Methacholine Challenge Research Articles

Use of capnography for prediction of obstruction severity in non-intubated COPD and asthma patients

BackgroundCapnography waveform contains essential information regarding physiological characteristics of the airway and thus indicative of the level of airway obstruction. Our aim was to develop a capnography-based, point-of-care tool that can estimate the level of obstruction in patients with asthma and COPD.MethodsTwo prospective observational studies conducted between September 2016 and May 2018 at Rabin Medical Center, Israel, included healthy, asthma and COPD patient groups. Each patient underwent spirometry test and continuous capnography, as part of, either methacholine challenge test for asthma diagnosis or bronchodilator reversibility test for asthma and COPD routine evaluation. Continuous capnography signal, divided into single breaths waveforms, were analyzed to identify waveform features, to create a predictive model for FEV1 using an artificial neural network. The gold standard for comparison was FEV1 measured with spirometry.Measurements and main resultsOverall 160 patients analyzed. Model prediction included 32/88 waveform features and three demographic features (age, gender and height). The model showed excellent correlation with FEV1 (R = 0.84), R2 achieved was 0.7 with mean square error of 0.13.ConclusionIn this study we have developed a model to evaluate FEV1 in asthma and COPD patients. Using this model, as a point-of-care tool, we can evaluate the airway obstruction level without reliance on patient cooperation. Moreover, continuous FEV1 monitoring can identify disease fluctuations, response to treatment and guide therapy.Trial registrationclinical trials.gov, NCT02805114. Registered 17 June 2016, https://clinicaltrials.gov/ct2/show/NCT02805114

Blood eosinophils, FeNO and small airways dysfunction in predicting airway hyperresponsiveness in patients with asthma-like symptoms

Purpose In patients with suspected asthma and no airflow limitation in spirometry, methacholine challenge testing (MCT) for airway hyperresponsiveness (AHR) is an option of documenting variable airflow limitation. The goal of the study was to assess the ability of blood eosinophils, fractional concentration of exhaled nitric oxide (FeNO) and distal airways function to discriminate patients with AHR from those with normal airway responsiveness (AR). Methods We analyzed baseline data from 42 participants who underwent MCT because of asthma-like symptoms and no airflow limitation in spirometry. Results Eosinophil count was higher among participants with borderline AHR comparing to those with normal AR (340 cells/µL, IQR 285-995 vs. 125 cells/µL, IQR 75-180, post-hoc p = 0.041). FeNO and percent predicted of functional residual volume (FRC%pred) were higher in participants with moderate-marked AHR compared to those with normal AR (40 ppb, IQR 30.5-100.5 vs. 18 ppb, IQR 13-50, post-hoc p = 0.008; 140.1%±17.0% vs. 107.3%±20.7%, post-hoc p < 0.001, respectively). Percentage predicted of the maximal expiratory flow at 25% of the forced vital capacity (MEF25%pred) was lower in participants with mild AHR and borderline AHR compared to those with normal AR (72.9%±16.9% vs. 113.0%±36.8%, post-hoc p = 0.017; 73.3%±15.9% vs. 113.0%±36.8%, post-hoc p = 0.045; respectively). Level of AHR correlated with eosinophil count, FeNO, MEF25%pred, forced expiratory flow between 25% and 75% of vital capacity (FEF25-75%pred), FRC%pred and specific airway resistance (sRaw). Conclusions Blood eosinophils, FeNO and small airways dysfunction markers are related to the level of AR to methacholine in patients with asthma-like symptoms and no airflow limitation in spirometry.

Supramolecular green chemistry; An eco-friendly spectrophotometric approach for determination of non-chromophoric methacholine via host-guest interactions with 4-sulfocalix[4]arene

