Asthma Endotypes Research Articles

Airway Wall Remodeling in Childhood Asthma—A Personalized Perspective from Cell Type-Specific Biology

Airway wall remodeling is a pathology occurring in chronic inflammatory lung diseases including asthma, chronic obstructive pulmonary disease, and fibrosis. In 2017, the American Thoracic Society released a research statement highlighting the gaps in knowledge and understanding of airway wall remodeling. The four major challenges addressed in this statement were: (i) the lack of consensus to define “airway wall remodeling” in different diseases, (ii) methodologic limitations and inappropriate models, (iii) the lack of anti-remodeling therapies, and (iv) the difficulty to define endpoints and outcomes in relevant studies. This review focuses on the importance of cell-cell interaction, especially the bronchial epithelium, in asthma-associated airway wall remodeling. The pathology of “airway wall remodeling” summarizes all structural changes of the airway wall without differentiating between different pheno- or endo-types of asthma. Indicators of airway wall remodeling have been reported in childhood asthma in the absence of any sign of inflammation; thus, the initiation event remains unknown. Recent studies have implied that the interaction between the epithelium with immune cells and sub-epithelial mesenchymal cells is modified in asthma by a yet unknown epigenetic mechanism during early childhood.

Metabo-Endotypes of Asthma Reveal Differences in Lung Function: Discovery and Validation in Two TOPMed Cohorts.

Rationale: Current guidelines do not sufficiently capture the heterogeneous nature of asthma; a more detailed molecular classification is needed. Metabolomics represents a novel and compelling approach to derive asthma endotypes (i.e., subtypes defined by functional and/or pathobiological mechanisms). Objectives: To validate metabolomic-driven endotypes of asthma and explore their underlying biology. Methods: In the Genetics of Asthma in Costa Rica Study (GACRS), untargeted metabolomic profiling, similarity network fusion, and spectral clustering was used to identify metabo-endotypes of asthma, and differences in asthma-relevant phenotypes across these metabo-endotypes were explored. The metabo-endotypes were recapitulated in the Childhood Asthma Management Program (CAMP), and clinical differences were determined. Metabolomic drivers of metabo-endotype membership were investigated by meta-analyzing findings from GACRS and CAMP. Measurements and Main Results: Five metabo-endotypes were identified in GACRS with significant differences in asthma-relevant phenotypes, including prebronchodilator (p-ANOVA = 8.3 × 10-5) and postbronchodilator (p-ANOVA = 1.8 × 10-5) FEV1/FVC. These differences were validated in the recapitulated metabo-endotypes in CAMP. Cholesterol esters, trigylcerides, and fatty acids were among the most important drivers of metabo-endotype membership. The findings suggest dysregulation of pulmonary surfactant homeostasis may play a role in asthma severity. Conclusions: Clinically meaningful endotypes may be derived and validated using metabolomic data. Interrogating the drivers of these metabo-endotypes has the potential to help understand their pathophysiology.

Clinical relevance of Alternaria alternata sensitization in patients within type 2-high and type 2-low asthma

Alternaria sensitization is correlated with persistent asthma. Type 2 (T2)-asthma endotypes are characterized by the release of eosinophils. However, the prevalence and sensitization patterns in patients with Alternaria asthma between T2-high and T2-low endotypes are unknown. We retrospectively reviewed 582 patients with Alternaria asthma and divided them into T2-high (n = 376) and T2-low (n = 206) groups with a threshold of 300 cells/µL in blood eosinophil counts. Data for basic information, skin test or IgE detection results, and blood eosinophil counts were collected. The age of patients in the T2-high group (13.66 ± 13.23) was lower than that of the T2-low group (18.02 ± 15.03). Patients with T2-high asthma had relatively higher rates of taking inhaled corticosteroids (ICS) and positive family history than the T2-low group. Pet keepers and allergen immunotherapy (AIT) patients were comparable between these groups, In the T2-high group, patients had higher levels of total serum IgE (T-IgE) and showed a significant positive correlation with eosinophil counts (r = 0.166, P = 0.001), followed by higher Alternaria-specific IgE (sIgE) levels (median, 13.7; range, 4.86–25.3). Compared to the T2-low group, the frequency of poly-sensitized patients and the rate of each allergen among the nine common allergens were all higher in the T2-high group; the statistical differences mainly focused on pollens such as birch (P = 0.005), firmiana (P = 0.004), and mugwort (P = 0.005). Young, male patients had a high prevalence of T2-high Alternaria asthma, along with higher rates of T-IgE, sIgE levels, and poly-sensitized patterns.

