Assess Airway Hyperresponsiveness Research Articles

Bronchom assuages airway hyperresponsiveness in house dust mite-induced mouse model of allergic asthma and moderates goblet cell metaplasia, sub-epithelial fibrosis along with changes in Th2 cytokines and chemokines.

Asthma is a common obstructive airway disease with an inflammatory etiology. The main unmet need in the management of asthma is inadequate adherence to pharmacotherapy, leading to a poorly-controlled disease state, necessitating the development of novel therapies. Bronchom is a calcio-herbal formulation, which is purported to treat chronic asthma. The objective of the current study was to examine the in-vivo efficacy of Bronchom in mouse model of allergic asthma. Ultra high performance liquid chromatography was utilized to analyze the phytocompounds in Bronchom. Further, the in-vivo efficacy of Bronchom was evaluated in House dust mite (HDM)-induced allergic asthma in mice. Mice were challenged with aerosolized methacholine to assess airway hyperresponsiveness. Subsequently, inflammatory cell influx was evaluated in bronchoalveolar lavage fluid (BALF) followed by lung histology, wherein airway remodeling features were studied. Simultaneously, the levels of Th2 cytokines and chemokines in the BALF was also evaluated. Additionally, the mRNA expression of pro-inflammatory and Th2 cytokines was also assessed in the lung along with the oxidative stress markers. Phytocompounds present in Bronchom included, gallic acid, protocatechuic acid, methyl gallate, rosmarinic acid, glycyrrhizin, eugenol, 6-gingerol and piperine. Bronchom effectively suppressed HDM-induced airway hyperresponsiveness along with the influx of leukocytes in the BALF. Additionally, Bronchom reduced the infiltration of inflammatory cells in the lung and it also ameliorated goblet cell metaplasia, sub-epithelial fibrosis and increase in α-smooth muscle actin. Bronchom decreased Th2 cytokines (IL-4 and IL-5) and chemokines (Eotaxin and IP-10) in the BALF. Likewise, it could also suppress the mRNA expression of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6 and IL-33), and IL-13. Moreover, Bronchom restored the HDM-induced diminution of endogenous anti-oxidants (GSH and SOD) and the increase in pro-oxidants (GSSG and MDA). Furthermore, Bronchom could also decrease the nitrosative stress by lowering the observed increase in nitrite levels. Taken together, the results of the present study data convincingly demonstrate that Bronchom exhibits pharmacological effects in an animal model of allergic asthma. Bronchom mitigated airway hyperresponsiveness, inflammation and airway remodeling evoked by a clinically relevant allergen and accordingly it possesses therapeutic potential for the treatment of asthma.

Use of a Viral Filter to Reduce Exposure to Exhaled Aerosol Does Not Affect Methacholine Dose Delivery During Bronchoprovocation Testing.

Methacholine challenge testing (MCT) is a common bronchoprovocation technique used to assess airway hyper-responsiveness. We previously demonstrated that the addition of a viral filter to the nebulizer exhalation limb substantially reduced expelled particles during MCT. Our aim was to evaluate whether this modification affects the delivered dose of methacholine. A mechanical ventilator was connected to a lung simulator with breathing frequency 15 breaths/min, tidal volume 500 mL, inspiratory-expiratory ratio 1:1, with a sinusoidal waveform. We compared methacholine dose delivery using the Hudson Micro Mist or AeroEclipse II BAN nebulizers powered by either a dry gas source or a compressor system. A filter placed in line between the nebulizer and test lung was weighed before and after 1 min of nebulized methacholine delivery. Mean inhaled mass was measured 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. The addition of a viral filter did not significantly affect methacholine dose delivery across all devices tested. Using a 50-psi dry gas source, dose delivered with or without a viral filter did not differ with the Hudson (422.3 μg vs 282.0 μg, P = .11) or the AeroEclipse nebulizer (563.0 μg vs 657.6 μg, P = .59). Using the compressor, dose delivered with and without a viral filter did not differ with the Hudson (974.0 μg vs 868.0 μg, P = .03) or the AeroEclipse nebulizer (818.0 μg vs 628.5 μg, P = .42). The addition of a viral filter to the nebulizer exhalation limb did not affect methacholine dose during bronchoprovocation testing. Routine use of a viral filter should be considered to improve pulmonary function technician safety and infection control measures during the ongoing COVID-19 pandemic.

