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Chest Aug 2020In patients with a history suggestive of asthma, diagnosis is usually confirmed by spirometry with bronchodilator response (BDR) or confirmatory methacholine challenge...
BACKGROUND
In patients with a history suggestive of asthma, diagnosis is usually confirmed by spirometry with bronchodilator response (BDR) or confirmatory methacholine challenge testing (MCT).
RESEARCH QUESTION
We examined the proportion of participants with negative BDR testing who had a positive MCT (and its predictors) result and characteristics of MCT, including effects of controller medication tapering and temporal variability (and predictors of MCT result change), and concordance between MCT and pulmonologist asthma diagnosis.
STUDY DESIGN AND METHODS
Adults with self-reported physician-diagnosed asthma were recruited by random-digit dialing across Canada. Subjects performed spirometry with BDR testing and returned for MCT if testing was nondiagnostic for asthma. Subjects on controllers underwent medication tapering with serial MCTs over 3 to 6 weeks. Subjects with a negative MCT (the provocative concentration of methacholine that results in a 20% drop in FEV [PC] > 8 mg/mL) off medications were examined by a pulmonologist and had serial MCTs after 6 and 12 months.
RESULTS
Of 500 subjects (50.5 ± 16.6 years old, 68.0% female) with a negative BDR test for asthma, 215 (43.0%) had a positive MCT. Subjects with prebronchodilator airflow limitation were more likely to have a positive MCT (OR, 1.90; 95% CI, 1.17-3.04). MCT converted from negative to positive, with medication tapering in 18 of 94 (19.1%) participants, and spontaneously over time in 25 of 165 (15.2%) participants. Of 231 subjects with negative MCT, 28 (12.1%) subsequently received an asthma diagnosis from a pulmonologist.
INTERPRETATION
In subjects with a self-reported physician diagnosis of asthma, absence of bronchodilator reversibility had a negative predictive value of only 57% to exclude asthma. A finding of spirometric airflow limitation significantly increased chances of asthma. MCT results varied with medication taper and over time, and pulmonologists were sometimes prepared to give a clinical diagnosis of asthma despite negative MCT. Correspondingly, in patients for whom a high clinical suspicion of asthma exists, repeat testing appears to be warranted.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asthma; Bronchial Provocation Tests; Bronchodilator Agents; Cohort Studies; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Middle Aged; Predictive Value of Tests; Spirometry; Young Adult
PubMed: 32298731
DOI: 10.1016/j.chest.2020.03.052 -
American Journal of Physiology. Lung... May 2020Transient receptor potential ankyrin-1 (TRPA1) is a ligand-gated cation channel that responds to endogenous and exogenous irritants. TRPA1 is expressed on multiple cell...
Transient receptor potential ankyrin-1 (TRPA1) is a ligand-gated cation channel that responds to endogenous and exogenous irritants. TRPA1 is expressed on multiple cell types throughout the lungs, but previous studies have primarily focused on TRPA1 stimulation of airway sensory nerves. We sought to understand the integrated physiological airway response to TRPA1 stimulation. The TRPA1 agonists allyl isothiocyanate (AITC) and cinnamaldehyde (CINN) were tested in sedated, mechanically ventilated guinea pigs in vivo. Reproducible bronchoconstrictions were induced by electrical stimulation of the vagus nerves. Animals were then treated with intravenous AITC or CINN. AITC and CINN were also tested on isolated guinea pig and mouse tracheas and postmortem human trachealis muscle strips in an organ bath. Tissues were contracted with methacholine, histamine, or potassium chloride and then treated with AITC or CINN. Some airways were pretreated with TRPA1 antagonists, the cyclooxygenase inhibitor indomethacin, the EP receptor antagonist PF 04418948, or tetrodotoxin. AITC and CINN blocked vagally mediated bronchoconstriction in guinea pigs. Pretreatment with indomethacin completely abolished the airway response to TRPA1 agonists. Similarly, AITC and CINN dose-dependently relaxed precontracted guinea pig, mouse, and human airways in the organ bath. AITC- and CINN-induced airway relaxation required TRPA1, prostaglandins, and PGE receptor activation. TRPA1-induced airway relaxation did not require epithelium or tetrodotoxin-sensitive nerves. Finally, AITC blocked airway hyperreactivity in two animal models of allergic asthma. These data demonstrate that stimulation of TRPA1 causes bronchodilation of intact airways and suggest that the TRPA1 pathway is a potential pharmacological target for bronchodilation.
