Methacholine Challenge Research Articles

141 Sickle cell disease and physical activity: Is it safe?

Primary Subject areaHematology and Oncology - PaediatricBackgroundThough physical activity (PA) is beneficial for healthy individuals and for those with chronic disease, its impact on sickle cell disease (SCD) children remains poorly studied. Moreover, patients may refrain from PA given a perceived fear of SCD complications.Objectives1) Evaluate whether SCD children engage differently in PA compared to their peers. 2) Evaluate the cardiopulmonary impact of PA in a group of SCD patients.Design/MethodsPrior to the COVID-19 pandemic, SCD patients aged 8-17 years old consented to answer a PA questionnaire (PAQ) and have their school peers answer the same PAQ. PAQ, a well-described surrogate marker of PA, is a standardized questionnaire evaluating PA during the last 7 days. Patients and their peers were approached only during the school year. A set of HbSS patients were invited to participate in a supervised exercise test including pre- and post-effort PFT, echocardiography, EKG, measurement of troponins and NT-proBNP and a methacholine challenge to evaluate exercise-induced bronchial hyperreactivity. T-test was used as statistical analysis, using SPSS V24. The study received IRB approval.ResultsQuestionnaires from 25 SCD children (13 SS and 12 SC) were compared with 36 matched-school peers. SCD patients were overall less active (p=0.04). While their level of activity was similar at school, SCD patients were overall less active after school (p=0.028), in the evening (p=0.008) and weekends (p=0.049). While the difference was significant for both SS and SC patients, SS were less active than SC, although this difference was statistically not significant. Five HbSS patients on HU were subjected to an exercise test. There were no statistical differences in the pre- and post-PA evaluations including measurements of troponin, NT-proBNP and functional testing. None of them had exercise-induced hyperreactivity.ConclusionOverall, SCD patients are less active than their peers, mostly outside of school. The absence of cardiopulmonary modifications during PA is reassuring, although our study was limited to 5 HbSS patients on HU. Whether HU has a protective role cannot be excluded. Our results encourage us to further evaluate PA interventions outside of school in SCD patients. Interventional studies evaluating the risk-benefit ratio of PA in SCD children are further needed.

Long-term predictors of severe exacerbations and mortality in a cohort of well-characterised adults with asthma

BackgroundWe aimed to explore long-term predictors of severe exacerbations and mortality in adults with well-characterised asthma.Study design and methodsAdults (aged ≥ 15) with an objectively verified diagnosis of asthma were recruited from a Danish respiratory outpatient clinic between 1974 and 1990. All individuals were followed in Danish registries for vital status, hospital admissions for asthma and cause of death until end of 2017. Predictors of exacerbations were obtained from a repeated measures model. Standardised mortality rates (SMR) for all-causes were compared with the Danish background population. Hazard ratios for mortality were obtained from a cox proportional hazards model in a two-step process.ResultsAt baseline, the cohort comprised 1071 patients (mean age 38, SD 16, 61% women), of whom 357 (33%) died during follow-up, with 93 (26%) dying from asthma (primary diagnosis). We found an SMR of 1.24 (95% CI 1.11–1.37, p < 0.001) for all-cause mortality. Baseline predictors for asthma-related death and repeated severe exacerbations were increasing age, ever smoker, FEV1 < 80% pred., high blood eosinophils, longer duration of symptoms and use of SABA > twice daily. Being non-atopic, having a positive histamine challenge test and symptoms more than twice a week were also predictors of repeated exacerbations.ConclusionsMarkers of poor asthma control, including high use of SABA, are predictors of long-term exacerbation rate and mortality over 30 years in patients with well-characterised asthma. Improving asthma control, including lung function and reducing use of reliever medication, is vital for improving the long-term outcome of asthma.