Aerosol Generation and Mitigation During Methacholine Bronchoprovocation Testing: Infection Control Implications in the Era of COVID-19.

Methacholine bronchoprovocation or challenge testing (MCT) is commonly performed to assess airway hyper-responsiveness in the setting of suspected asthma. Nebulization is an aerosol-generating procedure, but little is known about the risks of MCT in the context of the ongoing coronavirus disease 2019 (COVID-19) pandemic. We aimed to quantify and characterize aerosol generation during MCT by using different delivery methods and to assess the impact of adding a viral filter. Seven healthy subjects performed simulated MCT in a near particle-free laboratory space with 4 different nebulizers and with a dosimeter. Two devices continuously sampled the ambient air during the procedure, which detected ultrafine particles, from 0.02-1 μm, and particles of sizes 0.3, 0.5, 1.0, 2.0, 5.0, and 10 µm, respectively. Particle generation was compared among all the devices, with and without viral filter placement. Ultrafine-particle generation during simulated MCT was significant across all the devices. Ultrafine-particle (0.02-1 μm) concentrations decreased 77%-91% with the addition of a viral filter and varied significantly between unfiltered (P < .001) and filtered devices (P < .001). Ultrafine-particle generation was lowest when using the dosimeter with filtered Hudson nebulizer (1,258 ± 1,644 particle/mL). Ultrafine-particle concentrations with the filtered nebulizer devices using a compressor were higher than particle concentrations detected when using the dosimeter: Monaghan (3,472 ± 1,794 particles/mL), PARI (4,403 ± 2,948), Hudson (6,320 ± 1,787) and AirLife (9,523 ± 5,098). The high particle concentrations generated during MCT pose significant infection control concerns during the COVID-19 pandemic. Particle generation during MCT was significantly reduced by using breath-actuated delivery and a viral filter, which offers an effective mitigation strategy.

Diagnosis and management of cough-variant asthma

Abstract Cough is a natural defence mechanism of the lungs to prevent aspiration and to keep the airway clean. Cough, wheezing and shortness of breath are common symptoms of asthma. Cough-variant asthma is one of the phenotypes of asthma with the main symptom of cough without shortness of breath and wheezing. Cough-variant asthma is largely observed in patients with bronchial hyperresponsiveness who experience cough due to innocuous stimuli, and it is associated with a family history and seasonal allergy. In the present study, in patients with cough-variant asthma, no abnormalities were found during the lung function test, particularly forced expiratory flow in the first second (FEV1) or peak expiratory flow (PEF), although these values were lower than those in normal individuals. A bronchial provocation test using methacholine is needed to assess airway hyperresponsiveness, and depending on the outcome of the test, an assessment can be made as to the probability of the patient requiring a diagnosis of cough-variant asthma. Administration of inhalation therapy with bronchodilators and corticosteroids is the mainstay of management in patients with cough-variant asthma presenting with the symptom of persistent cough. Until now, there have been no specific guidelines for drug selection, dose and duration of inhaled corticosteroid use in cough-variant asthma. If symptoms do not resolve with inhaled corticosteroid monotherapy, consideration may be given to increase the inhalation dose or to add other drugs such as long-acting B2 agonists, slow-release theophylline or leukotriene receptor antagonist (LTRA).

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

Bronchial provocation test measured by using the forced oscillation technique to assess airway responsiveness.