Topics: Acrolein; Animals; Bronchoconstriction; Dinoprostone; Electric Stimulation; Gene Expression Regulation; Guinea Pigs; Histamine; Humans; Indomethacin; Isothiocyanates; Male; Methacholine Chloride; Mice; Muscle, Smooth; Organ Culture Techniques; Potassium Chloride; Prostaglandin-Endoperoxide Synthases; Respiration, Artificial; Signal Transduction; TRPA1 Cation Channel; Tetrodotoxin; Trachea; Vagus Nerve
PubMed: 32233794
DOI: 10.1152/ajplung.00277.2019 -
Toxicological Sciences : An Official... Jun 2019Sex differences clearly exist in incidence, susceptibility, and severity of airway disease and in pulmonary responses to air pollutants such as ozone (O3). Prior rodent...
Sex differences clearly exist in incidence, susceptibility, and severity of airway disease and in pulmonary responses to air pollutants such as ozone (O3). Prior rodent O3 exposure studies demonstrate sex-related differences in the expression of lung inflammatory mediators and signaling. However, whether or not sex modifies O3-induced airway physiologic responses remains less explored. To address this, we exposed 8- to 10-week-old male and female C57BL/6 mice to either 1 or 2 ppm O3 or filtered air (FA) for 3 h. At 12, 24, 48, and 72 h following exposure, we assessed airway hyperresponsiveness to methacholine (MCh), bronchoalveolar lavage fluid cellularity, cytokines and total protein/albumin, serum progesterone, and whole lung immune cells by flow cytometry. Male mice generated consistent airway hyperresponsiveness to MCh at all time points following exposure. Alternatively, females had less consistent airway physiologic responses to MCh, which were more variable between individual experiments and did not correlate with serum progesterone levels. Bronchoalveolar lavage fluid total cells peaked at 12 h and were persistently elevated through 72 h. At 48 h, bronchoalveolar lavage cells were greater in females versus males. Bronchoalveolar lavage fluid cytokines and total protein/albumin increased following O3 exposure without sex differences. Flow cytometry of whole lung tissue identified dynamic O3-induced immune cell changes also independent of sex. Our results indicate sex differences in acute O3-induced airway physiology responses and airspace influx without significant difference in other injury and inflammation measures. This study highlights the importance of considering sex as a biological variable in acute O3-induced airway physiology responses.
Topics: Acute Disease; Animals; Cytokines; Female; Immunophenotyping; Male; Methacholine Chloride; Mice; Mice, Inbred C57BL; Ozone; Progesterone; Respiratory Hypersensitivity; Sex Characteristics
PubMed: 30825310
DOI: 10.1093/toxsci/kfz056 -
Pediatric Research Jun 2020Supplemental oxygen exposure administered to premature infants is associated with chronic lung disease and abnormal pulmonary function. This study used mild (40%),...
BACKGROUND
Supplemental oxygen exposure administered to premature infants is associated with chronic lung disease and abnormal pulmonary function. This study used mild (40%), moderate (60%), and severe (80%) oxygen to determine how hyperoxia-induced changes in lung structure impact pulmonary mechanics in mice.
METHODS
C57BL/6J mice were exposed to room air or hyperoxia from birth through postnatal day 8. Baseline pulmonary function and methacholine challenge was assessed at 4 and 8 weeks of age, accompanied by immunohistochemical assessments of both airway (smooth muscle, tethering) and alveolar (simplification, elastin deposition) structure.
RESULTS
Mild/moderate hyperoxia increased baseline airway resistance (40% only) and airway hyperreactivity (40 and 60%) at 4 weeks accompanied by increased airway smooth muscle deposition, which resolved at 8 weeks. Severe hyperoxia increased baseline compliance, baseline resistance, and total elastin/surface area ratio without increasing airway hyperreactivity, and was accompanied by increased alveolar simplification, decreased airway tethering, and changes in elastin distribution at both time points.
CONCLUSIONS
Mild to moderate hyperoxia causes changes in airway function and airway hyperreactivity with minimal parenchymal response. Severe hyperoxia drives its functional changes through alveolar simplification, airway tethering, and elastin redistribution. These differential responses can be leveraged to further develop hyperoxia mouse models.