Predictors of methacholine challenge testing results in subjects without airflow obstruction

Objective Methacholine challenge testing (MCT) is considered when asthma remains clinically suspected despite normal spirometry. Few studies have attempted to determine the predictive factors of MCT results. We aimed to establish which demographic data, clinical symptoms, pulmonary function testing results, and laboratory values were associated with abnormal MCT (provocation concentration causing a 20% decrease in FEV1 (PC20) ≤ 16 mg/mL) in subjects without airflow obstruction on spirometry. Methods All patients who completed MCT at Montfort Hospital between January 1st, 2016 and December 31st, 2018 were identified. Subjects with a reduced FEV1/FVC ratio were excluded. We used Pearson’s chi-squared test and point-biserial correlation method to determine which variables had a significant relationship (p < 0.05) with MCT results. Results 23.3% of patients who underwent MCT had airflow limitation. In the 1126 subjects with a normal FEV1/FVC ratio, PC20 ≤ 16 mg/mL was found in 13.0%. Younger age, female gender, body mass index ≥ 40, and reported wheezing were factors associated with increased probability of airway hyper responsiveness. Lower FEV1, significant improvement of the FEV1 post-bronchodilator, reduced FEF25%-75%, greater FEF25%-75% reversibility, airway resistance measurements above the upper limit of normal, and increased blood eosinophil counts were predictive of abnormal MCT. Conclusions Only 13.0% of patients referred for MCT had a PC20 ≤ 16 mg/mL when the FEV1/FVC ratio was normal, highlighting the need to further define in which individuals this test is truly warranted. Further investigation is required to develop an easy-to-use and validated prediction model in order to better understand patients’ pretest probability of abnormal MCT.

USE OF VIRAL FILTER TO REDUCE EXPOSURE TO EXHALED AEROSOL DOES NOT AFFECT METHACHOLINE DOSE DELIVERY DURING BRONCHOPROVOCATION TESTING

TOPIC: Respiratory Care TYPE: Original Investigations PURPOSE: Methacholine challenge testing (MCT) is a common bronchoprovocation technique used to assess airway hyperresponsiveness. Current ERS guidelines recommend that measures should be taken to minimize technician exposure to methacholine aerosol, with added infection control concerns in the context of the ongoing COVID-19 pandemic. We previously demonstrated that the addition of a viral filter to the nebulizer exhalation limb reduced expelled particle concentrations by 77-91% during MCT. Our aim was to evaluate whether this modification resulted in a change in the delivered dose of methacholine. METHODS: Following published industry testing standards for MCT, we connected a Hamilton-G5 mechanical ventilator and Michigan lung simulator in series with respiratory rate 15 breaths/min, tidal volume (VT) 500 mL, I:E ratio 1:1 with a sinusoidal waveform. We compared methacholine dose delivery using the Hudson MicroMist and AeroEclipse II BAN nebulizers powered by either a dry gas source at 50 psi and 4.5 L/min or the Ombra compressor system, in addition to our current MCT protocol which utilizes Hudson MicroMist nebulizer with KoKo dosimeter (3 breaths). A filter placed in line between the nebulizer and test lung was weighed before and after 1 minute of nebulized methacholine delivery. Mean inhaled mass was calculated from three trials of each method with and without a viral filter on the exhalation limb. Dose delivery was calculated by multiplying the mean inhaled mass by the respirable fraction (particles < 5 µm) and inhalation time. Unpaired t-test was used to compare methacholine dose delivery with and without viral filter placement. Due to multiple independent comparisons, Bonferroni correction was used and alpha level was set at 0.01. RESULTS: The addition of a viral filter did not significantly affect methacholine dose delivery across all devices tested. Using the 50 psi dry gas source, dose delivered with the Hudson MicroMist did not differ with (461.0 µg) or without (307.8 µg) a viral filter (P=0.11) or with the AeroEclipse II BAN with (580.8 µg) or without (678.4) a viral filter (P=0.59). Using the Ombra compressor, dose delivered with the Hudson MicroMist did not differ with (1063.3 µg) or without (947.5 µg) a viral filter (P=0.026) or with AeroEclipse II BAN with (843.8 µg) or without (648.3) viral filter (P=0.42). Dose delivery did not differ significantly when using the KoKo dosimeter and Hudson MicroMist with or without a viral filter (P=0.20) using a 3-breath protocol. CONCLUSIONS: The addition of a viral filter to the nebulizer expiratory limb did not result in a significant change in the in the delivered dose of methacholine. CLINICAL IMPLICATIONS: Based on these findings, use of a viral filter to limit the concentration of expelled aerosol during MCT should be considered to improve pulmonary function technician safety and potentially reduce the risk of infectious exposure during the ongoing COVID-19 pandemic. DISCLOSURES: No relevant relationships by Kaiser Lim, source=Web Response no disclosure submitted for todd meyer; No relevant relationships by Alexander Niven, source=Web Response No relevant relationships by Paul Scanlon, source=Web Response No relevant relationships by Yosuf Subat, source=Web Response No relevant relationships by Keith Torgerud, source=Web Response

