Bronchial Challenge Research Articles

Nasal allergen and methacholine provocation tests influence co‑expression patterns of TGF‑β/SMAD and MAPK signaling pathway genes in patients with asthma.

Asthma is characterized by chronic bronchial inflammation and is a highly heterogeneous disease strongly influenced by both specific and non-specific exogenous factors. The present study was performed to assess the effect of nasal allergen provocation tests and methacholine provocation tests on the mRNA co-expression patterns of genes (SMAD1/3/6/7, MPK1/3 and TGFB1/3) involved in SMAD and non-SMAD TGF-β signaling pathways in patients with asthma. Reverse transcription-quantitative PCR was performed on blood samples taken pre-provocation and 1 h post-provocation to assess gene expression changes. Of the 59 patients studied, allergen provocations were administered to 27 patients and methacholine provocations to 32 patients. Correlations between expression levels of studied genes were found to be influenced markedly by the challenge administered, challenge test result and time elapsed since challenge. Importantly, increases in expression levels for four gene pairs (MAPK1-SMAD3, MAPK3-SMAD3, SMAD1-SMAD3 and SMAD3-TGFB1) were found to correlate significantly with asthma occurrence in the allergen provocation cohort, but not in the methacholine provocation cohort. The present study allows us to draw the conclusion that both intranasal allergen and bronchial methacholine challenges influence mRNA co-expression patterns of the SMAD1/3/6/7, MPK1/3 and TGFB1/3 genes.

Rapid Access Diagnostics for Asthma (RADicA): protocol for a prospective cohort study to determine the optimum series of investigations to diagnose asthma using conventional and novel tests

IntroductionThe diagnosis of asthma is often based on characteristic patterns of symptoms in the absence of an alternative explanation, resulting in over and under diagnosis. Therefore, diagnostic guidelines usually recommend...

Asthma diagnosis: a comparison of established diagnostic guidelines in adults with respiratory symptoms

Considerable variability exists between asthma diagnostic guidelines. We tested the performance characteristics of the European Respiratory Society (ERS), the National Institute for Health and Care Excellence (NICE) and the Global Initiative for Asthma (GINA) guidelines for the diagnosis of asthma in adults. In this prospective observational study (ISRCTN-11676160, May 2019-June 2022), participants referred from primary care with clinician-suspected asthma underwent comprehensive investigation including: spirometry, bronchodilator reversibility, fractional exhaled nitric oxide, peak expiratory flow variability, bronchial challenge testing with methacholine and mannitol, and responsiveness to inhaled corticosteroid therapy. Results were reviewed by a panel of asthma specialists to determine asthma diagnosis (reference standard) and compared to each diagnostic test and the ERS, NICE and GINA diagnostic algorithms (index tests). The sensitivity, specificity, positive predictive and negative predictive values were calculated. One hundred and forty adults were enrolled and 118 given a definitive diagnostic outcome [75 female; mean (SD) age 36 (12) years; 70 (59%) with asthma] and included in the analysis. Sensitivity of individual tests was poor (15-62%), but they provided good specificity at the most stringent thresholds (range: 88-100%). The sensitivity/specificity of ERS, NICE and GINA was 81/85%, 41/100% and 47/100%, respectively. Concordance between guidelines was only moderate (Cohen's Kappa 0.45-0.51). Current guidelines for the diagnosis of asthma in adults provide either excellent specificity but low sensitivity (GINA and NICE) or only reasonable sensitivity and specificity (ERS). All guidelines therefore have limitations with regards to their clinical application; new guidelines are needed but should be tested prospectively before roll out. This work was supported by the Manchester NIHR Biomedical Research Centre (BRC) (grant no. BRC-1215-20007, and NIHR203308), Asthma UK/Innovate (grant no. AUK-PG-2018-406), GSK ID 212474 and North West Lung Centre Charity.

Implementation of a Virtual Pulmonary Physiology Course in Latin America.

