CF and type 2 inflammation.ResultsWe present three patients with CF (63, 34 and 24 year of age) and personal history of asthma, who displayed significant eosinophilic inflammation and high total serum IgE concentrations (type 2 inflammation) who were treated with mepolizumab. All three patients were colonized with multiple organisms including Pseudomonas aeruginosa and Aspergillus fumigatus and tested positive for specific IgE to multiple allergens. We examined the effect of mepolizumab on patients’ lung function (FEV1), blood markers of type 2 inflammation, systemic corticosteroid use and frequency of CF exacerbations. One patient had a substantial increase in lung function after starting mepolizumab and all three patients had a substantial benefit in regards to reduced oral CCS use. While none of the patients showed significant changes in the exacerbation rates there was markedly reduced requirements for oral CCS with exacerbations. In addition, mepolizumab had a positive effect on type 2 inflammatory markers, reducing markers of allergic inflammation in all 3 patients.ConclusionsMepolizumab appears to have a positive effect on clinical course in patients with CF presenting with a type 2 phenotype characterized by allergic sensitization and hyper-eosinophilia.

Nutrient intake is a predictor of lung function in obese asthmatic adolescents undergoing interdisciplinary therapy.

Asthma-obesity is a multifactorial disease with specific asthma phenotypes that aggravate due to overweight and an unbalanced diet. Furthermore, obese asthmatic patients are corticotherapy-resistant. Therefore, the aims of the present study were to evaluate the effects of an interdisciplinary intervention on food consumption, body composition, lung function and adipokines in asthmatic and non-asthmatic obese adolescents and to investigate the influence of nutrients on lung function. Obese non-asthmatic (n 42) and obese asthmatic (n 21) adolescents of both sexes were enrolled in the present study. Food intake, adipokine levels, body composition, asthma symptoms and lung function were assessed across the study. After the intervention of 1 year, there was a reduction (P ≤ 0·01) in BMI, body fat percentage, visceral and subcutaneous fat and an increase (P ≤ 0·01) in lean mass and all lung function variables in both groups, except the relation between forced expiratory volume in 1 s and forced vital capacity (FEV1:FVC) in non-asthmatic patients. Moreover, both groups decreased lipid and cholesterol consumption (P ≤ 0·01). The highest energy consumption (β = -0·021) was associated with lower values of FVC. Similarly, carbohydrate consumption (β = -0·06) and cholesterol were negative predictors (β = -0·05) in FEV1:FVC. However, the consumption of Ca (β = 0·01), fibres (β = 1·34) and vitamin A (β = 0·01) were positive predictors of FEV1:FVC. Asthma-obesity interdisciplinary treatment promoted an improvement on food consumption and lung function in adolescents and demonstrated that the consumption of nutrients influenced an increase in lung function.

Asthma Phenotypes as a Guide for Current and Future Biologic Therapies.

Asthma has been increasingly recognized as being a heterogeneous disease with multiple distinct mechanisms and pathophysiologies. Evidence continues to build regarding the existence of different cell types, environmental exposures, pathogens, and other factors that produce a similar set of symptoms known collectively as asthma. This has led to a movement from a "one size fits all" symptom-based methodology to a more patient-centered, individualized approach to asthma treatment targeting the underlying disease process. A significant contributor to this shift to more personalized asthma therapy has been the increasing availability of numerous biologic therapies in recent years, providing the opportunity for more targeted treatments. When targeted biologics began to be developed for treatment of asthma, the hope was that distinct biomarkers would become available, allowing the clinician to determine which biologic therapy was best suited for which patients. Presence of certain biomarkers, like eosinophilia or antigen-specific IgE, is important features of specific asthma phenotypes. Currently available biomarkers can help with decision making about biologics, but are generally too broad and non-specific to clearly identify an asthma phenotype or the single biologic best suited to an asthmatic. Identification of further biomarkers is the subject of intense research. Yet, identifying a patient's asthma phenotype can help in predicting disease course, response to treatment, and biologic therapies to consider. In this review, major asthma phenotypes are reviewed, and the evidence for the utility of various biologics, both those currently on the market and those in the development process, in each of these phenotypes is explored.

Microfibrillar‐associated protein 4 in serum is associated with asthma in Danish adolescents and young adults

BackgroundMicrofibrillar‐associated protein 4 (MFAP4) is an extracellular matrix protein belonging to the fibrinogen‐related protein superfamily, which plays multifaceted roles in innate immunity and normal endothelial function. It has been proposed that MFAP4 promotes the development of asthma in vivo and proasthmatic pathways of bronchial smooth muscle cells in vitro. The aim of this study was to investigate the significance of serum MFAP4 in adolescents and young adolescents with persistent asthma.MethodsProspective, observational study including adolescents and young adults (age 11‐27 years) previously diagnosed with asthma during childhood 2003 to 2005 (0‐15 years) at the four pediatric outpatient clinics in the Region of Southern Denmark (n = 449). Healthy controls were recruited at follow‐up (n = 314). Detection of serum MFAP4 was performed by AlphaLISA technique.ResultsCurrent asthma was associated to a 14% higher mean level of serum MFAP4 compared with controls (expβ 1.14, 95% confidence intervals [CI], 1.05‐1.23) and a 6% higher mean level compared with subjects with no current asthma (expβ 1.06, 95% CI, 0.99‐1.13). No association was found at follow‐up between serum MFAP4 and self‐reported atopic symptoms (other than asthma), Asthma Control Test‐score, fractional exhaled nitric oxide (FeNO), nor to flow rate at 1 second, forced vital capacity, and forced expiratory flow 25% to 75%, response to short‐acting beta 2 agonist or mannitol.ConclusionsWe found a significantly higher mean level of serum MFAP4 in adolescent and young adults with mild to moderate asthma compared with healthy controls but no association to FeNO and lung function nor to the response to short‐acting beta 2 agonist or mannitol. The result supports the hypothesis that MFAP4 plays a role in the pathogenesis of asthma although the marker did not demonstrate any obvious potential as an asthma biomarker in adolescents and young adults with asthma. To understand the possible proasthmatic functions of MFAP4, further investigation in specific asthma phenotypes and the underlying molecular mechanisms is warranted.

