Small Airway Dysfunction in Cough Variant Asthma: Prevalence, Clinical, and Pathophysiological Features

Introduction: Small airway dysfunction (SAD) commonly presents in patients with classic asthma, which is associated with airway inflammation, disease severity, and asthma control. However, the prevalence of SAD, its relationship with cough severity and airway inflammation, and its development after antiasthmatic treatment in patients with cough variant asthma (CVA) need to be clarified. This study aimed to investigate the prevalence of SAD and its relationship with clinical and pathophysiological characteristics in patients with CVA and the change in small airway function after antiasthmatic treatment.Methods: We retrospectively analyzed 120 corticosteroid-naïve patients with CVA who had finished a standard questionnaire and relevant tests in a specialist cough clinic, such as cough visual analog scale (VAS), differential cells in induced sputum, fractional exhaled nitric oxide (FeNO) measurement, spirometry, and airway hyper-responsiveness. Information of 1-year follow-up was recorded in a part of patients who received complete cough relief after 2 months of treatment. SAD was defined as any two parameters of maximal mid-expiratory flow (MMEF)% pred, forced expiratory flow at 50% of forced vital capacity (FEF50%) pred, and forced expiratory flow at 75% of forced vital capacity (FEF75%) pred measuring <65%.Results: SAD occurred in 73 (60.8%) patients with CVA before treatment. The patients with SAD showed a significantly longer cough duration (24.0 vs. 6.0, p = 0.031), a higher proportion of women (78.1 vs. 59.6%, p = 0.029), older mean age (41.9 vs. 35.4, p = 0.005), and significantly lower forced expiratory volume in 1 s (FEV1%) pred, FEV1/FVC, MMEF% pred, FEF50% pred, FEF75% pred, PEF% pred, and PD20 (all p < 0.01) as compared with patients without SAD. There were no significant differences in cough VAS, sputum eosinophils count, FeNO, and TIgE level between patients with SAD and those without SAD. Among 105 patients who completed 2 months of antiasthmatic treatment and repeatedly experienced spirometry measurement, 57 (54.3%) patients still had SAD, despite a significant improvement in cough VAS, sputum eosinophils, FeNO, FEF50% pred, and PEF% pred (all p < 0.01). As compared with patients without SAD, patients with SAD showed no significant differences in the relapse rate (50.0 vs. 41.9%, p = 0.483) and wheeze development rate (10.4 vs. 0%, p = 0.063) during the follow-up.Conclusions: Small airway dysfunction occurred in over half of patients with CVA and persisted after short-term antiasthmatic treatment, which showed distinctive clinical and pathophysiological features.

Enhanced airway sensory nerve reactivity in non-eosinophilic asthma

BackgroundNeural mechanisms may play an important role in non-eosinophilic asthma (NEA). This study compared airway sensory nerve reactivity, using capsaicin challenge, in eosinophilic asthma (EA) and NEA and non-asthmatics.MethodsThirty-eight asthmatics and 19 non-asthmatics (aged 14–21 years) underwent combined hypertonic saline challenge/sputum induction, fractional exhaled nitric oxide, atopy and spirometry tests, followed by capsaicin challenge. EA and NEA were defined using a sputum eosinophil cut-point of 2.5%. Airway hyperreactivity was defined as a ≥15% drop in FEV1 during saline challenge. Sensory nerve reactivity was defined as the lowest capsaicin concentration that evoked 5 (C5) coughs.ResultsNon-eosinophilic asthmatics (n=20) had heightened capsaicin sensitivity (lower C5) compared with non-asthmatics (n=19) (geometric mean C5: 58.3 µM, 95% CI 24.1 to 141.5 vs 193.6 µM, 82.2 to 456.0; p<0.05). NEA tended to also have greater capsaicin sensitivity than EA, with the difference in capsaicin sensitivity between NEA and EA being of similar magnitude (58.3 µM, 24.1 to 141.5 vs 191.0 µM, 70.9 to 514.0) to that observed between NEA and non-asthmatics; however, this did not reach statistical significance (p=0.07). FEV1 was significantly reduced from baseline following capsaicin inhalation in both asthmatics and non-asthmatics but no differences were found between subgroups. No associations with capsaicin sensitivity and atopy, sputum eosinophils, blood eosinophils, asthma control or treatment were observed.ConclusionNEA, but not EA, showed enhanced capsaicin sensitivity compared with non-asthmatics. Sensory nerve reactivity may therefore play an important role in the pathophysiology of NEA.