Fractional exhaled nitric oxide levels in relation to work-related respiratory burden and sensitization to wheat flour and multigrain in bakers.

BackgroundWork‐related lower airway symptoms (WR‐LAS), rhinitis (WRR), and asthma (WRA) are very common among bakers, due to airborne exposure to wheat flour and multigrain. Limited data is available regarding fractional exhaled nitric oxide (FeNO) in bakers in relation to respiratory burden and occupational sensitization in a real‐life situation.ObjectiveTo analyze FeNO levels in relation to WRR, WR‐LAS, and WRA with regard to allergic sensitization to occupational allergen in bakers.MethodsCross‐sectional, observational study of 174 bakers employed in traditional small bakeries in the Verona District. Subjects did FeNO measurements, spirometry, methacholine challenge, and skin prick test to common inhalant aeroallergens and bakeries occupational allergens.ResultsFeNO levels were higher in subjects sensitized to occupational allergens compared with bakers not sensitized to occupational allergens (22.8 ppb (18.9, 27.6) vs. 12.0 ppb (9.9, 14.5), p < 0.05). FeNO levels were higher in bakers with WRR and occupational sensitization (25.4 (20.6, 31.3)) than in bakers with WRR without occupational sensitization compared and bakers without respiratory burden (13.4 (9.6, 18.6) and 11.9 (9.8, 14.5), both p < 0.001). Similar findings were found for WR‐LAS with regard to the same categories (31.2 (24.1, 40.4) vs 13.3 (11.4, 15.6) and 15.3 (8.5, 27.5), p < 0.001 and p = 0.005). Bakers with WRA, with or without occupational allergic sensitization, had higher levels of FeNO than bakers without respiratory burden (both p ≤ 0.001). These findings were consistent after adjustments for gender, age, height, weight, smoking, and sensitization to common inhalant aeroallergens and lung function.ConclusionsWRR and lower airway symptoms in bakers sensitized to occupational allergens relate to increased FeNO. Our study suggests that FeNO is associated with work‐related allergic inflammation in occupational sensitized bakers, but future studies are needed to assess how FeNO should be integrated in the diagnostic work‐up of occupational disease in bakers.

Atypical asthma in children who present with isolated chest tightness: risk factors and clinical features

ObjectiveAsthmatic children presenting with chest tightness as the only symptom have not been widely recognized. This study attempted to find risk factors, summarize clinical features and offer some suggestions for the diagnosis of this atypical asthma.Methods: We studied 94 children, aged 6 to 14 years, who complained only of chest tightness. Data from clinical manifestations and laboratory tests were analyzed. The atypical asthma group (n = 58) showed positive bronchial challenge tests, and symptoms either improved or resolved in response to the bronchodilator. The control group (n = 36) had negative results on the bronchial challenge, diurnal PEF, and BDR tests, and no response to asthma treatment with bronchodilator.Results: Pollution, weather, recent house renovation, and air-conditioning use may be risk factors for children with atypical asthma. These children had more accompanying symptoms of rhinitis and rhinitis family history (P < 0.05), and a higher positive detection rate of inhaled allergens and multiple sensitizations. Parameters of the pulmonary function test were lower in the atypical asthma group than in the control group, and they also had higher FeNO values. If a cutoff value of improvement in FEV1 of BDR were set at 8.9%, sensitivity would be 48.2%, which is higher than a 12% cutoff.Conclusions: Environmental factors appeared to cause development of the isolated chest tightness symptom. Clinical history and laboratory tests could provide partial values for this diagnosis. In the absence of a bronchial challenge test, a margin of improvement in FEV1 of BDR set at 8.9% may be helpful.