Asthma phenotypes and endotypes.

Asthma is a complex disorder characterized by expiratory airflow limitation, wheeze, shortness of breath, chest tightness and cough, which can vary over time and in intensity. Being highly heterogeneous, asthma was characterized and classified in several asthma phenotypes and endotypes from 1947 until today. The present systematic review aims to summarize and describe evidence that was published in the last ten years in the field of asthma phenotyping and endotyping. The systematic review resumed high-quality evidence (clinical trials and randomized control trials) retrieved on MEDLINE and EMBASE databanks and involving adult asthmatic populations. Analyses of literature were conducted according to PRISMA and CASP guidelines. Querying MEDLINE and EMBASE databanks, 5019 and 12261 entries were retrieved, respectively. Applying limitations for year of publication, age of participants, and type of publication, the search results were reduced to 98 and 132 articles, respectively. After data abstraction and resolution of duplications, only 50 articles were further evaluated. The research products were then classified first in macro-areas of interest (phenotypes or endotypes) and then in detailed micro-areas. This systematic review overviews the principal findings available from high-quality literature in the last decade concerning asthma phenotypes and endotypes. Asthma has been described from different points of view, characterizing symptoms, microbiota composition, comorbidities, viral infections, and airway and/or systemic inflammatory status. The comprehension of precise mechanisms underlying asthma pathogenesis is thereby the basis for the development of novel therapeutic strategies, likely essential to the development of precision medicine.

Childhood asthma: pathogenesis and phenotypes.

In the pathogenesis of asthma in children there is a pivotal role for a type 2 inflammatory response to early life exposures or events. Interactions between infections, atopy, genetic susceptibility and environmental exposures (such as farmyard environment, air pollution and tobacco smoke exposure) influence the development of wheezing illness and the risk of progression to asthma. The immune system, lung function and the microbiome in gut and airways develop in parallel, and dysbiosis of the microbiome may be a critical factor in asthma development. Increased infant weight gain and preterm birth are other risk factors for development of asthma and reduced lung function. The complex interplay between these factors explains the heterogeneity of asthma in children. Subgroups of patients can be identified as phenotypes, based on clinical parameters, or endotypes, based on a specific pathophysiological mechanism. Paediatric asthma phenotypes and endotypes may ultimately help to improve diagnosis of asthma, prediction of asthma development and treatment of individual children, based on clinical, temporal, developmental or inflammatory characteristics. Unbiased, data-driven clustering, using a multidimensional or systems biology approach may be needed to better define phenotypes. The present knowledge on inflammatory phenotypes of childhood asthma has now been successfully applied in the treatment with biologicals of children with severe therapy-resistant asthma, and it is to be expected that more personalised treatment options may become available.

Asthma and COVID-19: Аn overview of the guidelines for the management of asthma patients during the COVID-19 pandemic

The emergence of a new disease COVID-19 (coronavirus disease 2019), caused by the coronavirus named SARS-CoV-2, has significantly changed the usual interaction pattern between a doctor and a patient. Previous large studies have identified risk factors for a severe course of COVID-19, including old age, hypertension, diabetes, cardiovascular diseases, and chronic obstructive pulmonary disease. However, asthma and respiratory allergy have not been identified as risk factors for the severe disease. These factors give clues to the pathogenesis of COVID-19, approaches to the controller medications, target therapy, allergen-specific immunotherapy (ASIT) in patients with various phenotypes and endotypes of asthma during the pandemic.The purposeof this review is to summarize the currently available knowledge about SARS-CoV-2, T2-endotype of asthma, eosinophilic inflammation. The article provides an overview of the data from studies of COVID-19 patients with asthma, the main recommendations of the Global Initiative for Asthma (2021) and the Ministry of Health of the Russian Federation. It shows that targeting the endotypes and phenotypes of asthma can influence the management of COVID-19 patients with asthma. The influence of the imbalance of the immune system, pro-inflammatory cytokines, and effector cells in patients with asthma on the development and progression of COVID-19 is considered. Recommendations are given for the controller medications, targeted therapy, allergen-specific immunotherapy during the pandemic.Conclusion.The current recommendations for asthma treatment, based on the latest research of COVID-19, deepen our understanding of the course of COVID-19 in patients with different phenotypes and endotypes of asthma, approaches to traditional methods of treating asthma according to clinical guidelines during the pandemic.