The sputum transcriptome better predicts COPD exacerbations after the withdrawal of inhaled corticosteroids than sputum eosinophils

IntroductionContinuing inhaled corticosteroid (ICS) use does not benefit all patients with chronic obstructive pulmonary disease (COPD), yet it is difficult to determine which patients may safely sustain ICS withdrawal. Although eosinophil levels can facilitate this decision, better biomarkers could improve personalised treatment decisions.MethodsWe performed transcriptional profiling of sputum to explore the molecular biology and compared the predictive value of an unbiased gene signature versus sputum eosinophils for exacerbations after ICS withdrawal in COPD patients. RNA-Seq data of induced sputum samples from 43 COPD patients were associated with the time to exacerbation after ICS withdrawal. Expression profiles of differentially expressed genes were summarised to create gene signatures. In addition, we built a Bayesian network model to determine co-regulatory networks related to the onset of COPD exacerbations after ICS withdrawal.ResultsIn multivariate analyses, we identified a gene signature (LGALS12, ALOX15, CLC, IL1RL1, CD24, EMR4P) associated with the time to first exacerbation after ICS withdrawal. The addition of this gene signature to a multiple Cox regression model explained more variance of time to exacerbations compared to a model using sputum eosinophils. The gene signature correlated with sputum eosinophil as well as macrophage cell counts. The Bayesian network model identified three co-regulatory gene networks as well as sex to be related to an early versus late/non- exacerbation phenotype.ConclusionWe identified a sputum gene expression signature that exhibited a higher predictive value for predicting COPD exacerbations after ICS withdrawal than sputum eosinophilia. Future studies should investigate the utility of this signature, which might enhance personalised ICS treatment in COPD patients.

A study on asthma and chronic obstructive pulmonary disease overlaps among patients with obstructive airway diseases

There is a need to re-evaluate the concept of asthma and chronic obstructive pulmonary disease (COPD) as separate conditions, and to consider situations when they may coexist, or when one condition may evolve into the other. This is prospective, observational and descriptive study conducted at MNR Medical College and Hospital, Sangareddy, India from June 2020 to December 2020 among chronic airway diseases who were classified into three groups (COPD, Asthma, and Asthma and COPD overlap (ACO)). Patients with COPD and ACO were diagnosed according to GOLD guidelines 2020 and patients with asthma were diagnosed according to Global Initiative for Asthma (GINA) guidelines 2020. : Regarding the age difference between groups, it was found that patients who were diagnosed as having COPD and ACO were with mean age of 57.23±8.54 and 56.26±7.73 years, respectively. The men age of patients of Asthma was 57.51±8.43. In our study, 28 (30%) patients as having COPD, 39 (45.5%) patients were diagnosed as having ACO, 23 (24.4%) patients were diagnosed as having asthma. In our study comparison of groups regarding history of atopy. We found that 71.7% of ACO group, 78.2% of asthma group and 25% of COPD group had a positive history of atopy. Comparison of study groups regarding sputum eosinophils revealed that 30.7 % of ACO group, 73.9% of asthma group and 32.1% of COPD group had positive sputum eosinophils. ACO represents a large percentage among patients with obstructive airway diseases. It shares some features of asthma such as atopy and positive sputum eosinophilia, and some features of COPD like old age of presentation and positive smoking history.