Background: The bronchial provocation test (BPT) performed by using the forced oscillation technique (FOT) is cooperated without forced expiratory effort. However, a comparison of the application value and safety of BPTs measured by using the FOT and the standardized dosimeter method is lacking, which limits its clinical practice. Objective: We aimed to analyze the diagnostic value and safety of the BPT as measured by the FOT in patients with asthma and in healthy subjects. Methods: This was a randomized cross-over clinical study. Airway responsiveness was measured by using the FOT and the aerosol provocation system (APS) dosimeter method in all the participants. The between-test interval was 24 hours. The diagnostic value and safety of the two tests were analyzed. Results: Asthma control status was assessed based on ACT scores, and patients with asthma (including 27 uncontrolled, 34 partially controlled, and 32 controlled) were collected, and 69 healthy subjects were recruited. Receiver operating characteristic curves revealed slightly superior screening capability of cumulative dose of methacholine causing a 20% decrease (PD20)-forced expiratory volume in the first second of expiration when measured by using the APS-dosimeter method (area under the curve [AUC] 0.981 [95% confidence interval {CI}, 0.952-1.000]) over that of cumulative dose of inhaled methacholine at the inflection point when respiratory resistance began to increase continuously (Dmin) by using the FOT (AUC 0.959 [95% CI, 0.924-0.994]). The sensitivity and specificity were 98.9% and 98.6%, respectively, with the APS-dosimeter method, and 100% and 87.0%, respectively, with the FOT. It took an average of 9.0 minutes (range, 6.0-11.0 minutes) when using the FOT and an average of 17.0 minutes (range, 14.0-25.0 minutes) when using APS-dosimeter method (p < 0.01) in all the participants. The measurement time for the FOT was reduced by 47.1% than the APS-dosimeter. The incidence rate of the adverse events with the FOT was slightly higher than that with the APS-dosimeter method (p < 0.05). Both tests were well tolerated. No serious adverse event was found. Conclusion: The FOT, characterized as being simple, safe, and time saving, could be used to assess airway hyperresponsiveness in patients with asthma and worthy of clinical application.

Effect of IL‑7 on Th17 cell responses in a mouse model of neutrophilic asthma.

Neutrophilic asthma (NA) is characterized by neutrophil-mediated inflammation and the presence of Th17 cells. However, the mechanisms underlying Th17 cell responses in NA remain unknown. The aim of the present study was to examine the effects of interleukin (IL)-7 on Th17 cell responses in NA. A NA mouse model was sensitized by airway delivery of ovalbumin (OVA) and lipopolysaccharide and challenged with 1% OVA aerosol from day 21 for 3 consecutive days. Airway resistance was then measured to assess airway hyper-responsiveness (AHR). Cells from bronchoalveolar lavage fluid (BALF) underwent Diff-Quick and hematoxylin and eosin staining for classification. The levels of IL-17 in the BALF were determined by ELISA. The effects of IL-7 administration and STAT5 inhibition on Th17 cells were also characterized in vitro using splenic CD4+ T cells. Ki-67, Bcl-2 and activated caspase-3 expression in differentiated Th17 cells were analyzed by flow cytometry. The mouse model of NA was characterized by increased AHR, elevated levels of IL-17, high neutrophil counts in BALF, accumulated inflammatory cells in the lung and Th17 cell responses. IL-7 promoted the expression of Ki-67 and Bcl-2 while reducing caspase-3 expression. STAT5 inhibitor treatment decreased the levels of Ki-67 and Bcl-2, and resulted in increased expression of caspase-3. These results suggested that the IL-7/JAK/STAT5 signaling pathway may be involved in Th17 cell responses in NA.

Assessment of Ozone-Induced Lung Injury in Mice.

Ozone is a major pollutant in the air we breathe, and elevated levels lead to significant morbidity and mortality. As the climate warms, levels of ozone are predicted to increase. Accordingly, studies to assess the mechanisms of ozone-induced lung diseases are paramount. This chapter describes mouse models of ozone exposure and methods for assessing the effects of ozone in the lungs. These include bronchoalveolar lavage, necropsy, and measurement of lung function. Lavage allows for assessment of cell infiltration, cytokine production, tissue damage and capillary leakage in the airspaces. Necropsy provides tissue for gene expression, histology, and protein assessment in the whole lung. Lung physiology is used to assess airway hyperresponsiveness, tissue and total lung resistance, compliance, and elastance.