Strategies Targeting Type 2 Inflammation: From Monoclonal Antibodies to JAK-Inhibitors.

Bronchial asthma and its frequent comorbidity chronic rhinosinusitis (CRS), are characterized by an inflammatory process at lower and upper respiratory tract, with a variability in terms of clinical presentations (phenotypes) and distinct underpin pathophysiological mechanisms (endotypes). Based on the characteristics of inflammation, bronchial asthma can be distinguished into type 2 (eosinophilic) or nontype 2 (noneosinophilic) endotypes. In type 2 asthma endotype, the pathogenic mechanism is sustained by an inflammatory process driven by Th2 cells, type 2 innate lymphoid cells (ILC2) and type 2 cytokines, which include interleukin (IL)-4, IL-5, IL-9 and IL-13. The definition of asthma and chronic rhinusinusitis phenotype/endotype is crucial, taking into account the availability of novel biologic agents, such as monoclonal antibodies targeting the classical type 2 cytokines. Recently, new therapeutic strategies have been proposed and analyzed in preliminary clinical trials. Among them Janus kinase (JAK) inhibitors, now largely used for the treatment of other chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases, is receiving great relevance. The rationale of this strategy derives from the data that JAK is a tyrosine kinase involved in the signaling of T cell receptor and of several cytokines that play a role in allergic respiratory disease, such as IL-2, IL-4 and IL-9. In this review, we discuss whether treatment with biological agents and JAK inhibitors may be equally effective in controlling type 2 inflammatory process in both asthma and CRS.

MBD2 as a Potential Novel Biomarker for Identifying Severe Asthma With Different Endotypes.

Background: Studies have shown that methyl-CpG binding domain protein 2 (MBD2) expression is significantly elevated in a neutrophil-dominant severe asthma mouse model. It also regulates Th17 cell differentiation. The objective of this study was to investigate the relationship between serum MBD2 levels in patients with severe asthma with different endotypes.Methods: Eligible adults with confirmed asthma (n = 63) underwent a clinical assessment, asthma control test and pulmonary function test and were classified as having mild, moderate or severe asthma. Severe asthma endotypes were defined according to the percentage of Th2 and Th17 cells in the peripheral blood and by the type of inflammation. The percentage of Th2 and Th17 cells in the peripheral blood was determined by flow cytometry. Serum MBD2, eosinophilic cationic protein and myeloperoxidase were measured by enzyme-linked immunosorbent assay. Correlations of MBD2 expression with clinical parameters were evaluated using Spearman's rank correlation analysis.Results: Serum MBD2 levels were upregulated in patients with severe asthma compared to healthy controls and patients with mild to moderate asthma. MBD2 was also significantly increased in patients with Th17 severe asthma compared to patients with type 2 severe asthma. Furthermore, MBD2 was positively correlated with MPO and Th17 cells but negatively correlated with ECP and Th2 cells in patients with severe asthma.Conclusions: These findings suggest that serum MBD2 may be a potential new biomarker for identifying severe asthma, Th17 severe asthma and the type of airway inflammation. However, these findings are still preliminary and need to be further investigated.

Lung function, airway and peripheral basophils and eosinophils are associated with molecular pharmacogenomic endotypes of steroid response in severe asthma

IntroductionAsthma is a complex disease with heterogeneous expression/severity. There is growing interest in defining asthma endotypes consistently associated with different responses to therapy, focusing on type 2 inflammation (Th2) as...

Eosinophils as Drivers of Severe Eosinophilic Asthma: Endotypes or Plasticity?

Asthma is now recognized as a heterogeneous disease, encompassing different phenotypes driven by distinct pathophysiological mechanisms called endotypes. Common phenotypes of asthma, referred to as eosinophilic asthma, are characterized by the presence of eosinophilia. Eosinophils are usually considered invariant, terminally differentiated effector cells and have become a primary therapeutic target in severe eosinophilic asthma (SEA) and other eosinophil-associated diseases (EADs). Biological treatments that target eosinophils reveal an unexpectedly complex role of eosinophils in asthma, including in SEA, suggesting that “not all eosinophils are equal”. In this review, we address our current understanding of the role of eosinophils in asthma with regard to asthma phenotypes and endotypes. We further address the possibility that different SEA phenotypes may involve differences in eosinophil biology. We discuss how these differences could arise through eosinophil “endotyping”, viz. adaptations of eosinophil function imprinted during their development, or through tissue-induced plasticity, viz. local adaptations of eosinophil function through interaction with their lung tissue niches. In doing so, we also discuss opportunities, technical challenges, and open questions that, if addressed, might provide considerable benefits in guiding the choice of the most efficient precision therapies of SEA and, by extension, other EADs.