Knowledge of respiratory physiology is essential for the diagnosis and treatment of respiratory diseases. During the coronavirus disease (COVID-19) pandemic, face-to-face education was inadequate, leading to the implementation of virtual programs for pulmonary fellows from Latin America. This study describes our experience with the implementation of a virtual education program involving pulmonary function tests (PFTs) for pulmonary fellows in Latin America. A learning program on PFTs was designed by the Department of Respiratory Physiology at the National Institute of Respiratory Diseases in Mexico City, and fellows in pulmonology were invited to participate in the program by their academic professors. The program was performed virtually on an online platform over 3 months. The topics covered included respiratory mechanics, gas exchange, and cardiopulmonary exercise tests. Students were asked to complete an evaluation before and after each lecture as well as before and after the entire course. A total of 205 fellows from 12 countries participated in the course, and fewer than 50% completed assessments before and after the course. The results showed that fellows had relatively high initial knowledge of oxygen desaturation and cardiopulmonary exercise tests, whereas relative deficiencies were found in maximal respiratory pressure and bronchial challenge tests. The highest grade was in the spirometry test, whereas the lowest was in the bronchial challenge test. Overall, the fellows demonstrated improved performance in the post-course evaluations. Virtual education in PFTs is feasible and can have a positive impact on the training of pulmonary fellows from Latin America.

Local Allergic Rhinitis

Local allergic rhinitis (LAR) is defined by a clinical history suggestive of allergic rhinitis (AR), negativity of systemic IgE measurement and positive response to nasal allergen challenge (NAC). The term local respiratory allergy includes LAR, local allergic asthma (positive response in bronchial allergen challenge) and dual allergic rhinitis defined by the coexistence of AR and LAR. LAR worsens in severity and presence of comorbidities over time, and it is an independent entity from AR. Prevalence is higher in Mediterranean countries. LAR onset occurs during childhood in 36% of cases. Physiopathological features of LAR are: increased nasal eosinophilic inflammation, tryptase and eosinophil cationic protein, and presence of nasal specific IgE in secretions of 20-40% of subjects. A recent study demonstrated increase in sequential class switch recombination to IgE markers in mucosa of LAR with accumulation of IgE+ CD38+ plasmablasts. Moreover, there is increased expression in B cells of mucosal homing receptors CXCR3+ and CXCR4 in peripheral blood, with accumulation of Th9 and Th2 cells. NAC is the gold standard in the diagnosis of LAR. The measurement of specific IgE in nasal secretions basophil activation test or are still not suitable for diagnosis. There is ample evidence of the usefulness of allergen immunotherapy in the treatment in LAR after 4 DBPCRT in 152 patients. In conclusion, knowledge about LAR is continuously increasing, with detailed definition of physiopathological mechanisms and new phenotypes. More awareness of the disease should be promoted among different specialists, and NAC must be considered an essential diagnostic tool in any age group, including children.

The Fractional exhaled Nitric Oxide (FeNO)- test as add-on test in the diagnostic work-up of asthma: a study protocol.

Asthma is a common disease characterized by chronic inflammation of the lower airways, bronchial hyperactivity, and (reversible) airway obstruction. The Global Initiative of Asthma Guideline recommends a flowchart to diagnose asthma with first-step spirometry with reversibility and a bronchial challenge test (BPT) with histamine or methacholine as a second step [1]. The BPT is considered burdensome, time-consuming for patients and staff, can cause side effects, and is expensive. In addition, this test strongly encumbers lung function capacity. Elevated Nitric Oxide (NO) is associated with airway eosinophilic inflammation in asthma patients and can be measured in exhaled air with the Fractional exhaled (Fe) NO-test. This low-burden FeNO-test could be used as an 'add-on' test in asthma diagnostics [2, 3]. This multi-center prospective study (Trial number: NCT06230458) compares the 'standard asthma diagnostic work-up' (spirometry with reversibility and BPT) to the 'new asthma diagnostics work-up' (FeNO-test as an intermediate step between the spirometry with reversibility and the BPT), intending to determine the impact of the FeNO-based strategy, in terms of the number of avoided BPTs, cost-effectiveness and reduced burden to the patient and health care. The cost reduction of incorporating the FeNO-test in the new diagnostic algorithm will be established by the number of theoretically avoided BPT. The decrease in burden will be studied by calculating differences in the Visual Analogue Scale (VAS) -score and Asthma Quality of Life Questionnaire (AQLQ) -score after the BPT and FeNO-test with an independent T-test. The accuracy of the FeNO-test will be calculated by comparing the FeNO-test outcomes to the (gold standard) BPTs outcomes in terms of sensitivity and specificity. The intention is to include 171 patients. The local medical ethics committee approved the proposed study and is considered a low-burden and risk-low study. The local medical ethics committee registration number: R23.005. Strengths: This is the first study that investigates the value of the FeNO-test (cut off ≥ 50 ppb) as an add-on test, to determine the impact of the FeNO-based strategy, in terms of the number of avoided BPTs, cost-effectiveness, and reduced burden on the patient and health care. High FeNO levels may also be observed in other diseases such as eosinophilic chronic bronchitis and allergic rhinitis. The FeNO-test can be used to rule in a diagnosis of asthma with confidence, however, due to the poor sensitivity it is not suitable to rule out asthma.