Supramolecular chemistry has gained an increasing attention in different disciplines of pharmaceutical community. Methacholine chloride (MCh) is a parasympathomimetic bronchoconstrictor which is a gold standard diagnostic tool for asthma through methacholine challenge test. The determination of MCh is a substantial analytical problem due to the lack of chromophore in its structure, therefore direct spectrophotometry becomes not possible for MCh quantification. In this work, we have exploited the high spectral absorptivity of 4-sulfocalix[4]arene (SCX4) and its exceptional complexation towards choline-mimetic guests to develop a method to quantify MCh. The host guest interaction between MCh and SCX4 produces an inclusion complex that can be investigated using different UV-spectrophotometric methods [dual wavelength method (DWM), ratio difference method (RDM) and ratio derivative method (1DD)]. The proposed methods are based on measurement of the manipulated absorbance of the formed complex peak after resolving the overlap from the host SCX4 spectrum followed by quantitation of MCh. Validation of the methods was performed in compliance with ICH guidelines, regression analysis showed good linearity over the concentration ranges of 10.0–150.0 μM for DWM and 10.0–170.0 μM for RDM and 1DD. The limit of quantification and detection were estimated to be 7.5 μM, 2.5 μM for DWM, 5.2 μM, 1.6 μM for RDM and 5.0 μM, 1.7 μM for 1DD, respectively. The complexation binding ratio and stability constant were calculated to be 1:1 and 7.20 × 104 ± 1.60 M−1, respectively, using continuous variation Job's method. Also, these methods have been used to determine MCh in Povocholine® formulation and in spiked human plasma. Moreover, the greenness of the proposed analytical procedures was evaluated by National Environmental Methods Index and Analytical Eco-Scale and the promising junction between the supramolecular chemistry and the eco-friendly spectrophotometric approaches was highlighted.

Identifying bronchoconstriction from the ratio of diaphragm EMG to tidal volume

BackgroundA fall of ≥ 20 % in forced expiratory volume in the first second (FEV1) with a cumulative dose of histamine ≤ 7.8 μmol is considered to indicate bronchial hyperactivity, but no method exists for patients who cannot perform spirometry properly. Here we hypothesized that increases in respiratory central output measured by chest wall electromyography of the diaphragm (EMGdi-c) expressed as a function of tidal volume (EMGdi-c/VT) would have discriminative power to detect a ‘positive’ challenge test. MethodsIn a physiological study EMGdi was recorded from esophageal electrode (EMGdi-e) in 16 asthma patients and 16 healthy subjects during a histamine challenge test. In a second study, EMGdi from chest wall surface electrodes (EMGdi-c) was measured during a histamine challenge in 44 asthma patients and 51 healthy subjects. VT was recorded from a digital flowmeter during both studies. ResultsWith histamine challenge test the change in EMGdi-e/VT in patients with asthma was significantly higher than that in healthy subjects (104.2 % ± 48.6 % vs 0.03 % ± 17.1 %, p < 0.001). Similarly there was a significant difference in the change of EMGdi-c/VT between patients with asthma and healthy subjects (90.5 % ± 75.5 % vs 2.4 % ± 21.7 %, p < 0.001). At the optimal cut-off point (29 % increase in EMGdi-c/VT), the area under the ROC curve (AUC) for detection of a positive test was 0.91 (p < 0.001) with sensitivity 86 % and specificity 92 %. ConclusionsWe conclude that EMGdi-c/VT may be used as an alternative for the assessment of bronchial hypersensitivity and airway reversibility to differentiate patients with asthma from healthy subjects.

SKP2-Promoted Ubiquitination of FOXO3 Promotes the Development of Asthma.

Asthma is a respiratory disease with a dramatically increasing incidence globally. The present study explored the roles of S-phase kinase-associated protein 2 (SKP2) and forkhead box O3 (FOXO3) in asthma and their involvement in the Krüppel-like factor 15-lipoprotein receptor-related protein 5 (KLF15-LRP5) axis. SKP2 expression in patients with asthma and OVA-induced asthmatic Sprague Dawley rats was detected by reverse transcription quantitative PCR and Western blot assays. Alterations in SKP2 and LRP5 expression were evaluated in OVA-induced asthmatic rats, followed by measurement of inflammatory cytokines using ELISA and airway resistance using a methacholine challenge test. We applied TGF-β1 to establish the airway smooth muscle cell (ASMC) proliferation model of asthma. The FOXO3 ubiquitination and changes in cell biological behaviors were detected using immunoprecipitation, MTT, and Annexin V/propidium iodide assays. Flow cytometry was adopted to detect cell cycle, and ELISA was used to measure the concentrations of IL-4, IL-5, IL-13, and IgE in rat bronchoalveolar lavage fluid. SKP2 was highly expressed and FOXO3 was poorly expressed in patients with asthma and in OVA-induced asthmatic rats. SKP2 silencing decreased IL-4, IL-5, IL-13, and IgE expression in rat bronchoalveolar lavage fluid, whereas SKP2 enhanced FOXO3 ubiquitination to upregulate KLF15, which bound to the LRP5 promoter in TGF-β1-induced ASMCs and increased LRP5 expression. SKP2 enhanced airway hyperresponsiveness and inflammation in the OVA-induced rat model and augmented TGF-β1-induced ASMC proliferation by inhibiting the FOXO3/KLF15/LRP5 axis. Additionally, overexpressed SKP2 resulted in reduced numbers of ASMCs in the G1 phase but increased numbers in the G2/M phase. Collectively, we show that SKP2 promotes FOXO3 ubiquitination to suppress the KLF15-LRP5 axis, thereby exacerbating asthma.