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The Montelukast Therapy in Asthmatic Children with and without Food Allergy: Does It Make Any Difference?

Introduction: Children with food allergy are at increased risk for asthma and asthma morbidity. Since leukotrienes are implicated in the pathogenesis of both asthma and probably in food allergies, we hypothesized that asthmatic children with concomitant food allergy may have a favorable response to antileukotriene treatment. Methods: Asthmatic children aged 6–18 years with and without food allergy were treated with montelukast and placebo in a double-blind, placebo-controlled cross-over parallel-group study. The primary outcome of the study was improvement in FEV1%. Asthma control tests, spirometry and methacholine challenges were performed as well as Fractional Exhaled Nitric Oxide (FeNO) levels. PGD2, CystLT, and lipoxin levels were measured in exhaled breath condensate (EBC). Results: A total of 113 children were enrolled and 87 completed the study in accordance with the protocol. At baseline, children with food allergy and asthma (FAA) had higher levels of PGD2 and CysLT levels in the EBC than children with asthma alone (AA) (p < 0.001 for each). In the montelukast arm, although FEV1% was significantly higher in the FAA group compared to AA (p = 0.005), this effect was linked to the baseline difference of FEV1% between both arms. Montelukast treatment failed to improve FEV1% in both groups compared to the placebo. No effect of montelukast was observed in the remaining study parameters. Conclusion: Although children with FAA do not show a more favorable response to montelukast treatment compared to AA, a significant difference between baseline PGD2 and CystLT levels between FAA and AA groups may point to a different endotype of childhood asthma.

The STE20 kinase TAOK3 controls the development of house dust mite–induced asthma in mice

The most common endotype of asthma is type 2-high asthma, which is sometimes driven by adaptive allergen-specific TH2 lymphocytes that react to allergens presented by dendritic cells (DCs), or sometimes by an innate immune response dominated by type 2 innate lymphocytes (ILC2s). Understanding the underlying pathophysiology of asthma is essential to improve patient-tailored therapy. The STE20 kinase thousand-and-one kinase 3 (TAOK3) controls key features in the biology of DCs and lymphocytes, but to our knowledge, its potential usefulness as a target for asthma therapy has not yet been addressed. We examined if and how loss of Taok3 affects the development of house dust mite (HDM)-driven allergic asthma in an invivo mouse model. Wild-type Taok3+/+ and gene-deficient Taok3-/- mice were sensitized and challenged with HDM, and bronchoalveolar lavage fluid composition, mediastinal lymph node cytokine production, lung histology, and bronchial hyperreactivity measured. Conditional Taok3fl/fl mice were crossed to tissue- and cell-specific specific deletor Cre mice to understand how Taok3 acted on asthma susceptibility. Kinase-dead (KD) Taok3KD mice were generated to probe for the druggability of this pathway. Activation of HDM-specific T cells was measured in adoptively transferred HDM-specific T-cell receptor-transgenic CD4+ T cells. ILC2 biology was assessed by invivo and invitro IL-33 stimulation assays in Taok3-/- and Taok3+/+, Taok3KD, and Red5-Cre Taok3fl/fl mice. Taok3-/- mice failed to mount salient features of asthma, including airway eosinophilia, TH2 cytokine production, IgE secretion, airway goblet cell metaplasia, and bronchial hyperreactivity compared to controls. This was due to intrinsic loss of Taok3 in hematopoietic and not epithelial cells. Loss of Taok3 resulted in hampered HDM-induced lung DC migration to the draining lymph nodes and defective priming of HDM-specific TH2 cells. Strikingly, HDM and IL-33-induced ILC2 proliferation and function were also severely affected in Taok3-deficient and Taok3KD mice. Absence of Taok3 or loss of its kinase activity protects from HDM-driven allergic asthma as a result of defects in both adaptive DC-mediated TH2 activation and innate ILC2 function. This identifies Taok3 as an interesting drug target, justifying further testing as a new treatment for type 2-high asthma.

Association between occupational exposure to irritant agents and a distinct asthma endotype in adults

AimThe biological mechanisms of work-related asthma induced by irritants remain unclear. We investigated the associations between occupational exposure to irritants and respiratory endotypes previously identified among never asthmatics (NA) and...