Prevalence and Factors Affecting the Optimal and Non-optimal Peak Inspiratory Flow Rate in Stable and Exacerbation Phases of Chronic Obstructive Pulmonary Disease and Bronchial Asthma in India.

Chronic obstructive pulmonary disease (COPD) and bronchial asthma pose significant threats and challenges to global health care, emphasizing the need for precise inhaler therapies to overcome this burden. The optimal peak inspiratory flow rate (PIFR) is a crucial determinant for the right selection and effective use of an inhaler device. It also helps to improve the treatment effectiveness of obstructive airway diseases worldwide as it allows effective drug delivery to distal airways and lung parenchyma. It is used as a selection criterion by physicians around the worldfor selecting personalized inhaler devices. To find out the optimal and non-optimal PIFR prevalence and its influencing factors in stable and exacerbation phases of COPD and bronchial asthma in Tamil Nadu, India. It is a single-center, observational, cross-sectional study conducted from February 2022 to August 2023. The patients who meet the diagnostic criteria specified by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for COPD and the Global Initiative for Asthma (GINA) guidelines for bronchial asthma are enrolled in our study. The PIFR was measured using a hand-held digital spirometry device, along with demographic data collection. Statistical analyses, including t-tests and chi-square tests, were performed using SPSS version 21 (IBM Corp., Armonk, NY). Gender, height, and disease severity significantly impacted the PIFR. Females, normal BMI individuals, and those with moderate disease severity exhibited higher optimal PIFR rates. Stable or exacerbation phases, disease, and smoking status do not influence either optimal or non-optimal PIFR. Notably, substantial differences in lung function parameters were observed between optimal (60-90 L/min) and non-optimal PIFR (insufficient: <30 L/min, suboptimal: 30-60 L/min, excessive: >90 L/min) groups, highlighting their impact on respiratory health. This study emphasizes the importance of personalized inhaler strategies, considering gender, height, and disease severity. Proper inhaler device selection, continuous monitoring of inhaler technique, and tailored inhaler education at every OPD visit are vital for optimizing effective COPD and bronchial asthma management and improving adherence to treatment.

Standard technical specifications for methacholine chloride (Methacholine) bronchial challenge test (2023)

Standard technical specifications for methacholine chloride (Methacholine) bronchial challenge test (2023)

Novel Serum Biomarkers for Patients with Allergic Asthma Phenotype.

In distinguishing the allergic asthma (AA) phenotype, it has been identified that specific biomarkers could assist; however, none of them are considered ideal. This study aimed to analyze three groups of biologically active substances in the serum. Twenty steroid-free AA patients, sensitized to Dermatophagoides pteronyssinus, and sixteen healthy subjects (HSs) were enrolled in this study. Blood samples were collected from all patients. Additionally, all AA patients underwent a bronchial allergen challenge (BAC) with Dermatophagoides pteronyssinus, all of which were positive, and blood samples were collected again 24 h later. The concentrations of ten biologically active substances were measured in the serum samples, using enzyme-linked immunosorbent assay (ELISA) and the Luminex® 100/200™ System technology for bead-based multiplex and singleplex immunoassays. Descriptive and analytical statistical methods were used. A p-value of 0.05 or lower was considered statistically significant. The soluble interleukin 5 receptor subunit alpha (sIL-5Rα) and thioredoxin 1 (TRX1) concentrations were significantly increased, whereas those of tyrosine-protein kinase Met (MET), pentraxin 3 (PTX3), and I C-telopeptide of type I collagen (ICTP) were decreased in the AA group compared with the HS group. A significant positive correlation was noted for sIL-5Rα with fractional exhaled nitric oxide (FeNO), blood eosinophil (EOS) count, and total immunoglobulin E (IgE) levels, and a negative correlation was noted with forced expiratory volume in 1 s (FEV1). Moreover, PTX3 showed negative correlations with blood EOS count and total IgE levels, whereas ICTP exhibited a negative correlation with the blood EOS count. In conclusion, this study demonstrated that the serum concentrations of MET, PTX3, TRX1, ICTP, and particularly sIL-5Rα could potentially serve as biomarkers of the AA phenotype.