Enhanced sensory nerve reactivity in non-eosinophilic asthma

ABSTRACT Background: Neural mechanisms may play an important role in non-eosinophilic asthma. This study compared airway sensory nerve reactivity, using capsaicin challenge, in eosinophilic and non-eosinophilic asthma and non-asthmatics. Methods: Thirty-eight asthmatics and nineteen non-asthmatics (aged 14-21 years) underwent combined hypertonic saline challenge/sputum induction, exhaled nitric oxide (FeNO), atopy, and spirometry tests, followed by capsaicin challenge. Eosinophilic (EA) and non-eosinophilic asthma (NEA) were defined using a sputum eosinophil cut-point of 2.5%. Airway hyperreactivity (AHR) was defined as a ≥15% drop in FEV1 during saline challenge. Sensory nerve reactivity was defined as the lowest capsaicin concentration that evoked 5 (C5) coughs. Results: Non-eosinophilic asthmatics (n=20) had heightened capsaicin sensitivity (lower C5) compared to non-asthmatics (n=19) (geometric mean C5: 58.3μM, 95% confidence interval 24.1-141.5 vs 193.6μM, 82.2-456.0; p<0.05). There was a similar (but non-significant) difference in capsaicin sensitivity in NEA compared with EA (n=18), (58.3μM, 24.1-141.5 vs 191.0μM, 70.9-514.0; p=0.07). FEV1 was significantly reduced from baseline following capsaicin inhalation in both asthmatics and non-asthmatics but no differences were found between subgroups. No associations with capsaicin sensitivity and atopy, sputum eosinophils, blood eosinophils, asthma control, or treatment were observed. Conclusion: Non-eosinophilic asthma, but not eosinophilic asthma, showed enhanced capsaicin sensitivity compared with non-asthmatics. Sensory nerve reactivity may therefore play an important role in the pathophysiology of non-eosinophilic asthma.

Understanding the key issues in the treatment of uncontrolled persistent asthma with type 2 inflammation

Asthma is a complex respiratory disease that varies in severity and response to treatment. Several asthma phenotypes with unique clinical and inflammatory characteristics have been identified. Endotypes, based on distinct molecular profiles, help to further understand the heterogeneity within asthma. Type 2 inflammation, involving both the innate (type 2 innate lymphoid cell) and adaptive (T helper type 2 cells) immune systems, underpins the complex pathophysiology of chronic inflammation in asthma, as well as the presence of comorbid disease (such as chronic rhinosinusitis with nasal polyps, allergic rhinitis, and atopic dermatitis). Type 2 inflammation is characterised by upregulation of type 2 cytokines interleukin (IL)-4, IL-5, and IL-13, immunoglobulin E (IgE)-mediated release of immune mediators, and dysfunction of epithelial or epidermal barriers. Targeting these key proximal type 2 cytokines has shown efficacy in recent studies adopting a personalised approach to treatment using targeted biologics. Elevated levels of biomarkers downstream of type 2 cytokines, including fractional exhaled nitric oxide, serum IgE, and blood and sputum eosinophils, have been linked to mechanisms involved in type 2 inflammation, and have the potential to aid diagnosis, and predict and monitor response to treatment. The objective of this review is to summarise the current understanding of the biology of type 2 inflammation in asthma, examine its influence on type 2 inflammatory comorbidities, and discuss how type 2 inflammatory biomarkers can be harnessed to further personalise treatments in the age of biologic medicines.

Small airway dysfunction in patients with cough variant asthma: a retrospective cohort study

Background Cough variant asthma (CVA) is one of the special populations of asthma. The aim of the study was to compare small airways, the degree of bronchial hyperresponsiveness (BHR) and airway inflammatory subtypes between CVA and classic asthma (CA), and investigate the relationship between these markers to determine the accuracy as indicators of CVA. Methods A total of 825 asthmatic patients participated in the study and 614 were included. 614 patients underwent spirometry and a bronchial challenge with methacholine and 459 patients performed induction sputum cell test. Results The number of CVA patients showed less small airway dysfunction than those of CA patients (p < 0.005). The degree of small airways dysfunction was higher in the CA group compared with the CVA group (p < 0.001). Small airways dysfunction was severer in the eosinophilic airway inflammatory subtype compared with other subtypes (p < 0.05).The area under curve of MMEF, FEF50 and FEF75 (% predicted) was 0.615, 0.621, 0.606, respectively. 0.17mcg of PD20 and 4.7% of sputum eosinophils was the best diagnostic value for CVA with an AUC of 0.582 and 0.575 (p = 0.001 and p = 0.005, respectively). Conclusions The eosinophilic airway inflammatory subtype may be increased small airway dysfunction. The value of small airways, BHR and induction sputum cells in CVA prediction, which reflected significant, but not enough to be clinically useful.