Treatment outcome clustering patterns correspond to discrete asthma phenotypes in children

Despite widely and regularly used therapy asthma in children is not fully controlled. Recognizing the complexity of asthma phenotypes and endotypes imposed the concept of precision medicine in asthma treatment. By applying machine learning algorithms assessed with respect to their accuracy in predicting treatment outcome, we have successfully identified 4 distinct clusters in a pediatric asthma cohort with specific treatment outcome patterns according to changes in lung function (FEV1 and MEF50), airway inflammation (FENO) and disease control likely affected by discrete phenotypes at initial disease presentation, differing in the type and level of inflammation, age of onset, comorbidities, certain genetic and other physiologic traits. The smallest and the largest of the 4 clusters- 1 (N = 58) and 3 (N = 138) had better treatment outcomes compared to clusters 2 and 4 and were characterized by more prominent atopic markers and a predominant allelic (A allele) effect for rs37973 in the GLCCI1 gene previously associated with positive treatment outcomes in asthmatics. These patients also had a relatively later onset of disease (6 + yrs). Clusters 2 (N = 87) and 4 (N = 64) had poorer treatment success, but varied in the type of inflammation (predominantly neutrophilic for cluster 4 and likely mixed-type for cluster 2), comorbidities (obesity for cluster 2), level of systemic inflammation (highest hsCRP for cluster 2) and platelet count (lowest for cluster 4). The results of this study emphasize the issues in asthma management due to the overgeneralized approach to the disease, not taking into account specific disease phenotypes.

Associations Between Gut Microbiota and Asthma Endotypes: A Cross-Sectional Study in South China Based on Patients with Newly Diagnosed Asthma.

ObjectiveThis study aimed to investigate the gut microbiome profile in different inflammatory phenotypes of treatment-naive newly diagnosed asthmatic adults, to gain insight on the associations between intestinal microbiota and phenotypic features that characterize asthma heterogeneity to develop new treatments for asthma.MethodsFresh stool samples were obtained from 20 healthy subjects and 47 newly diagnosed asthmatic patients prior to any interventions. The asthmatics were divided into allergic and non-allergic cohorts. Intestinal microbiota was analyzed by 16S rRNA next-generation sequencing. Demographic and clinical parameters were collected. Alpha and beta diversity analysis were calculated to detect differences within sample phylotype richness and evenness between controls and asthmatic patients. Statistically significant differences between samples were analyzed for all used metrics, and features of gut bacterial community structure were evaluated in relation to extensive clinical characteristics of asthmatic patients.ResultsGut microbial compositions were significantly different between asthmatic and healthy groups. Alpha-diversity of the gut microbiome was significantly lower in asthmatics than in controls. The microbiome between allergic and non-allergic asthmatic patients were also different, and 28 differential species were identified. PPAR signaling pathway, carotenoid biosynthesis, and flavonoid biosynthesis were significantly positively correlated with allergy-associated clinical index, including FENO value, blood eosinophil counts, and serum IgE and IL-4 levels. A combination of Ruminococcus bromii, Brevundimonas vesicularis, and Clostridium disporicum showed an AUC of 0.743 in the specific allergic/non-allergic cohort. When integrating C. disporicum, flavone, flavonol biosynthesis, and serum IL-4 values, the AUC achieved 0.929 to classify asthmatics. At the same time, C. colinum and its associated functional pathway exhibited an AUC of 0.78 to distinguish allergic asthmatics from those without allergies.ConclusionWe demonstrated a distinct taxonomic composition of gut microbiota in different asthmatic phenotypes, highlighting their significant relationships. Our study may support considerations of intestinal microbial signatures in delineating asthma phenotypes.

Imbalanced Coagulation in the Airway of Type-2 High Asthma with Comorbid Obesity.

Asthma is a common, chronic airway inflammatory disease marked by airway hyperresponsiveness, inflammation, and remodeling. Asthma incidence has increased rapidly in the past few decades and recent multicenter analyses have revealed several unique asthma endotypes. Of these, type-2 high asthma with comorbid obesity presents a unique clinical challenge marked by increased resistance to standard therapies and exacerbated disease development. The extrinsic coagulation pathway plays a significant role in both type-2 high asthma and obesity. The type-2 high asthma airway is marked by increased procoagulant potential, which is readily activated following damage to airway tissue. In this review, we summarize the current understanding of the role the extrinsic coagulation pathway plays in the airway of type-2 high asthma with comorbid obesity. We propose that asthma control is worsened in obesity as a result of a systemic and local airway shift towards a procoagulant and anti-fibrinolytic environment. Lastly, we hypothesize bariatric surgery as a treatment for improved asthma management in type-2 high asthma with comorbid obesity, facilitated by normalization of systemic procoagulant and pro-inflammatory mediators. A better understanding of attenuated coagulation parameters in the airway following bariatric surgery will advance our knowledge of biomolecular pathways driving asthma pathobiology in patients with obesity.