The effect of serine protease inhibitors on airway inflammation in a chronic allergen-induced asthma mouse model.

Serine protease inhibitors reportedly attenuated airway inflammation and had antioxidant in multiorgan. However, the effects of the serine protease inhibitors nafamostat mesilate (FUT), gabexate mesilate (FOY), and ulinastatin (UTI) on a long-term challenged mouse model of chronic asthma are unclear. BALB/c mice (6 mice/group) were intratracheally inoculated with five doses of Dermatophagoides pteronyssinus (Der p; 50 μL, 1 mg/mL) at one-week intervals. Therapeutic doses of FUT (0.0625 mg/kg), FOY (20 mg/kg), or UTI (10,000 U/kg) were, respectively, injected intraperitoneally into these mice. Control mice received sterile PBS. At 3 days after the last challenge, mice were sacrificed to assess airway hyperresponsiveness (AHR), remodeling, and inflammation; lung histological features; and cytokine expression profiles. Compared with untreated controls, mice treated with FUT, FOY, and UTI had decreased AHR and goblet cell hyperplasia, decreased eosinophil and neutrophil infiltration, decreased Der p-induced IL-4 levels in serum and IL-5, IL-6, IL-13, and IL-17 levels in bronchoalveolar lavage fluid, and inhibited nuclear factor (NF)-κB activity in lung tissues. The serine protease inhibitors FUT, FOY, and UTI have potential therapeutic benefits for treating asthma by downregulating Th2 cytokines and Th17 cell function and inhibiting NF-κB activation in lung tissue.

Bronchial hyperresponsiveness testing in athletes of the Swiss Paralympic team

BackgroundThe aim of this study was to assess airway hyperresponsiveness to eucapnic voluntary hyperventilation and dry powder mannitol challenge in athletes aiming to participate at the Paralympic Games 2008 in Beijing, especially in athletes with spinal cord injury.MethodsForty-four athletes with a disability (27 with paraplegia (group 1), 3 with tetraplegia (group 2) and 14 with other disabilities such as blindness or single limb amputations (group 3) performed spirometry, skin prick testing, measurement of exhaled nitric oxide, eucapnic voluntary hyperventilation challenge test (EVH) and mannitol challenge test (MCT). A fall in FEV1 of ≥10% in either challenge test was deemed positive for exercise-induced bronchoconstriction.ResultsFourteen (32%) athletes were atopic and 7 (16%) had a history of physician-diagnosed asthma. Absolute lung function values were significantly lower in patients of group 1 and 2 compared to group 3. Nine (20%) athletes were positive to EVH (8 paraplegics, 1 tetraplegic), and 8 (18%) athletes were positive to MCT (7 paraplegics, 1 tetraplegic). Fourteen (22.7%) subjects were positive to at least one challenge; only three athletes were positive to both tests. None of the athletes in group 3 had a positive test. Both challenge tests showed a significant association with physician-diagnosed asthma status (p = 0.0001). The positive and negative predictive value to diagnose physician-diagnosed asthma was 89% and 91% for EHV, and 75% and 86% for MCT, respectively.ConclusionEVH and MCT can be used to identify, but especially exclude asthma in Paralympic athletes.