Exploring the association between ingestion of foods with higher potential salicylate content and symptom exacerbation in chronic rhinosinusitis. Data from the National Chronic Rhinosinusitis Epidemiology Study

Pharmacological salicylates are known to trigger respiratory exacerbations in patients with Non-Steroidal Exacerbated Respiratory Disease (N-ERD), a specific phenotype of Chronic Rhinosinusitis (CRS) and asthma. The impact of dietary sources of salicylates across subgroups of CRS is not well understood. The hypothesis is that in patients with nasal polyps present, there is likely to be a higher incidence of symptom exacerbation due to dietary salicylates regardless of any known response to pharmacological salicylate. The Chronic Rhinosinusitis Epidemiology Study (CRES) was a questionnaire-based case-control study which sought to characterise the UK CRS population in terms of sociological, economic and medical factors. Using specific questions to examine participant responses relating to symptom exacerbation from food groups thought to be high in salicylate content, this analysis of the CRES database sought to compare an estimate of the prevalence of dietary sensitivity due to food with higher potential salicylate content across patients with CRS with (CRSwNPs) and without nasal polyposis (CRSsNPs) and with allergic fungal rhinosinusitis (AFRS). The CRSwNPs group were significantly more likely than controls to report symptom exacerbation due to ingestion of food groups with higher potential dietary salicylate content. The same trend was observed amongst CRSsNPs participants to a lesser degree. Reported response to the individual specific food groups wine, nuts, spicy foods, fruit and vegetables demonstrated that a statistically significant proportion of CRSwNPs and AFRS participants reported sensitivity to wine. This analysis suggests that there is an association between symptom exacerbation in response to food products with higher potential salicylate content, specifically wine, in CRS patients both with and without nasal polyposis when compared to controls, but especially in the CRSwNPs and AFRS phenotypes. Further studies are needed to detail if this relationship represents a causal relationship to dietary salicylate. The data present the possibility that a wider group of CRS patients may elicit salicylate sensitivity than those with known N-ERD.

A cis-eQTL allele regulating reduced expression of CHI3L1 is associated with late-onset adult asthma in Japanese cohorts

BackgroundThe chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome. Deregulation of inflammasome activation is emerging as a key modulator of pathologic airway inflammation in patients with asthma. We determined whether cis-expression quantitative trait loci (eQTLs) of the gene that encodes YKL-40, chitinase 3-like 1 (CHI3L1), are involved in the onset of asthma or in specific asthma phenotypes.MethodsThis case-control study, which was conducted at the University of Tsukuba, Japan, included a total of 2709 adults from the Tsukuba genome-wide association study (GWAS) cohort (734 healthy volunteers and 237 asthma patients), the Tsukuba replication cohort (375 healthy adult volunteers and 381 adult asthma patients), and the Hokkaido replication cohort (554 healthy adult volunteers and 428 adult asthma patients). Among 34 cis-eQTLs in CHI3L1 in the lung, rs946261 was associated with adult asthma in these Japanese cohorts. The genetic impact of rs946261 on asthma was also examined according to the age at onset and adult asthma clusters.ResultsIn the Tsukuba GWAS cohort, the C allele at rs946261 was significantly associated with reduced expression of CHI3L1 mRNA in the lung and with development of asthma (odds ratio (OR) 1.27; P = 0.036). The association was also observed following analysis of the three Japanese cohorts (OR 1.16; P = 0.013). A stronger association was found with late-onset asthma that developed at 41 years of age or later (OR 1.24; 95% confidence interval (CI) 1.07–1.45; P = 0.0058) and with a specific asthma phenotype characterized by late onset, less atopy, and mild airflow obstruction (OR 1.29; 95% CI 1.03–1.61; P = 0.027).ConclusionsThe genotype consisting of the cis-eQTL allele that reduces expression of CHI3L1 was specifically associated with late-onset adult asthma. Given the important role of YKL-40 in many pathophysiological processes, including cell growth, migration, chemotaxis, reorganization, and tissue remodeling, it may be involved in an important pathogenic role in the establishment of inflammation and remodeling in asthmatic airways. Our findings may indicate the presence of a specific endotype related to exaggerated activation of YKL-40 in the pathogenesis of late-onset adult asthma.

Bronchiectasis in severe asthma: a distinct phenotype?

The presence of bronchiectasis has been described in about 30% of severe asthma patients. The coexistence of these two respiratory conditions poses new challenges from both clinical and research perspectives. We will review the available literature on this topic to discuss the existance of a specific clinical phenotype of asthma. Despite the paucity of literature, the presence of bronchiectasis with severe asthma is associated with older age, chronic bronchial expectoration, rhinosinusitis, more frequent and severe exacerbations, neutrophilic airway inflammation and poor response to usual treatment. Conversely, asthma features are also described in bronchiectasis patients even in the absence of an appropriate diagnosis of asthma. In both cases, there is some evidence supporting the use of bronchodilators, macrolides and respiratory physiotherapy, while the use of inhaled corticosteroids and antibiotics is controversial. Based on available evidence on the association between (severe) asthma and bronchiectasis, its pathophysiology, certain clinical aspects and prognosis are largely unclear. Although specific management appears to be required in most cases, in our opinion there is still insufficient evidence to consider it a distinct phenotype of severe asthma. Hopefully, future research will shed more light on this topic and define the best therapeutic approach.