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.

Ultra-high-resolution computed tomography shows changes in the lungs related with airway hyperresponsiveness in a murine asthma model

In vivo presentation of airway hyper-responsiveness (AHR) at the different time points of the allergic reaction is not clearly understood. The purpose of this study was to investigate how AHR manifests in the airway and the lung parenchyma in vivo following exposure to different stimuli and in the early and late phases of asthma after allergen exposure. Ovalbumin (OVA)-induced allergic asthma model was established using 6-week female BALB/c mice. Enhanced pause was measured with a non-invasive method to assess AHR. The dynamic changes of the airway and lung parenchyma were evaluated with ultra-high-resolution computed tomography (128 multi-detector, 1024 × 1024 matrix) for 10 h. While the methacholine challenge showed no grossly visible changes in the proximal airway and lung parenchyma despite provoking AHR, the OVA challenge induced significant immediate changes manifesting as peribronchial ground glass opacities, consolidations, air-trapping, and paradoxical proximal airway dilatations. After resolution of immediate response, multiple episodes of AHRs occurred with paradoxical proximal airway dilatation and peripheral air-trapping in late phase over a prolonged time period in vivo. Understanding of airflow limitation based on the structural changes of asthmatic airway would be helpful to make an appropriate drug delivery strategy for the treatment of asthma.

Methacholine challenges: comparison of different tidal breathing challenge methods.

Tidal-breathing methacholine challenges are now recommended by guidelines, to avoid the bronchoprotective effects of deep inhalation. This study compared different tidal breathing methacholine challenge methods; assessed the agreement between tidal dosimetric and continuous output challenges; and assessed challenge repeatability with different methods.15 asthma patients performed dosimetric challenges and a continuous-output breath-actuated challenge, all ≥3 days apart. All subjects had a pre-bronchodilator forced expiratory volume in 1 s (FEV1) ≥65% predicted, and a cumulative dose causing a 20% reduction in FEV1 (PD20) <1.2 mg.Of the dosimetric challenges, one method increased methacholine concentration (standard dosimetric challenge), and one adjusted nebuliser output time to increase dose (adjusted dosimetric challenge). The adjusted dosimetric and continuous output challenges were performed twice on separate days to assess for repeatability. All challenges were matched for dose at each dose step. The mean PD20 ratio of the standard dosimetric challenge to the adjusted dosimetric challenge was 0.90 (95% CI 0.66–1.23, p=0.49) and intraclass correlation coefficient (ICC) was 0.82. Repeated adjusted dosimetric challenges had an ICC 0.62 for PD20. Repeated continuous output challenges had an ICC 0.74 for PD20. The adjusted dosimetric and continuous output challenges correlated (r=0.69, p=0.0043; ICC 0.65), but PD20 was higher for the adjusted dosimetric challenge (mean PD20 ratio 2.31, 95% CI 1.57–3.40; p=0.0004).Tidal dosimetric methacholine challenge using adjustment of nebuliser output produces results with good repeatability. The results of this adjusted dosimetric method differed from the continuous output method, underscoring that the results of different methacholine challenge methodologies may not be directly comparable.