Correlation between allergic rhinitis and asthma

The concept of the „unified respiratory disease” emphasizes the close connection between the upper and lower respiratory pathways in allergic diseases. The structure and function of the upper and lower respiratory pathways are closely interconnected, forming a single morphofunctional entity. Studies show that allergic rhinitis and asthma share the same inflammatory cells and Th2-type cytokines in nasal and bronchial biopsy samples. Additionally, bronchial challenges can induce inflammation in the nasal area and vice versa, suggesting a close link between the two conditions. The epithelial barrier, through its junctions and constituent proteins, plays an essential role in maintaining homeostasis and protection against external factors, and the complex interactions between these two segments of the respiratory pathways are an important research topic. Tight junctions, adhesion junctions, gap junctions, as well as desmosomes contribute to maintaining epithelial integrity and regulating inflammation. The constituent proteins of these junctions and their interactions play crucial roles in the proper functioning of the epithelial barrier. Respiratory allergens such as dust mites, pollen, pets, and fungi are risk factors for both conditions. Recent studies have highlighted numerous environmental factors capable of compromising epithelial integrity and disrupting its barrier function, including allergens with protease activity. Allergenic proteases from various sources, such as dust mites, pollen, fungi, and kitchen cockroaches, have been identified and characterized. Studies have shown the significant role these allergens play in compromising the integrity of the respiratory epithelium and triggering allergic responses. They can activate specific receptors, inducing inflammation and disrupting the epithelium’s barrier function. For example, proteases from dust mites cleave junctional proteins, promoting allergen transport and triggering the release of proinflammatory cytokines. The same effect is observed with pollen, fungi, and kitchen cockroaches. The proteolytic activity of allergens contributes to sensitization and the progression of allergic diseases. Understanding these mechanisms can guide the development of effective therapeutic strategies for preventing and treating these conditions.

Usefulness of functional tests in the diagnosis of allergic asthma

Respiratory function tests are of crucial importance in the diagnosis, assessment and management of asthma. Asthma, a chronic respiratory condition characterized by inflammation and airway obstruction, affects millions of people globally. Respiratory function tests, such as spirometry and bronchial challenge tests, are vital tools in determining the severity and type of asthma, providing objective data on lung function. This article highlights how these tests help in personalizing treatment, allowing doctors to adjust medication regimens and monitor their effectiveness. It also discusses the role of the tests in identifying patients’ responses to various triggers and in the management of asthma exacerbations. Through the regular and strategic use of respiratory function tests, better asthma control can be achieved, significantly improving the patients’ quality of life.

Anticipating undiagnosed asthma in symptomatic adults with normal pre- and post-bronchodilator spirometry: a decision tool for bronchial challenge testing