Respiratory Viral and Bacterial Factors That Influence Early Childhood Asthma.

Asthma is a chronic respiratory condition characterised by episodes of shortness of breath due to reduced airway flow. The disease is triggered by a hyperreactive immune response to innocuous allergens, leading to hyper inflammation, mucus production, changes in structural cells lining the airways, and airway hyperresponsiveness. Asthma, although present in adults, is considered as a childhood condition, with a total of about 6.2 million children aged 18 and below affected globally. There has been progress in understanding asthma heterogeneity in adults, which has led to better patient stratification and characterisation of multiple asthma endotypes with distinct, but overlapping inflammatory features. The asthma inflammatory profile in children is not well-defined and heterogeneity of the disease is less described. Although many factors such as genetics, food allergies, antibiotic usage, type of birth, and cigarette smoke exposure can influence asthma development particularly in children, respiratory infections are thought to be the major contributing factor in poor lung function and onset of the disease. In this review, we focus on viral and bacterial respiratory infections in the first 10 years of life that could influence development of asthma in children. We also review literature on inflammatory immune heterogeneity in asthmatic children and how this overlaps with early lung development, poor lung function and respiratory infections. Finally, we review animal studies that model early development of asthma and how these studies could inform future therapies and better understanding of this complex disease.

Small-Airway Dysfunction is Involved in the Pathogenesis of Asthma: Evidence from Two Mouse Models.

BackgroundThere has been growing evidence of small-airway dysfunction in patients with asthma. Few studies have evaluated the mechanism of small-airway dysfunction in mouse models of asthma.PurposeWe explored the correlation between small-airway spirometric variables and large-airway function or inflammation in different endotypes of asthma.MethodsOvalbumin (OVA) sensitization/challenge was used to produce a type 2 (T2)-high asthma model, and OVA combined with ozone exposure (OVA + ozone) was used for the T2-low asthma model with increased neutrophils. Spirometry, airway responsiveness, cytokine levels in bronchoalveolar lavage fluid (BALF), and pathological analyses of lung slices stained with hematoxylin-eosin, periodic acid–Schiff, and Masson’s trichrome stain were all determined. Muc5ac expression in lung tissue was evaluated by the reverse transcription-polymerase chain reaction (RT-PCR), and alpha-smooth muscle actin was measured by immunohistochemistry.ResultsInflammatory cells infiltrated the lung tissue and inflammatory cytokines were increased in the BALF of both the OVA and OVA + ozone groups, compared with the control group. Peribronchial hypersecretion and collagen deposition were evident in the models. The OVA + ozone group showed greater neutrophilic infiltration and peribronchial smooth muscle proliferation than the OVA group. Large-airway obstruction, small-airway dysfunction, and airway hyperresponsiveness were confirmed in both models. Small-airway functional variables, such as MMEF (mean midexpiratory flow, average flow from 25 to 75% forced vital capacity [FVC]) and FEF50 (forced expiratory flow at 50% of FVC), were positively correlated with large-airway function and had a stronger negative correlation with airway inflammation, mucus secretion, and responsiveness than large-airway function.ConclusionSmall-airway dysfunction was evident in the two endotypes of asthma and was correlated with severe airway inflammation, mucus hypersecretion, and airway hyperresponsiveness. The small airways may be an important target in asthma treatment, and further research in the role of small-airway variables in the pathogenesis of asthma is warranted.

Biologic Therapy and Severe Asthma in Children.

Severe asthma is a heterogeneous, complex and chronic disease widespread in the pediatric population. According to the recent findings about the different endotypes of asthma in children, each one characterized by specific intracellular molecular pathways, several innovative biologic therapies have been developed. Due to their precise ability to target specific inflammatory type 2 mediators, biologics have revolutionized the care of chronic allergic diseases in the pediatric and adult population. In this review, we aim to provide the latest evidence about the use, indications, efficacy and safety of biologic therapies to treat severe asthma in children and adolescents.