Methacholine challenge test: Diagnostic characteristics in asthmatic patients receiving controller medications

The methacholine challenge test (MCT) is commonly used to assess airway hyperresponsiveness, but the diagnostic characteristics have not been well studied in asthmatic patients receiving controller medications after the use of high-potency inhaled corticosteroids became common. We investigated the ability of the MCT to differentiate participants with a physician's diagnosis of asthma from nonasthmatic participants. We conducted a cohort-control study in asthmatic participants (n= 126) who were receiving regular controller medications and nonasthmatic control participants (n= 93) to evaluate the sensitivity and specificity of the MCT. The overall sensitivity was 77% and the specificity was 96% with a threshold PC(20) (the provocative concentration of methacholine that results in a 20% drop in FEV(1)) of 8 mg/mL. The sensitivity was significantly lower in white than in African American participants (69% vs 95%, P= .015) and higher in atopic compared with nonatopic (82% vs 52%, P= .005). Increasing the PC(20) threshold from 8 to 16 mg/mL did not noticeably improve the performance characteristics of the test. African American race, presence of atopy, and lower percent predicted FEV(1) were associated with a positive test result. The utility of the MCT to rule out a diagnosis of asthma depends on racial and atopic characteristics. Clinicians should take into account the reduced sensitivity of the MCT in white and nonatopic asthmatic patients when using this test for the diagnosis of asthma.

IgG Immune Complex Induces the Recruitment of Inflammatory Cells into the Airway and TNF-Mediated Late Airway Hyperresponsiveness via NF-κB Activation in Mice

Background. Many of the inflammatory proteins that are expressed in asthmatic airways are regulated, at least partially, by nuclear factor (NF)-κB. Blockade of NF-κB activity has resulted in attenuation of the cardinal features of asthma. Thus, delineating the mechanisms involved in NF-κB activation in asthma might provide an interesting approach to improving the management of asthma. However, despite its importance, the mechanism for NF-κB activation in asthma has not yet been determined. Objective. To examine the role of IgE and IgG antibodies (Abs) in the activation of NF-κB in mouse lungs. Methods. To examine the effect of IgE, mice underwent intratracheal (i.t.) instillation of an IgE immune complex (IgE-IC) (anti-2,4-dinitrophenyl hapten (DNP) IgE + DNP-BSA or DNP-OVA) and anaphylactogenic anti-IgE (LO-ME-2). For IgG, mice underwent i.t. instillation with a complex of anti-chicken gamma globulin (CGG) IgG1 mAb + CGG. NF-κB activation was determined by gel shift assay. Small interfering RNA was used for blockade of p50 expression. The effect of tumor necrosis factor (TNF) blockade was determined using anti-TNF Ab. A previously established murine model of asthma was used to assess airway hyperresponsiveness (AHR). Results. A single i.t. instillation of either IgE-IC or LO-ME-2 failed to induce activation of NF-κB in the lungs. In contrast, single i.t. instillation of IgG-IC was capable of inducing NF-κB activation, as well as NF-κB-dependent proinflammatory molecules, such as TNF and CXC chemokines. Pretreatment of p50 small interfering RNA decreased bronchoalveolar lavage fluid levels of TNF and macrophage inflammatory protein-2 induced by IgG-IC instillation. Single i.t. instillation of IgG-IC caused the recruitment of neutrophils and macrophages into the airway and TNF-mediated late AHR, but failed to induce Th2 cell-mediated asthmatic phenotypes. Conclusion. IgG, but not IgE, is the major Ab that induces not only NF-κB activation and NF-κB-dependent proinflammatory molecules in the lungs but also subsequent recruitment of inflammatory cells into the airway and TNF-mediated late AHR.

Effect of Insulin on Airway Responsiveness in Patients with Type 2 Diabetes Mellitus: A Cohort Study