Increased risk of asthma at age 10 years for children sensitized to multiple allergens

BackgroundChildhood sensitization patterns have been previously found to be related to variable risk of early life allergic disease in several birth cohorts. ObjectiveTo determine whether these risks persist into later childhood. MethodsIn the birth cohort of the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study, previous latent class analysis based on sensitization to 10 allergens found the following 4 early life sensitization patterns at age 2 years: “highly sensitized,” “milk/egg dominated,” “peanut and inhalant(s),” and “low to no sensitization.” At an age 10 study-specific visit, children were evaluated by an allergist for current asthma and atopic dermatitis through a physical examination and interviews with the child and parent or guardian. Total and specific immunoglobulin E (IgE), spirometry, and methacholine challenge were also completed. ResultsCompared with children sensitized to none or 1 allergen, children sensitized to 4 or more food and inhalant allergens at age 2 had the highest risk of current asthma (relative risk [RR], 4.42; 95% confidence interval [CI], 2.58-7.59; P < .001) and bronchial hyperresponsiveness (RR, 1.77; 95% CI, 1.29-2.42; P < .001). In addition, they had the highest levels of total IgE (geometric mean, 800 IU/mL; 95% CI, 416-1536) among the 4 groups. Risk of current atopic dermatitis did not depend on pattern of sensitization but remained increased for children with any sensitization (RR, 2.23; 95% CI, 1.40-3.55; P < .001). No differences in spirometry (forced expiratory volume in 1 second, forced expiratory flow between 25% and 75%, and forced expiratory volume in 1 second/forced vital capacity) were identified. ConclusionThe previously reported importance of a specific pattern of sensitization in early life (sensitization to ≥4 inhalant and food allergens) continues to be associated with an increased risk of asthma, bronchial hyperresponsiveness, and high total IgE at age 10 years.

Cough - an Interdisciplinary Condition: The Pneumologist's Perspective

Cough - an Interdisciplinary Condition: The Pneumologist's Perspective Abstract. Cough is one of the most frequent reasons for a medical consultation. Patients mostly suffer from acute cough (< 2 weeks duration) and subacute cough (2 - 8 weeks) during consultation at primary care. Chronic cough (> 8 weeks) is mostly cared for by specialists. Acute and subacute cough is most frequently caused by infections with primarily viral pathogens. Chronic cough is commonly associated with obstructive airway disease (i. e. Asthma, COPD), gastroesophageal reflux and upper airway cough syndrome. Pulmonary causes are investigated by spirometry, bodyplethysmography, blood eosinophil count, exhaled nitric oxide, methacholine challenge test, chest x-rays and computed tomography. Treatment should target underlying diseases, causing cough. Trials of inhaled corticosteroids can be considered if an asthmatic cause is suspected. Secretolytics and cough-suppressing medications should be used only to reduce patient symptoms if there is no alternative causal treatment. Clinical trials show positive results for treatment of chronic refractory (no improvement of symptoms despite adequate treatment of the underlying condition) and chronic idiopathic cough with Gefapixant, a P2X3 purinergic receptor antagonist. If recent trial results are confirmed a first specific cough modulating substance might be available soon.