Asthma-like symptoms and oxidative stress in adults from the GEIRD Cohort

BACKGROUND AND AIM: Oxidative Stress (OS) is an imbalance between reactive oxygen species production and scavenging. This pre-pathological condition could be involved in the perpetuation and amplification of airway inflammation and other chronic diseases. The present study aimed at investigating OS in both healthy and asthma-like-diseased subjects. METHODS: Overall, 208 subjects were randomly selected from the GEIRD Cohort (Gene Environment Interaction in Respiratory Diseases). Based on the positive response to the Methacholine Challenge Testing or the obstructive impairment tested by spirometry, 124 volunteers were classified as “healthy”, while 84 as suffering from Asthma-Like Symptoms (A-LSs). Subjects participated after providing their informed consent, underwent anthropometric measurements, and provided a urinary sample. Urinary 15-F2t-IsoP and GSSG were quantified (ELISA technique) as biomarkers of OS. Urinary cotinine was measured as biomarker of tobacco smoking exposure. All biomarkers were normalised by creatinine. The association between OS and A-LSs was tested using two Multivariable Linear Regression Models and log(e)-transformed variables. RESULTS:Subjects were aged from 18 to 64 years and 41.3% were males. Sex, age, height and weight were not significantly affecting parameter estimates of any models, thus they have been excluded. We observed a significant increase of 15-F2t-IsoP in subjects suffering from A-LSs compared to healthy subjects (+1.58 folds, p 0.001), even adjusting for cotinine and GSSG. Similarly, when considering GSSG as dependent variable, we found a GSSG increase of 1.79 folds in symptomatic subjects compared to healthy ones, adjusting for cotinine and 15-F2t-IsoP. Finally, 15-F2t-IsoP levels were redoubled for each unit of increase of urinary cotinine (p 0.001). CONCLUSIONS:In conclusion, our findings suggest that 15-F2t-IsoP and GSSG are reliable and sensitive monitors of OS in various respiratory diseases, including A-LSs. Additionally, urinary 15-F2t-IsoP is effective to quantify some of the in vivo effects of tobacco smoking exposure. KEYWORDS: Molecular epidemiology, Respiratory outcomes, Asthma

Evaluation of Supranormal Spirometry Values With an Obstructive Ratio for Airway Hyperreactivity.

Published guidelines on spirometry interpretation suggest an elevated FVC and FEV1 > 100% of predicted with an obstructive ratio may represent a physiological variant. Further evidence is needed on whether this finding indicates symptomatic airways obstruction and what additional evaluation should be done. Participants were prospectively enrolled to undergo additional testing for a technically adequate spirometry study with an FEV1 > 90% of predicted, and FEV1/FVC below the lower limit of normal, based on 95th percentile confidence intervals. Further testing consisted of full pulmonary function testing, impulse oscillometry (IOS), post-bronchodilator testing, fractional exhaled nitric oxide (FeNO), and methacholine challenge testing (MCT). A total of 49 patients meeting entry criteria enrolled and completed testing. Thirty-three were considered symptomatic based on clinical indications for initial testing and 16 were considered asymptomatic. Baseline pulmonary function test values were not different between groups while IOS R5 values (% predicted) were higher in the symptomatic group (126.5 ± 0.37 vs 107.1 ± 0.31). Bronchodilator responsiveness on PFT or IOS was infrequent in both groups. There was a 29% positivity rate for MCT in the symptomatic group compared to one borderline study in asymptomatic participants. FeNO was similar for symptomatic, 26.17 ± 31.3 ppb, compared to asymptomatic, 22.8 ± 13.5 ppb (p = 0.93). The dysanapsis ratio was higher in the symptomatic (0.15 ± 0.03) compared to the asymptomatic (0.13 ± 0.02) (p < 0.05). Normal FEV1 > 90% of predicted and obstructive indices may not represent a normal physiological variant in all patients. In symptomatic patients, a positive MCT and elevated baseline IOS values were more common than in asymptomatic patients with similar PFT characteristics. These findings suggest that clinicians should still evaluate for airway hyperresponsiveness in patients with exertional dyspnea with airway obstruction and FEV1 > 90% of predicted and consider alternative diagnoses to include a normal physiologic variant if non-reactive.

Can bronchial challenge test with adenosine or methacholine at preschool age predict school‐age asthma?

Bronchial challenge test (BCT) measures current airways-hyperreactivity, however, its predictive role in pre-school children (<6 years) for the diagnosis of asthma at school age is still debatable. We aimed to find whether preschool children with a positive adenosine or methacholine BCT are more prone to asthma at school age. We included children aged 6-13 years with respiratory symptoms that were previously referred to our pulmonary function laboratory for BCT (methacholine or adenosine, depending on the question asked) at age 10 months to 6 years (baseline). BCT was considered positive based on spirometry results or wheezing, desaturation, and tachypnea reactions. The primaryoutcome measure was asthma diagnosis at school age using the well-validated International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. We used logistic regression analysis to explore whether positive BCT could predict school-age asthma while including age and collected modified asthma predictive indexin the model. One hundred and fifty-one of 189 children (53% males), completed the ISAAC questionnaire (response rate = 80%). Mean ages at BCT and at follow-up were 3.9 ± 1.28 and 9.4 ± 1.85 years, respectively. At baseline, 40 of 67 had a positive adenosine test and 73 of 84 had a positive methacholine BCT. Thirty-nine children were diagnosed with asthma at school age. Logistic regression analysis showed that a positive adenosine test at pre-school age was the best predictor, significantly increasing the odds of asthma at school age by 6.34 (95% CI: 1.23-32.81, p = .028), while methacholine did not show significance (p = .69). Choosing the relevant BCT for the question asked, positive adenosine, but not methacholine test, at pre-school, may predict asthma at school age.