Prevalence of asthma—chronic obstructive pulmonary disease overlap in patients with airflow limitation

Background Asthma-COPD overlap (ACO) according to GINA and GOLD is not a single disease and is described by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD. Some different protocols were proposed to diagnose ACO, besides those reported in GINA and GOLD guidelines. Despite the discrepancy between all the proposed diagnostic protocols, the diagnosis of ACO is still worthy as it may lead to a more appropriate treatment plan. In Egypt, prevalence of ACO is hardly estimated due to lack of database of patients. Our aim of work was to detect the prevalence of ACO in patients diagnosed as having a chronic airflow limiting disease. Results In asthma group (75 patients), 53.3% (40 patients) were diagnosed as ACO with 3 statistically significant favoring diagnostic criteria; post-BDR test FEV1/FVC < 70%, longer disease duration, and sputum neutrophilia ≥ 57%. While in COPD group (75 patients), 42.7% (32 patients) were diagnosed as ACO with four statistically significant favoring diagnostic criteria; higher BDR, presence of personal history of either asthma or atopy and sputum eosinophils > 1%. Conclusions ACO has an underestimated prevalence among those diagnosed with either asthma or COPD. More consensus guidelines are needed to focus on the more effective and the more practical criteria to diagnose such hidden disease.

Clinical and Inflammatory Features of Exacerbation-Prone Asthma: A Cross-Sectional Study Using Multidimensional Assessment

<b><i>Background:</i></b> Reducing asthma exacerbations is a major target of current clinical guidelines, but identifying features of exacerbation-prone asthma (EPA) using multidimensional assessment (MDA) is lacking. <b><i>Objective:</i></b> To systemically explore the clinical and inflammatory features of adults with EPA in a Chinese population. <b><i>Methods:</i></b> We designed a cross-sectional study using the Severe Asthma Web-based Database from the Australasian Severe Asthma Network (ASAN). Eligible Chinese adults with asthma (<i>n</i> = 546) were assessed using MDA. We stratified patients based on exacerbation frequency: none, few (1 or 2), and exacerbation prone (≥3). Univariate and multivariable negative binomial regression analyses were performed to investigate features associated with the frequency of exacerbations. <b><i>Results:</i></b> Of 546 participants, 61.9% had no exacerbations (<i>n</i> = 338), 29.6% had few exacerbations (<i>n</i> = 162), and 8.4% were exacerbation prone (<i>n</i> = 46) within the preceding year. EPA patients were characterized by elevated blood and sputum eosinophils but less atopy, with more controller therapies but worse asthma control and quality of life (all <i>p</i> &#x3c; 0.05). In multivariable models, blood and sputum eosinophils (adjusted rate ratio = 2.23, 95% confidence interval = [1.26, 3.84] and 1.67 [1.27, 2.21], respectively), FEV₁ (0.90 [0.84, 0.96]), bronchodilator responsiveness (1.16 [1.05, 1.27]), COPD (2.22 [1.41, 3.51]), bronchiectasis (2.87 [1.69, 4.89]), anxiety (2.56 [1.10, 5.95]), and depression (1.94 [1.20, 3.13]) were found. Further, upper respiratory tract infection (1.83 [1.32, 2.54]) and food allergy (1.67 [1.23, 2.25]) were at high risk of asthma symptom triggers. <b><i>Conclusion:</i></b> EPA is a clinically recognizable phenotype associated with several recognizable traits that could be addressed by targeted treatment.