Background. The correlation between low insulin levels and a decreased sensitivity of the muscarinic receptor has been shown on induced-diabetes animal models. We designed a cohort study with the aim of evaluating the effects of insulin therapy on airway responsiveness (AR) in human patients with type 2 diabetes mellitus. Methods. We enrolled 92 patients with type 2 diabetes who had switched from oral anti-diabetic therapy to treatment by insulin subcutaneous injection. Patients were administered the methacholine challenge test (MCT) at time 0 (pre-insulin therapy) and at intervals of 15, 30, 90, 180, and 360 days after insulin treatment. The decline of forced expiratory volume in 1 second (FEV1)% from baseline (Δ FEV1) in response to inhaled methacholine (MCH) was determined to assess airway hyper-responsiveness (AHR). Results. A total of 81 patients (18 women and 63 men) completed the study. Their mean age was 58 ± 7 years and the mean duration of disease was 13.5 ± 7.7 years. The mean decrease of FEV1 at pre-insulin assessment was 2.96 ± 2.6%. Compared with the pre-insulin value, a significant increase of Δ FEV1 was observed at 15, 30, and 90 days after treatment (6.25%, CI 95% 5.4 to 7.2, p = 0.0005; 7.64%, CI 95% 6.6 to 8.1, p < 0.001; 6.45%, CI 95% 5.5 to 7.3, p = 0.0004, respectively), while after 180 and 360 days AR was similar to pre-insulin values (Δ FEV1, 3.62%, CI 95% 2.7 to 3.5 and 3.11%, CI 95% 7.9 to 9.3, respectively). Conclusions. The finding of an increased AR in patients with type 2 diabetes during the first 3 months of insulin therapy may underline the importance of monitoring pulmonary function and respiratory symptoms in patients switching from oral anti-diabetic drugs to insulin therapy, especially in the subset of individuals with respiratory disorders.

Monitoring asthma therapy using indirect bronchial provocation tests*

Bronchial provocation tests that assess airway hyperresponsiveness (AHR) are known to be useful in assisting the diagnosis of asthma and in monitoring inhaled corticosteroid therapy. We reviewed the use of bronchial provocation tests that use stimuli that act indirectly for monitoring the benefits of inhaled corticosteroids. Published clinical trials investigating the effect of inhaled corticosteroids on bronchial hyperresponsiveness in persons with asthma were used for this review. Studies using indirect stimuli to provoke airway narrowing such as exercise, eucapnic voluntary hyperventilation, cold air hyperventilation, hypertonic saline, mannitol, or adenosine monophosphate (AMP) to assess the effect of inhaled corticosteroids were selected. Stimuli acting indirectly result in the release of a variety of bronchoconstricting mediators such as leukotrienes, prostaglandins, and histamine, from cells such as mast cells and eosinophils. A positive response to indirect stimuli is suggestive of active inflammation and AHR that is consistent with a diagnosis of asthma. Persons with a positive response to indirect stimuli benefit from daily treatment with inhaled corticosteroids. Symptoms and lung function are not useful to predict the long-term success of inhaled corticosteroid dose as they usually resolve rapidly, and well before inflammation and AHR has resolved. Following treatment, AHR to indirect stimuli is attenuated. Further, during long-term treatment, asthmatics can become as non-responsive as non-asthmatic healthy persons, suggesting that asthma is not active. Non-responsiveness to indirect bronchial provocation tests following inhaled corticosteroids occurs weeks to months following the resolution of symptoms and lung function. Non-responsiveness to indirect stimuli may provide a goal for adequate therapy with inhaled corticosteroids.

Cold Air and Exercise Challenge—Influence of Minute Ventilation

Exercises testing and cold air challenges are frequently used to assess airway hyperresponsiveness (AHR), but different goals are set for the two tests. We, therefore, wished to determine whether cold air and exercise challenge testing yielded similar responses and if any differences were due to differences in the maximum minute ventilation achieved.Twenty asthmatic subjects each performed a cold air (CACh) and an exercise (EXCh) challenge. Baseline forced expiratory volume in one second (FEV1) was recorded immediately pre-challenge and then serially for at least 10 minutes post-challenge. The maximum minute ventilation achieved was recorded. In the subjects who had at least a decrease in FEV1 of 15% in response to the first CACh, a second CACh was performed, but at the maximum minute ventilation achieved during EXCh.Eleven subjects after CACh and four after EXCh had a greater than 15% decrease in FEV1 (p = 0.05). The median decrease in FEV1 was greater following the CACh (16.7%[25th to 75th percentile 10.4 to 19.9]) than the EXCh (6.9%[25th to 75th percentile 4.3 to 14.6]); (p = 0.0004). The median maximum minute ventilation achieved was greater with the CACh (89[66–141] L/min) than with the EXCh (61(40 to 102)L/min); (p < 0.0001). Only one of seven subjects who had previously responded to the CACh had a 15% decrease in FEV1 when the CACh was repeated at the same maximum minute ventilation achieved during EXCh (p = 0.007).In conclusion, cold air and exercise challenges do not produce the same response. Our results highlight than an explanation is the differences in the maximum-minimum ventilation achieved.