Kisspeptin Inhibits Airway Hyperresponsiveness in a Murine Model of Asthma

Rationale A recognized aspect of asthma is age and sex-related differences in epidemiology and clinical manifestation (boys>girls and women>men) suggesting a modulatory role of sex-steroids, particularly estrogen. However, the divergent role of estrogen in asthma pathophysiology suggests that upstream of estrogen might be crucial in asthma. Additionally, the central nervous system based studies have shown that kisspeptins (Kp) signaling is regulated by estrogen. Moreover, our recent studies have also shown that basal expression of Kp and its receptor (KISS1R) are reduced in human airway smooth muscle (ASM) cells in females as compared to males. Further, KISS1R-agonist, metastin (MTS) blunted PDGF-induced ASM cell proliferation. These shreds of evidence suggest that mechanisms upstream or independent of estrogen may be protective, but lost during the inflammatory conditions. In this study, we aimed to evaluate the effect of acute exposure of kisspeptins in regulating airway hyperresponsiveness (AHR) using a mixed allergen (MA)-induced mouse model of asthma. Methods WT C57BL/6J mice (males and females) were procured from Jackson Laboratory, USA and challenged intranasally with MA for 28 days according to NDSU IACUC approved protocol. The vehicle group received only PBS. On day 29, MTS (1.2mg/kg) was administered intranasally 10 min before the methacholine challenge. Mice were anesthetized and subjected to FlexiVent for lung mechanics to determine airway resistance (Rrs), elastance (Ers), compliance (Crs), Tissue damping (G) and elastance (H). Following this, bronchoalveolar lavage (BAL) and lung tissues were processed for differential leukocyte count (DLC) and histology (H&E and Masson's Trichome) respectively. Additionally, laser-capture microdissection (LCM) assisted qRT-PCR analysis in ASM cells was performed for genes relevant to airway remodeling. Results Interestingly, we observed thatunchallenged mice exposed to MTS alone showed decreased Rrs and improved Crs, albeit not significant compared to the vehicle group. MA-challenged mice showed a significant increase in Rrs, Ers, G, H and with reduced Crs compared to vehicle. Additionally, MA-challenged mice showed significant alterations in immune cell infiltration in the airways and remodeling changes, which were confirmed by DLC count and histology studies. MTS exposed mice showed significant improvement in MA-altered lung functions with decrease in Rrs, Ers, G, H and increased Crs compared to MA group. Conclusion Overall, our findings highlight the importance of acute kisspeptin signaling in ablating MA-induced airway inflammation and AHR. These findings suggest a novel and critical role for kisspeptin signaling in mitigating AHR, and serve as a potential therapeutic strategy to treat asthma.

Two-minute tidal breathing methacholine bronchial challenge: Comparison of two jet nebulisers.

The American Thoracic Society (ATS) guideline for methacholine challenge testing (MCT) recommended using the English Wright (EW) nebuliser. However, other brands of nebulisers are also indicated to be acceptable for this technique, but further validation of nebuliser performance is recommended. To compare the methacholine provocation concentration causing a 20% fall in forced expiratory volume in 1 second (PC20 -FEV1 ) measured by using EW nebuliser and DV 646 nebuliser. Subjects were randomly assigned to undergo 2-min tidal breathing methacholine challenge with either EW or DV 646 nebuliser on two separate days, which were at least 24 hours but not more than 7 days apart. The above procedure was repeated for each subject in 1 month, but the nebulisers were selected in a reverse order. The study includes 15 mild and stable asthmatic patients. The geometric means (SD) of methacholine PC20 measured with using EW and DV 646 nebulisers were 1.82 (6.38) mg/mL versus 0.83 (1.82) mg/mL, respectively in the initial two visits and 2.56 (6.29) mg/mL versus 0.78 (1.40) mg/mL in the following two visits (both P < 0.05). There are well correlations between PC20-EW1 and PC20-EW2 (r=0.99, P<0.01), PC20-DV1 and PC20-DV2 (r=0.88, P<0.01), and between PC20-EW1 and PC20-DV1 (r=0.91, P<0.01), PC20-EW2 and PC20-DV2 (r=0.78, P<0.01). PC20 -FEV1 measured by using the two conventional jet nebulisers was both repeatable and the results were highly correlated.

Economic Evaluation of the Use of FeNO for the Diagnosis and Management of Asthma Patients in Primary Care in Sweden.

ObjectiveTo determine the economic impact of the fraction of exhaled nitric oxide (FeNO) in asthma diagnosis and management in primary care in Sweden.MethodsAn economic model has been developed to determine the economic impact of the fraction of exhaled nitric oxide (FeNO) in asthma diagnosis and management in primary care in Sweden. The model includes the use and cost of commonly used tests, the associated outcomes and diagnostic accuracy. We compared FeNO with spirometry and reversibility testing, methacholine challenge test, allergy testing, and blood eosinophil count. One-way sensitivity analyses were performed to confirm the robustness of results.ResultsAdding FeNO measurement in asthma diagnosis resulted in cost savings of SEK 672 per patient by the fourth year. The use of FeNO testing in asthma management proved to be a dominant strategy when compared with each other test except methacholine challenge test. Sensitivity analyses confirmed the robustness of the results.ConclusionIntroducing FeNO testing in clinical practice for the diagnosis and management of asthma in primary care in Sweden is less costly than standard methods while providing similar health benefits.