BackgroundSome patients with asthma demonstrate normal spirometry and remain undiagnosed without further testing.ObjectiveTo determine clinical predictors of asthma in symptomatic adults with normal spirometry, and to generate a tool to help clinicians decide who should undergo bronchial challenge testing (BCT).MethodsUsing random-digit dialling and population-based case-finding, we recruited adults from the community with respiratory symptoms and no previous history of diagnosed lung disease. Participants with normal pre- and post-bronchodilator spirometry subsequently underwent BCT. Asthma was diagnosed in those with symptoms and a methacholine provocative concentration (PC20) of < 8 mg/ml. Sputum and blood eosinophils, and exhaled nitric oxide were measured. Univariate analyses identified potentially predictive variables, which were then used to construct a multivariable logistic regression model to predict asthma. Model sensitivity, specificity, and area under the receiver operating curve (AUC) were calculated.ResultsOf 132 symptomatic individuals with normal spirometry, 34 (26%) had asthma. Of those ultimately diagnosed with asthma, 33 (97%) answered ‘yes’ to a question asking whether they experienced cough, chest tightness or wheezing provoked by exercise or cold air. Other univariate predictors of asthma included female sex, pre-bronchodilator FEV1 percentage predicted, and percent positive change in FEV1 post bronchodilator. A multivariable model containing these predictive variables yielded an AUC of 0.82 (95% CI: 0.72–0.91), a sensitivity of 82%, and a specificity of 66%. The model was used to construct a nomogram to advise clinicians which patients should be prioritized for BCT.ConclusionsFour readily available patient characteristics demonstrated a high sensitivity and AUC for predicting undiagnosed asthma in symptomatic adults with normal pre- and post-bronchodilator spirometry. These characteristics can potentially help clinicians to decide which individuals with normal spirometry should be investigated with bronchial challenge testing. However, further prospective validation of our decision tool is required.

The effect of bradykinin 1 receptor antagonist BI 1026706 on pulmonary inflammation after segmental lipopolysaccharide challenge in healthy smokers

BackgroundBradykinin 1 receptor (B1R) signalling pathways may be involved in the inflammatory pathophysiology of chronic obstructive pulmonary disease (COPD). B1R signalling is induced by inflammatory stimuli or tissue injury and leads to activation and increased migration of pro-inflammatory cells. Lipopolysaccharide (LPS) lung challenge in man is an experimental method of exploring inflammation in the lung whereby interference in these pathways can help to assess pharmacologic interventions in COPD. BI 1026706, a potent B1R antagonist, was hypothesized to reduce the inflammatory activity after segmental lipopolysaccharide (LPS) challenge in humans due to decreased pulmonary cell influx. MethodsIn a monocentric, randomized, double-blind, placebo-controlled, parallel-group, phase I trial, 57 healthy, smoking subjects were treated for 28 days with either oral BI 1026706 100 mg bid or placebo. At day 21, turbo-inversion recovery magnitude magnetic resonance imaging (TIRM MRI) was performed. On the last day of treatment, pre-challenge bronchoalveolar lavage fluid (BAL) and biopsies were sampled, followed by segmental LPS challenge (40 endotoxin units/kg body weight) and saline control instillation in different lung lobes. Twenty-four hours later, TIRM MRI was performed, then BAL and biopsies were collected from the challenged segments. In BAL samples, cells were differentiated for neutrophil numbers as the primary endpoint. Other endpoints included assessment of safety, biomarkers in BAL (e.g. interleukin-8 [IL-8], albumin and total protein), B1R expression in lung biopsies and TIRM score by MRI as a measure for the extent of pulmonary oedema. ResultsAfter LPS, but not after saline, high numbers of inflammatory cells, predominantly neutrophils were observed in the airways. IL-8, albumin and total protein were also increased in BAL samples after LPS challenge as compared with saline control. There were no significant differences in cells or other biomarkers from BAL in volunteers treated with BI 1026706 compared with those treated with placebo. Unexpectedly, neutrophil numbers in BAL were 30% higher and MRI-derived extent of oedema was significantly higher with BI 1026706 treatment compared with placebo, 24 h after LPS challenge. Adverse events were mainly mild to moderate and not different between treatment groups. ConclusionsTreatment with BI 1026706 for four weeks was safe and well-tolerated in healthy smoking subjects. BI 1026706 100 mg bid did not provide evidence for anti-inflammatory effects in the human bronchial LPS challenge model. Trial registrationThe study was registered on January 14, 2016 at ClinicalTrials.gov (NCT02657408).

Changes in exhaled volatile organic compounds following indirect bronchial challenge in suspected asthma

BackgroundInhaled mannitol provokes bronchoconstriction via mediators released during osmotic degranulation of inflammatory cells, and, hence represents a useful diagnostic test for asthma and model for acute attacks. We hypothesised that...