Impact of obesity and ovariectomy on respiratory function in female mice

Obesity and the corresponding variations in female sex hormones are associated with severe lung disease. We determined the potential effects of obesity and sex hormones in female mice by investigating changes in lung structure and respiratory function in an obesity model induced by postnatal overnutrition. Obese female mice exhibited pronounced weight gain, abdominal fat accumulation and collagen type I deposition in the airways. However, neither elastic tissue nor estrogen receptors-α/-β were affected in obese female mice after ovariectomy or sham-operated mice. Bronchoconstriction in response to methacholine challenge in obese sham-operated mice was higher than in the obese group after ovariectomy. Our results suggest that the coexistence of obesity and ovariectomy impacted on respiratory system and airway resistance (attenuates bronchoconstriction after methacholine), on collagen I deposition and on airway estrogen β-receptors of mice.

Predictors of exercise-induced bronchoconstriction in subjects with mild asthma

BackgroundPhysical effort is capable of triggering airway obstruction in asthmatics, the so-called exercise-induced bronchoconstriction in asthma (EIBa). This study was performed in subjects with mild persistent asthma, aiming to find predictors for developing EIBa.MethodsIn 20 subjects with mild asthma, measurements of baseline functional respiratory parameters and airways responsiveness by a methacholine challenge were obtained on the first day. A maximal, symptom-limited incremental cardiopulmonary exercise test (CPExT) was performed the day after, with subsequent, repeated maneuvers of maximal full forced expiration to monitor the FEV1 change at 1,3,5,7,10 and 15 min after the end of the exercise.Results19 subjects completed the two-days protocol. No functional parameters both at rest and during effort were useful to predict EIBa after stopping exercise. In asthmatics with EIBa, mean Inspiratory Capacity (IC) did not increase with increasing ventilatory requirements during CPExT because 6 of them (50%) displayed dynamic pulmonary hyperinflation (DH), as documented by their progressive increase of end-expiratory lung volume. This subgroup, showing earlier post-exercise FEV1 fall, had significantly lower forced mean expiratory flow between 25% and 75% of forced vital capacity (FEF25-75%) at rest (p < 0.05) and higher airways responsiveness, expressed as PD20FEV1 (p < 0.05) as compared with other asthmatics with EIBa.ConclusionsNo functional respiratory parameters seem to predict EIBa in mild asthmatics. However, in those with EIBa, a subgroup developed DH during exercise, and this was associated with a baseline reduced forced expiratory flow rates at lower lung volumes and higher airway hyperresponsiveness, suggesting a prominent small airways impairment.

Response of upper and lower airway inflammation to bronchial challenge with house dust mite in Chinese asthmatics: a pilot study.

BackgroundAllergen nasal challenge can induce increase of eosinophils in sputum, but report about eosinophilic inflammation in upper airway after allergen bronchial challenge in Chinese asthmatics was rare. The article aims to evaluate response of upper and lower airways to house dust mite (HDM) allergen bronchial challenge.MethodsHDM allergen bronchial challenge was carried out in asthmatic patients with allergic rhinitis (AR). Bronchial methacholine challenge and blood test were performed before and at 24 hours after allergen challenge. Nasal lavage and induced sputum for differential cells count and fractional exhaled nitric oxide (FeNO) measurement were performed before, 7 and 24 hours after allergen challenge.ResultsEighteen asthmatic patients with AR underwent HDM allergen bronchial challenge with no serious adverse events reported. Fifteen patients showed dual asthmatic response (DAR), while 2 patients showed early (EAR) and 1 late asthmatic response (LAR) only. At 24 hours after allergen bronchial challenge testing, average PC20FEV1 to methacholine significantly decreased (1.58 to 0.81 mg/mL, P=0.03), while both FeNO and the percentage of eosinophils in blood and sputum were significantly increased [52.0 (54.0) to 69.0 (56.0) ppb, P=0.01; 4.82% to 6.91%, P<0.001; 20.70% to 27.86%, P=0.03, respectively], but with no significant differences found in the percentage of eosinophils in nasal lavage (39.36% to 38.58%, P=0.89). However, at 7 hours after allergen challenge, the eosinophils in sputum were significant increased to 40.45% (P<0.001), but there was an increase (39.36% to 48.07%) with no statistical difference (P=0.167) found in nasal lavage.ConclusionsHDM allergen bronchial challenge induced different response of airway inflammation in upper and lower airways.