Does the Inclusion of Wheeze Detection as an Outcome Measure Affect the Interpretation of Methacholine Challenge Tests? A Study in Workers at Risk of Occupational Asthma

Methacholine challenge testing (MCT) is widely used to assess airway hyperresponsiveness (AHR). Traditionally, a 20% or greater decline in forced expiratory volume in 1 (FEV(1)) is the primary outcome measure. We examined whether the inclusion of wheeze detection as outcome measure influenced the categorical interpretation of MCT in workers at risk of occupational asthma (OA). We examined 28 occupationally exposed smokers with asthma-like symptoms (SympAsth), 22 asymptomatic, occupationally exposed smokers (Symp0), and 30 nonexposed, asymptomatic controls (Ctrl). MCT was done using an abbreviated technique. Spirometry and tracheal wheezes were recorded using a computerized system. MCT was considered either positive or negative using three outcome measures separately: (1) > or = 20% fall in FEV(1) (MCT("FEV1")); (2) wheeze appearance (MCT("Wheeze")); and (3) whichever among the two was present (MCT("FEV1Wheeze")). The proportion of reactors in each group were, by outcome measure, as follows: MCT("FEV1"): Ctrl = 2 (6.7%), Symp0 = 6 (27.3%), SympAsth = l2 (42.8%) (chi(2) = 10.2; p = 0.006); MCT("Wheeze"): Ctrl = 1 (3.3%), Symp0 = 4 (18.2%), SympAsth = 13 (46.4%) (chi(2) = l5.7; p = 0.001); MCT("FEV1Wheeze") Ctrl = 2 (6.7%), Symp0 = 7 (31.8%), SympAsth = 18 (64.3%) (chi(2) = 21.5; p = 0.001). Overall, including wheeze detection increased the proportion of "reactors" detected by spirometry by 30% (27 reactors vs. 20). This increase reached 50% (18 vs. 12) among workers with asthma like symptoms. In summary, the inclusion of wheeze detection as outcome measure for MCT allowed the recognition as reactors of subjects that otherwise would be "missed" by spirometry. The resulting increase in the number of true positives improved the sensitivity of MCT to detect AHR in occupationally exposed workers at risk of occupational asthma.

Avaliação da hiperresponsividade brônquica à solução salina hipertônica em crianças e adolescentes

To assess airway hyperresponsiveness to 4.5% hypertonic saline solution in comparison to that obtained through challenge with other bronchoconstriction agents and in relation to patient allergic sensitization. A cross-sectional, experimental study was conducted, initially involving 85 subjects. After exclusions, the final sample consisted of 62 patients, divided into two groups: a study group of those with asthma (n = 45) and a control group of those with no asthma or allergies (n = 17). Hypertonic saline was nebulized using an ultrasonic nebulizer and administered successively for 0.5, 1, 2, 4 and 8 minutes until a drop in forced expiratory volume in one second of = 15% was achieved in relation to the baseline value. The level of specific immunoglobulin E to Dermatophagoides pteronyssinus level was determined by ImmunoCAP assay and was considered positive when > 0.35 kU/L. In the 36 asthma group subjects presenting a response, the mean drop in forced expiratory volume in one second after hypertonic saline nebulization was 27.4%. None of control group subjects (immunoglobulin E < 0.35 kU/L) presented a positive response to hypertonic saline. The mean forced expiratory volume in one second for control group subjects was 9%. The results of a bronchial provocation test were negative in 9 of the asthma group subjects. The frequency of bronchial provocation test positivity was higher in the subjects presenting elevated levels of specific immunoglobulin E, indicating that there is a relationship between bronchial hyperresponsiveness and the level of specific immunoglobulin E. The sensitivity and specificity of the test were 80% and 92%, respectively. Bronchial provocation with hypertonic saline presents satisfactory sensitivity and specificity. Therefore, in addition to being a low cost procedure that requires very little equipment, it is a useful means of assessing hyperresponsiveness in children and adolescents.