Organ-specific allergen challenges in airway allergy: current utilities and future directions.

Atopy has been long used as the screening method for airway allergy. Nevertheless, aeroallergens can trigger respiratory symptoms not only in atopic patients (atopic respiratory allergy, ARA), but also in non-atopic subjects (local respiratory allergy, LRA). Moreover, ARA and LRA can coexist in the same patient, and this clinical scenario has been called dual respiratory allergy (DRA). When the clinical history cannot determine the relevance of sensitizations in ARA patients, nasal, conjunctival or bronchial allergen challenges (NAC, CAC and BAC, respectively) should be conducted. Moreover, these tests are required to identify patients with LRA and DRA. The clarification of the allergic triggers of airway diseases has a profound impact on the management strategies the patients can be offered. Importantly, allergen immunotherapy (AIT) remains as the only disease-modifying intervention for ARA. Recent data indicate that AIT might have a similar effect on LRA patients. Nevertheless, AIT success relies largely on the correct phenotyping of allergic individuals, and NAC, CAC and BAC are very helpful tools in this regard. In this review, we will summarize the main indications and methodology of CAC, NAC and BAC. Importantly, the clinical implementation of these tests might translate into precision medicine approaches and better health outcomes for patients with airway allergy.

Use of methacoline challenge test to detect bronchial hyperresponsiveness in children with persistent rhinitis

Purpose: The incidence of persistent rhinitis in childhood is increasing day by day. Since bronchial hyperreactivity (BHR) and asthma can also be seen in a significant proportion of patients with persistent rhinitis, the use of markers that may indicate the risk of developing asthma in these patients is very important in clinical follow-up. In this study, it was aimed to demonstrate the relationship between persistent rhinitis and asthma in childhood using the bronchial methacoline challenge test (BMCT) and to investigate other factors associated with the risk of developing asthma in patients with persistent rhinitis.&#x0D; Materials and Methods: Patients aged 6-18 years who presented with findings of persistent rhinitis were evaluated with a detailed history, physical examination, and spirometry. Patients with normal examination findings and spirometry findings, and patients whose examination findings and nasal inflammation findings were compatible with moderate-to-severe rhinitis were included in the study, and their atopy status was evaluated by skin prick test, and their BHR was evaluated by BMCT.&#x0D; Results: Seventy-three patients were included in the study. The mean age was 9±2.7years, 45.2% of the patients were male. 63% of the patients were allergic and family history of allergy was present in 45.2% of the patients. 82.2% of the patients had BHR detected with BMCT. The median blood eosinophil count (BEC) was 320/mm3 and the IgE level was 160kU/L. Patients with atopy had statistically significantly higher IgE and BEC values compared with non-allergic patients. Patients with BHR were found to be younger, and had higher median BEC values. In multivariant analysis, it was observed that the patient's age300/mm3, and IgE levels&gt;250IU/L increased the probability of detecting BHR with BMCT. &#x0D; Conclusion: Care should be taken for every patient with persistent rhinitis because of the risk of BHR and asthma. Atopy examinations should be performed, but the possibility of developing BHR and asthma should not be overlooked even in the patients who are non- allergic.

ADX-629, A Reactive Aldehyde Species (RASP) Inhibitor, Reduced Eosinophilia In Asthmatic Subjects After Bronchial Allergen Challenge (BAC)

Aeroallergens including house dust mite (HDM) and pet dander are well-known provocateurs in atopic asthma. ADX-629, a novel RASP inhibitor, acts on inflammatory cytokines implicated in asthma. In this clinical trial, airway hypersensitivity with Methacholine Challenge (MCh), post-BAC FEV1, exhaled NO (FeNO), and sputum eosinophils (EOS) were studied to evaluate ADX-629 in asthma.

Allergen challenge tests in allergen immunotherapy: State of the art.