Chitinase-Induced Airway Hyperreactivity and Inflammation in a Mouse Model of Nonallergic Asthma

Introduction: Environmental exposure to mites and fungi has been proposed to critically contribute to the development of IgE-mediated asthma. A common denominator of such organisms is chitin. Human chitinases have been reported to be upregulated by interleukin-13 secreted in the context of Th2-type immune responses and to induce asthma. We assessed whether chitin-containing components induced chitinases in an innate immune-dependent way and whether this results in bronchial hyperresponsiveness. Materials and Methods: Monocyte/macrophage cell lines were stimulated with chitin-containing or bacterial components in vitro. Chitinase activity in the supernatant and the expression of the chitotriosidase gene were measured by enzyme assay and quantitative PCR, respectively. Non-sensitized mice were stimulated with chitin-containing components intranasally, and a chitinase inhibitor was administered intraperitoneally. As markers for inflammation leukocytes were counted in the bronchoalveolar lavage (BAL) fluid, and airway hyperresponsiveness was assessed via methacholine challenge. Results: We found both whole chitin-containing dust mites as well as the fungal cell wall component zymosan A but not endotoxin-induced chitinase activity and chitotriosidase gene expression in vitro. The intranasal application of zymosan A into mice led to the induction of chitinase activity in the BAL fluid and to bronchial hyperresponsiveness, which could be reduced by applying the chitinase inhibitor allosamidin. Discussion: We propose that environmental exposure to mites and fungi leads to the induction of chitinase, which in turn favors the development of bronchial hyperreactivity in an IgE-independent manner.

Airway hyperresponsiveness in patients with normal spirometry results and symptoms compatible with asthma: Primary care retrospective chart review.

To evaluate the proportion of patients with symptoms suggestive of asthma and normal lung function who exhibit airway hyperreactivity with methacholine challenge testing (MCT) in primary care. Retrospective chart review. Primary care lung clinic in Toronto, Ont. A total of 69 patients presenting to the lung clinic who had symptoms compatible with asthma, normal spirometry test results, and were referred for MCT. Descriptive statistics, frequency counts, independent t tests, and 2 tests were used to examine differences in the proportion of clinical and demographic variables identified in patients with or without a positive MCT result. Effect size was determined between MCT-positive and MCT-negative patients for both categorical ( coefficient) and continuous (Hedges g) data. Twenty-one patients (30.4%) had positive MCT results, and 48 patients (69.6%) had negative MCT results. Family history of asthma and reduced baseline and postbronchodilator forced expiratory volume in 1 second were associated with a positive MCT result. The findings of this study provide insight into the utility of simple spirometry for asthma diagnosis and the need to further clarify the role of MCT in the primary care setting.

The value of small airway function parameters and fractional exhaled nitric oxide for predicting positive methacholine challenge test in asthmatics of different ages with FEV1 ≥80% predicted.

BackgroundSmall airway function parameters (SAFPs) combined with fractional exhaled nitric oxide (FeNO) can predict a positive methacholine challenge test (MCT) for asthma diagnosis. However, their predictive utility in patients with forced expiratory volume in one second (FEV1) ≥80% predicted within different age ranges remains unclear. This study aimed to assess the utility of SAFPs, alone or combined with FeNO, to predict a positive MCT in patients in two age groups (<55 and ≥55 years) with asthma‐suggestive symptoms and FEV1 ≥80% predicted.MethodsWe enrolled 846 Chinese patients with suspected asthma and standard spirometry, FeNO, and MCT findings. Using the area under the curves (AUCs), the utility of SAFPs, alone or combined with FeNO, for predicting a positive MCT was analyzed in a discovery (n = 534) and validation cohort (n = 312) in both age groups with FEV1 ≥80% predicted.ResultsIn the discovery cohort, the optimal cut‐off values for predicting a positive MCT in patients aged <55 years (74.2% and 74.9% for forced expiratory flow (FEF)50% and FEF25%–75%, respectively) were higher than those in patients aged ≥55 years (65.0% and 62.9% for FEF50%, FEF25%–75%, respectively). However, the optimal FeNO value in patients aged <55 years (43 ppb) was lower than that in patients aged ≥55 years (48 ppb). FeNO combined with SAFPs (FEF50%, FEF25%–75%) significantly increased the AUCs in both groups (≥55 years [0.851 for FEF50% and 0.844 for FEF25%–75%]; <55 years [0.865 for FEF50% and 0.883 for FEF25%–75%]) compared with a single parameter (p < 0.05). These findings were confirmed in the validation cohort. Compared with patients ≥55 years, those aged <55 years had higher and lower optimal cut‐off values for SAFPs and FeNO, respectively. The AUCs of FeNO combined with SAFPs for predicting a positive MCT for asthma diagnosis were significantly higher than those of the individual parameters (p < 0.05) in both age groups.ConclusionsThere were age‐group differences in the utility of SAFPs combined with FeNO for predicting a positive MCT. Patients with an asthma‐suggestive history and a normal FEV1 should be stratified by age when using SAFPs combined with FeNO to predict a positive MCT.