Respiratory Syncytial Virus Infections: Old Challenges and New Opportunities

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and pneumonia among children aged < 1 year. The majority of children hospitalized for RSV infection are younger than 6 months of age. RSV also causes repeated infections including severe lower respiratory tract disease, which may occur at any age, especially among the elderly or those with compromised cardiac, pulmonary, or immune systems. Using the mouse model of RSV infection, this article examines the immunopathogenesis during acute and chronic phases of the disease. This model allows for measurement of basal enhanced pause, which reflects airway obstruction in the acute phase, and the response to methacholine challenge to assess airway hyperresponsiveness during the chronic phase. This article also summarizes some recent studies focusing on novel perspectives and strategies for treatment and prevention of RSV infections. Compared with the lungs of sham-inoculated control mice, mice inoculated with live RSV showed a persistent progression of the severity of pneumonia as determined by an increasing histopathologic score. Mucus production of RSV-infected mice in the acute phase illustrated increased periodic acid-Schiff-positive hypertrophic cells in central and peripheral airways. RSV-infected mice with persistent airway hyperresponsiveness exhibited the presence of abnormal chronic inflammatory changes and mucus overproduction, which likely contributed to long term airway disease induced by RSV infection. These findings provide a histologic correlation to the abnormal pulmonary responses documented by plethysmography. Current trials have demonstrated positive results in continuing to target different alternatives for a new RSV vaccine.

Provoking dose of mannitol to assess airway hyperresponsiveness in asthma: A retrospective analysis

Provoking dose of mannitol to assess airway hyperresponsiveness in asthma: A retrospective analysis

Temporal correlation of measurements of airway hyperresponsiveness in ovalbumin-sensitized mice.

Airway hyperresponsiveness, airway inflammation, and reversible airway obstruction are physiological hallmarks of asthma. These responses are increasingly being studied in murine models of antigen exposure and challenge, using whole body plethysmography to noninvasively assess airway hyperresponsiveness. This approach infrequently has been correlated with indexes of airway hyperresponsiveness measured by invasive means. Furthermore, correlation with quantitative histological data for tissue infiltration by inflammatory and immune cells, particularly in the wall of airways, during daily airway challenge is lacking. To address these uncertainties, we used C57BL/6 mice that were immunized with ovalbumin or vehicle (saline) and sensitized to aerosolized ovalbumin or vehicle 8 days later. The mice were subsequently exposed to aerosolized ovalbumin or vehicle, respectively, on days 14-22. We assessed airway hyperresponsiveness to methacholine noninvasively on days 14, 15, 18, or 22; we studied the same mice 24 h later while they were anesthetized for invasive analyses of airway hyperresponsiveness. Plasma total IgE concentration was significantly higher in the ovalbumin-treated mice compared with the vehicle-treated mice, but this did not correlate with eosinophil number. Peak airway hyperresponsiveness measured by either approach correlated early during daily antigen challenge (days 14 and 15), but this correlation was lost later during subsequent daily antigen challenges (days 18 and 22). On days 14 and 15, peak airway hyperresponsiveness correlated with transmigration of neutrophils and macrophages, but not lymphocytes, in the peribronchovascular connective tissue sheaths. This extravascular accumulation was found to be focal by three-dimensional microscopy. We conclude that, although ovalbumin treatment changed lung function in mice, correlation between noninvasive and invasive measures of peak airway hyperresponsiveness was inconsistent.