Treatment effects in allergen immunotherapy (AIT) studies are based on symptomatic improvement, and evaluations of naturally exposed patients do often show weak efficacy. Allergen challenge tests, such as conjunctival (CAC), nasal (NAC), or bronchial (BAC) challenge tests, or challenges in allergen exposure chambers (AEC) are accepted by regulators for AIT phase II studies only. This review aims to describe different allergen challenge test methods, summarizes safety and limitations for each, and discusses their potential for use in AIT trials. Organ-specific allergen challenges provide information about individual reactivity, reaction threshold, and organ-specific efficacy of AIT. AECs, targeting all affected organs simultaneously, were developed to investigate disease mechanisms and treatment effects under controlled and reproducible conditions. A high level of standardization is existing for NAC only; in CAC and BAC, the toolbox is limited to subjective symptom scoring with no validated objective parameters identified yet. AECs are complex and heterogenous; correlation of systems and comparability of study data is claimed. All challenge methods are safe when conducted by experienced staff.

Prediction of bronchodilation test in adults with chronic cough suspected of cough variant asthma.

Many patients with cough variant asthma (CVA) are underdiagnosed and undertreated due to the atypical symptoms, low diagnostic sensitivity of bronchodilator response (BDR), and limited application of bronchial challenge test. To investigate whether airway reversibility in BDR can predict CVA diagnosis in patients with chronic cough and negative BDR. This open-label, prospective cohort study included patients with chronic cough, nearly normal chest CT scan, and negative BDR results. Inhaled corticosteroids and long-acting β2 agonists were given for 4 weeks. The confirmed diagnosis of CVA was defined as improved symptoms and an increase of forced expiratory volume in 1 s (FEV1) by >12% and >200 mL after 4 weeks of treatment. Of 155 patients recruited, 140 completed the study. Patients in the CVA positive diagnosis group had greater absolute (Δ) and percent (Δ%) improvements in FEV1 and forced expiratory flows (FEFs), and higher fractional exhaled nitric oxide (FENO) than in the CVA negative diagnosis group. The area under the receiver operating characteristic curves (AUCs) of ΔFEV1%, FEF25-75%pred (percentage of predicted forced expiratory flow at 25% to 75%) and FENO for CVA positive diagnosis was 0.825, 0.714, and 0.637, with cutoff values of 5.90%, 61.99% and 41.50 ppb, respectively. A joint model of ΔFEV1% combined with FEF25-75%pred or FENO increased the AUC to 0.848 and 0.847, respectively. ΔFEV1% in BDR can predict a CVA diagnosis and response to anti-asthma treatment in patients with chronic cough and negative BDR. [http://www.chictr.org.cn/index.aspx], identifier [ChiCTR2000029065].

IL-5 and GM-CSF, but Not IL-3, Promote the Proliferative Properties of Inflammatory-like and Lung Resident-like Eosinophils in the Blood of Asthma Patients.

Blood eosinophils can be described as inflammatory-like (iEOS-like) and lung-resident-like (rEOS-like) eosinophils. This study is based on the hypothesis that eosinophilopoetins such as interleukin (IL)-3 and IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) alter the proliferative properties of eosinophil subtypes and may be associated with the expression of their receptors on eosinophils. We investigated 8 individuals with severe nonallergic eosinophilic asthma (SNEA), 17 nonsevere allergic asthma (AA), and 11 healthy subjects (HS). For AA patients, a bronchial allergen challenge with Dermatophagoides pteronyssinus was performed. Eosinophils were isolated from peripheral blood using high-density centrifugation and magnetic separation methods. The subtyping of eosinophils was based on magnetic bead-conjugated antibodies against L-selectin. Preactivation by eosinophilopoetins was performed by incubating eosinophil subtypes with IL-3, IL-5, and GM-CSF, and individual combined cell cultures were prepared with airway smooth muscle (ASM) cells. ASM cell proliferation was assessed using an Alamar blue assay. The gene expression of eosinophilopoetin receptors was analyzed with a qPCR. IL-5 and GM-CSF significantly enhanced the proliferative properties of iEOS-like and rEOS-like cells on ASM cells in both SNEA and AA groups compared with eosinophils not activated by cytokines (p < 0.05). Moreover, rEOS-like cells demonstrated a higher gene expression of the IL-3 and IL-5 receptors compared with iEOS-like cells in the SNEA and AA groups (p < 0.05). In conclusion: IL-5 and GM-CSF promote the proliferative properties of iEOS-like and rEOS-like eosinophils; however, the effect of only IL-5 may be related to the expression of its receptors in asthma patients.