Genetic variation in surfactant protein-A2 alters responses to ozone.

BackgroundIncreased exposure to Ozone (O3) is associated with adverse health effects in individuals afflicted with respiratory diseases. Surfactant protein-A (SP-A), encoded by SP-A1 and SP-A2, is the largest protein component in pulmonary surfactant and is functionally impaired by O3-oxidation.ObjectiveWe used humanized SP-A2 transgenic mice with allelic variation corresponding to a glutamine (Q) to lysine (K) amino acid substitution at position 223 in the lectin domain to determine the impact of this genetic variation in regards to O3 exposure.MethodsMice were exposed to 2ppm O3 or Filtered Air (FA) for 3 hours and 24 hrs post-challenge pulmonary function tests and other parameters associated with inflammation were assessed in the bronchoalveolar lavage (BAL) fluid and lung tissue. Additionally, mouse tracheal epithelial cells were cultured and TEER measurements recorded for each genotype to determine baseline epithelial integrity.ResultsCompared to FA, O3 exposure led to significantly increased sensitivity to methacholine challenge in all groups of mice. SP-A2 223Q variant mice were significantly protected from O3-induced AHR compared to SP-A-/- and SP-A2 223K mice. Neutrophilia was observed in all genotypes of mice post O3-exposure, however, SP-A2 223Q mice had a significantly lower percentage of neutrophils compared to SP-A-/- mice. Albumin levels in BAL were unchanged in O3-exposed SP-A2 223Q mice compared to their FA controls, while levels were significantly increased in all other genotypes of O3-exposed mice. SP-A 223Q MTECS has significant higher TEER values than all other genotypes, and WT MTECS has significantly higher TEER than the SP-A KO and SP-A 223K MTECS.SignificanceTaken together, our study suggests that expression of a glutamine (Q) as position 223 in SP-A2, as opposed to expression of lysine (K), is more protective in acute exposures to ozone and results in attenuated O3-induced AHR, neutrophilia, and vascular permeability.

A retrospective cohort study to evaluate the relationship of airway hyperresponsiveness to type 2 biomarkers in persistent asthma

irway hyperresponsiveness (AHR) is a hallmark of persistent asthma measured using direct or indirect airway bronchial challenge testing. The purpose of this study is to investigate the putative relationships between type 2 inflammatory biomarkers, airway geometry (FEV1 and FEF25-75) and specific IgE (RAST or skin prick) to AHR. We performed a retrospective analysis of our database (n = 131) of patients with asthma. Of these subjects, 75 had a histamine challenge and 56 had a mannitol challenge. Fractional exhaled nitric oxide (FeNO) and specific immunoglobulin E (IgE) but not blood eosinophils were significantly higher in patients with AHR to either histamine or mannitol. FEV1 % and FEF25 - 75 % were significantly lower in patients with AHR. Elevated Type 2 biomarkers including FeNO and specific IgE but not blood eosinophils were associated with AHR. Highlights: FeNO and specific IgE but not blood eosinophils are raised in patients with airway hyperresponsiveness.

Closing volume detection by single-breath gas washout and forced oscillation technique.