Bronchial hyperresponsiveness is common in Hanoi, Vietnam: Asthma probably underdiagnosed

BackgroundBronchial hyperresponsiveness (BHR) is a key pathophysiological feature of asthma. Methacholine challenge test (MCT) is a common bronchoprovocation test useful for confirming a diagnosis of asthma. Studies of BHR in the general population of Asian countries are rare. AimTo estimate prevalence and determinants of BHR in Hanoi, Vietnam, and to study the association between BHR and symptoms common in asthma and previously diagnosed asthma. Methods1500 out of 5872 randomly selected adults in urban and rural Hanoi, who had participated in a questionnaire survey (83% participated), were randomly selected and invited to clinical examinations. Totally 684 subjects (46%) participated. MCT was performed in 366 subjects. BHR was defined as a FEV1-decrease of ≥20% from baseline following methacholine inhalations (PC20). Cut offs used in the analyses were PC20 ≤ 1 mg/ml, ≤2 mg/ml and ≤8 mg/ml. ResultsThe prevalence of BHR was 16.4% at doses ≤8 mg/ml, while 9.6% reacted on doses ≤2 mg/ml. PC20 ≤ 2 mg/ml was associated with FEV1 <80% of predicted. PC20 ≤ 2 mg/ml, but not PC20 ≤ 8 mg/ml, was associated with multi-sensitization to airborne allergens. BHR defined as PC20 ≤ 8 mg/ml was associated with age >45y. The combination of asthmatic wheeze (wheezing with breathlessness apart from colds) and BHR, irrespectively of magnitude of BHR, was more common than the combination of BHR with previously diagnosed asthma. ConclusionsThe results indicate BHR to be more common in Hanoi than previously found in south-east Asia. Although the prevalence of physician diagnosed asthma has increased in Vietnam, our results indicate that asthma still may be underdiagnosed in Vietnam.

Microfabricated potentiometric sensor for personalized methacholine challenge tests during the COVID-19 pandemic

The methacholine challenge test is considered to be the gold standard bronchoprovocation test used to diagnose asthma, and this test is always performed in pulmonary function labs or doctors’ offices. Methacholine (MCH) acts by inducing airway tightening/bronchoconstriction, and more importantly, MCH is hydrolyzed by cholinesterase enzyme (ChE). Recently, the American Thoracic Society raised concerns about pulmonary function testing during the COVID-19 pandemic due to recently reported correlation between cholinesterase and COVID-19 pneumonia severity/mortality, and it was shown that cholinesterase levels are reduced in the acute phase of severe COVID-19 pneumonia. This work describes the microfabrication of potentiometric sensors using copper as the substrate and chemically polymerized graphene nanocomposites as the transducing layer for tracking the kinetics of MCH enzymatic degradation in real blood samples. The in-vitro estimation of the characteristic parameters of the MCH metabolism [Michaelis–Menten constant (Km) and reaction velocity (Vmax)] were found to be 241.041 μM and 56.8 μM/min, respectively. The proposed sensor is designed to be used as a companion diagnostic device that can (i) answer questions about patient eligibility to perform methacholine challenge tests, (ii) individualize/personalize medical dosing of methacholine, (iii) provide portable and inexpensive devices allowing automated readouts without the need for operator intervention (iv) recommend therapeutic interventions including intensive care during early stages and reflecting the disease state of COVID-19 pneumonia. We hope that this methacholine electrochemical sensor will help in assaying ChE activity in a “timely” manner and predict the severity and prognosis of COVID-19 to improve treatment outcomes and decrease mortality.