Closing volume (CV) is commonly measured by single-breath nitrogen washout (CVSBW). A method based on the forced oscillation technique was recently introduced to detect a surrogate CV (CVFOT). As the two approaches are based on different physiological mechanisms, we aim to investigate CVFOT and CVSBW relationship at different degrees and patterns of airway obstruction. A mathematical model was developed to evaluate the CVSBW and CVFOT sensitivity to different patterns of airway obstruction, either located in a specific lung region or equally distributed throughout the lung. The two CVs were also assessed during slow vital capacity (VC) maneuvers in triplicate in 13 healthy subjects and pre- and postmethacholine challenge (Mch) in 12 subjects with mild-moderate asthma. Model simulations suggest that CVSBW is more sensitive than CVFOT to the presence of few flow-limited or closed airways that modify the contribution of tracer-poor and tracer-rich lung regions to the overall exhaled gas. Conversely, CVFOT occurs only when at least ∼65% of lung units are flow limited or closed, regardless of their regional distribution. CVSBW did not differ between healthy subjects and those with asthma (17 ± 9% VC vs. 22 ± 10% VC), whereas CVFOT did (16 ± 5% VC vs. 23 ± 6% VC, P < 0.01). In patients with asthma, both CVSBW and CVFOT increased post-Mch (33 ± 7% VC P < 0.001 and 43 ± 12% VC P < 0.001, respectively). CVSBW weakly correlated with CVFOT (r = 0.45, P < 0.01). The closing capacities (CV+residual volume) were correlated (r = 0.74, P < 0.001), but the changes with Mch in both CVs and closing capacities did not correlate. CVFOT is easy to measure and provides a reproducible parameter useful for describing airway impairment in obstructive respiratory diseases.NEW & NOTEWORTHY The forced oscillation technique can identify a surrogate of closing volume (CVFOT). We investigated its relationship with the one measured by single-breath washout (CVSBW). CVFOT weakly correlates with CVSBW. The respective closing capacities were correlated, but their increases after methacholine challenge in asthmatics did not. Our results suggest that CVFOT is less sensitive than CVSBW to few flow-limited/closed airways but more specific in detecting increases in flow-limited/closed airways involving the majority of the lung.

Enhanced airway hyperresponsiveness in asthmatic children and mice with A(H1N1)pdm09 infection.

BackgroundSevere asthma exacerbation is an important comorbidity of the 2009 HIN1 pandemic (A(H1N1)pdm09) in asthmatic patients. However, the mechanisms underlying severe asthma exacerbation remain unknown. In this study, airway hyperresponsiveness (AHR) was measured in pediatric asthma patients infected with A(H1N1)pdm09. We also evaluated AHR in asthmatic mice with A(H1N1)pdm09 infection and those with seasonal influenza for comparison.MethodsAHRs in asthmatic children were defined as the provocative acetylcholine concentration causing a 20% reduction in forced expiratory volume in 1 s (PC20). To investigate the pathophysiology using animal models, BALB/c mice aged 6‐8 weeks were sensitized and challenged with ovalbumin. Either mouse‐adapted A(H1N1)pdm09, seasonal H1N1 virus (1 × 105 pfu/20 μl), or mock treatment as a control was administered intranasally. At 3, 7, and 10 days after infection, each group of mice was evaluated for AHR by methacholine challenge using an animal ventilator, flexiVent. Lung samples were resected and observed using light microscopy to assess the degree of airway inflammation.ResultsAHRs in the children with bronchial asthma were temporarily increased, and alleviated by 3 months after discharge. AHR was significantly enhanced in A(H1N1)pdm09‐infected asthmatic mice compared to that in seasonal H1N1‐infected mice (p < .001), peaking at 7 days postinfection and then becoming similar to control levels by 10 days postinfection. Histopathological examination of lung tissues showed more intense infiltration of inflammatory cells and severe tissue destruction in A(H1N1)pdm09‐infected mice at 7 days postinfection than at 10 days postinfection.ConclusionOur results suggest that enhanced AHR could contribute to severe exacerbation in human asthmatic patients with A(H1N1)pdm09 infection.

Nicotine in E-Cigarettes Dysregulates Pulmonary Inflammation and MMP-12 Expression without Effecting Respiratory Syncytial Virus Virulence