HDAC4 induces the development of asthma by increasing Slug-upregulated CXCL12 expression through KLF5 deacetylation

BackgroundAsthma is a frequently occurring respiratory disease with an increasing incidence around the world. Airway inflammation and remodeling are important contributors to the occurrence of asthma. We conducted this study aiming at exploring the effect of Histone deacetylase 4 (HDAC4)-mediated Kruppel-like factor 5 (KLF5)/Slug/CXC chemokine ligand-12 (CXCL12) axis on the development of asthma in regulation of airway inflammation and remodeling.MethodsAn asthmatic rat model was induced by ovalbumin (OVA) irrigation, and determined HDAC4, KLF5, Slug, and CXCL12 expression in the lung tissues by RT-qPCR and Western blot assay. OVA was also used to induce a cell model of asthma in human BEAS-2B and HBE135-E6E7bronchial epithelial cells. The airway hyperresponsiveness (AHR), and expression of inflammatory cytokines in model mice were examined using methacholine challenge test and ELISA. The biological behaviors were measured in asthma model bronchial smooth muscle cells (BSMCs) following loss- and gain- function approaches. The interactions between HDAC4, KLF5, Slug, and CXCL12 were also detected by IP assay, dual luciferase gene reporter assay, and ChIP.ResultsHDAC4 was upregulated in lung tissues of OVA-induced asthmatic mice, and inhibition of HDAC4 alleviated the airway inflammation and remodeling. HDAC4 increased KLF5 transcriptional activity through deacetylation; deacetylated KLF5 bound to the promoter of Slug and transcriptionally upregulated Slug expression, which in turn increased the expression of CXCL12 to promote the inflammation in bronchial epithelial cells and thus induce the proliferation and migration of BSMCs.ConclusionCollectively, HDAC4 deacetylates KLF5 to upregulate Slug and CXCL12, thereby causing airway remodeling and facilitating progression of asthma.

Intrauterine Growth Restriction Promotes Postnatal Airway Hyperresponsiveness Independent of Allergic Disease

Introduction: Intrauterine growth restriction (IUGR) is associated with asthma. Murine models of IUGR have altered airway responsiveness in the absence of any inflammatory exposure. Given that a primary feature of asthma is airway inflammation, IUGR-affected individuals may develop more substantial respiratory impairment if subsequently exposed to an allergen. This study used a maternal hypoxia-induced mouse model of IUGR to determine the combined effects of IUGR and allergy on airway responsiveness.Methods: Pregnant BALB/c mice were housed under hypoxic conditions (10.5% O2) from gestational day (GD) 11-GD 17.5 (IUGR group; term = GD 21). Following hypoxic exposure, mice were returned to a normoxic environment (21% O2). A second group of pregnant mice were housed under normoxic conditions throughout pregnancy (Control). All offspring were sensitized to ovalbumin (OVA) and assigned to one of four treatment groups: Control – normoxic and saline challenge; IUGR – hypoxic and saline challenge; Allergy – normoxic and OVA challenge; and IUGR + Allergy – hypoxic and OVA challenge. At 8 weeks of age, and 24 h post-aerosol challenge, mice were tracheostomised for methacholine challenge and assessment of lung mechanics by the forced oscillation technique, and lungs subsequently fixed for morphometry.Results: IUGR offspring were lighter than Control at birth and in adulthood. Both Allergy and IUGR independently increased airway resistance after methacholine challenge. The IUGR group also exhibited an exaggerated increase in tissue damping and elastance after methacholine challenge compared with Control. However, there was no incremental effect on airway responsiveness in the combined IUGR + Allergy group. There was no impact of IUGR or Allergy on airway structure and no effect of sex on any outcome.Conclusion: IUGR and aeroallergen independently increased bronchoconstrictor response, but when combined the pathophysiology was not worsened. Findings suggest that an association between IUGR and asthma is mediated by baseline airway responsiveness rather than susceptibility to allergen.

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