The safety of electronic cigarettes (e-cigarettes) is a major topic of discussion. The key goals of this study were to examine the contents of e-cigarette vapor and determine if nicotine altered inflammatory responses against respiratory syncytial virus (RSV) infection. E-cigarette vapor was passed through a hollow 3D-model of an adult lung, and gas chromatography detected over 50 compounds passed through the 3D model, including nicotine, propylene glycol (PG), ethanol, methanol, and diacetyl. The murine alveolar macrophage cell line MH-S cells were exposed to nicotine and e-cigarette vapor with and without nicotine. Nicotine significantly induced the expression of matrix metalloprotease (Mmp) 12 and reduced expression of Ifnβ and Tnfα. To examine the role of nicotine in lung defense against RSV infection, A/J mice were exposed to PBS, e-cigarette vapor with and without nicotine for 2 months before RSV infection. E-cigarette vapor did not influence RSV infection-induced animal weight loss, RSV infectivity, airway hyperresponsiveness during methacholine challenge, or immune cell infiltration into the lungs. However, e-cigarette vapor containing nicotine enhanced obstruction and induced secretion of MMP12 and reduced levels of Ifnβ and TNFα. In conclusion, nicotine in vaping products modulates immune responses that may impact the lungs during a respiratory infection.

Current Asthma Prevalence Using Methacholine Challenge Test in Korean Children from 2010 to 2014.

BackgroundMost epidemiological studies depend on the subjects' response to asthma symptom questionnaires. Questionnaire-based study for childhood asthma prevalence may overestimate the true prevalence. The aim of this study was to investigate the prevalence of “Current asthma” using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire and methacholine challenge test in Korean children.MethodsOur survey on allergic disease included 4,791 children (age 7–12 years) from 2010 to 2014 in Korean elementary schools. Bronchial hyperresponsiveness (BHR) was defined as provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1) (PC20) ≤ 16 mg/mL. “Current asthma symptoms” was defined as positive response to “Wheezing, current,” “Treatment, current,” or “Exercise, current.” “Current asthma” was defined when the subjects with “Current asthma symptoms” showed BHR on the methacholine challenge test or had less than 70% of predicted FEV1 value.ResultsThe prevalence of “Wheezing, ever,” “Wheezing, current,” “Diagnosis, ever,” “Treatment, current,” “Exercise, current,” and “Current asthma symptoms” was 19.6%, 6.9%, 10.0%, 3.3%, 3.5%, and 9.6%, respectively, in our cross-sectional study of Korean elementary school students. The prevalence of BHR in elementary school students was 14.5%. The prevalence of BHR in children with “Wheezing, ever,” “Wheezing, current,” “Diagnosis, ever,” “Treatment, current,” and “Exercise, current” was 22.3%, 30.5%, 22.4%, 28.8%, and 29.9%, respectively. BHR was 26.1% in those with “Current asthma symptoms.” The prevalence of “Current asthma” was 2.7%.ConclusionsOur large-scale study provides 2.7% prevalence of current asthma in Korean elementary school children. Since approximately one third of the children who have “Current asthma symptoms” present BHR, both subjective and objective methods are required to accurately predict asthma in subjects with asthma symptoms.

Analysis of PC20-FEF25%–75% and ΔFVC in the methacholine bronchial provocation test

Purpose: Forced expiratory flow between 25% and 75% (FEF25%-75%) is known to sensitively reflect bronchial obstruction. Methacho line challenge test (MCT) has shown varying reduction levels of forced vital capacity (FVC) with the reduction in forced expiratory volume in 1 second (FEV1) in asthma. The aim of this study was to evaluate the clinical implication of provocative concentration causing a 20% fall in FEF25%-75% (PC20-FEF25%-75%) and the percentage fall in FVC at the PC20 dose of methacholine (△FVC). Methods: A total of 194 children who visited the hospital due to respiratory symptoms and underwent MCT were analyzed retro spectively. The patients were divided into 3 groups. Group I had both PC20-FEV1 and PC20-FEF25%-75% above 16 mg/mL; group II had a PC20-FEF25%-75% that fell below 16 mg/mL but PC20-FEV1 was 16 mg/mL or above; group III had a PC20-FEV1 and a PC20-FEF25%-75% that both fell below 16 mg/mL. Results: In group II, PC20-FEV1 was lower (P=0.026) and the rate of change in FEV1 and FEF25%-75% from baseline to 16 mg/mL of methacholine concentration was greater than in group I (both P<0.001). Levels of PC20-FEF25%-75% were higher in group II compared to group III (P<0.001). △FVC showed a correlation with PC20-FEV1 (P<0.001) only in the whole group. Conclusion: In asthmatic children, PC20-FEF25%-75% may be associated with bronchial hyperresponsiveness. △FVC was not associated with other parameters in either group. For subjects with a positive finding of PC20-FEF25%-75% and a negative finding of MCT, the pro gression to asthma can be suspected. (Allergy Asthma Respir Dis 2021;9:141-147)