Topics: Animals; Animals, Newborn; Dose-Response Relationship, Drug; Female; Hyperoxia; Lung; Lung Compliance; Male; Methacholine Chloride; Mice; Mice, Inbred C57BL; Muscarinic Agonists; Muscle, Smooth; Pulmonary Alveoli; Respiratory Function Tests; Respiratory Mechanics; Sex Factors
PubMed: 31835269
DOI: 10.1038/s41390-019-0723-y -
JCI Insight Oct 2022Obesity-induced asthma responds poorly to all current pharmacological interventions, including steroids, suggesting that classic, eosinophilic inflammation is not a...
Obesity-induced asthma responds poorly to all current pharmacological interventions, including steroids, suggesting that classic, eosinophilic inflammation is not a mechanism. Since insulin resistance and hyperinsulinemia are common in obese individuals and associated with increased risk of asthma, we used diet-induced obese mice to study how insulin induces airway hyperreactivity. Inhaled 5-HT or methacholine induced dose-dependent bronchoconstriction that was significantly potentiated in obese mice. Cutting the vagus nerves eliminated bronchoconstriction in both obese and nonobese animals, indicating that it was mediated by a neural reflex. There was significantly greater density of airway sensory nerves in obese compared with nonobese mice. Deleting insulin receptors on sensory nerves prevented the increase in sensory nerve density and prevented airway hyperreactivity in obese mice with hyperinsulinemia. Our data demonstrate that high levels of insulin drives obesity-induced airway hyperreactivity by increasing sensory innervation of the airways. Therefore, pharmacological interventions to control metabolic syndrome and limit reflex-mediated bronchoconstriction may be a more effective approach to reduce asthma exacerbations in obese and patients with asthma.
Topics: Mice; Animals; Bronchoconstriction; Mice, Obese; Methacholine Chloride; Insulin; Receptor, Insulin; Serotonin; Asthma; Reflex; Hyperinsulinism; Obesity
PubMed: 36107629
DOI: 10.1172/jci.insight.161898 -
European Journal of Sport Science Aug 2023The aim of this study was to examine lung function, bronchial hyperresponsiveness (BHR) and exercise-induced respiratory symptoms in elite athletes performing different...
The aim of this study was to examine lung function, bronchial hyperresponsiveness (BHR) and exercise-induced respiratory symptoms in elite athletes performing different sports. Norwegian national-team athletes (30 swimmers, 32 cross-country skiers, 16 speed-skaters, 11 rowers/paddlers, 17 handball players and 23 soccer players) completed a validated questionnaire, measured exhaled nitric oxide (FE), spirometry, methacholine provocation (PD) and skin prick test. Three cut-off levels defined BHR; i.e. PD ≤2 µmol, ≤4 µmol and ≤8 µmol. Mean forced vital capacity (FVC) was highest in swimmers (Mean z-score[95%CI] = 1.16 [0.80, 1.51]), and close to or higher than reference values according to the Global Lung Initiative equation, across all sports. Mean forced expiratory volume in 1 s (FEV) was higher than reference values in swimmers (0.48 [0.13, 0.84]), and ball game athletes (0.69 [0.41, 0.97]). Mean forced expiratory flow between 25 and 75% of FVC (FEF), and/or FEV/FVC were lower than reference values in all endurance groups. BHR defined by ≤2 and ≤8 µmol methacholine was observed in respectively 50%-87% of swimmers, 25%-47% of cross-country skiers, 20%-53% of speed-skaters, 18%-36% of rowers/paddlers, and 0%-17% of the ball game athletes. Exercise-induced symptoms were common in all groups, most frequent in cross-country skiers (88%), swimmers (83%) and speed-skaters (81%).Swimmers and ball game athletes had higher mean FVC and FEV when compared to the reference values predicted by the Global Lung Initiative (GLI) reference equation. Contrasting this, across all sports except ball game athletes, mean FEF and/or FEV/FVC were lower than reference values.The prevalence of bronchial hyperresponsiveness (BHR) was high among elite athletes competing in swimming, cross-country skiing, speed skating and rowing/paddling, with swimmers being most affected.The majority of the elite athletes reported exercise-induced respiratory symptoms independent of lung function or BHR.
Topics: Humans; Methacholine Chloride; Bronchial Provocation Tests; Bronchial Hyperreactivity; Athletes; Swimming; Lung
PubMed: 35975407
DOI: 10.1080/17461391.2022.2113144 -
The Journal of Allergy and Clinical... Feb 2016The diagnosis of occupational asthma (OA) can be challenging and needs a stepwise approach. However, the predictive value of the methacholine challenge has never been...
BACKGROUND
The diagnosis of occupational asthma (OA) can be challenging and needs a stepwise approach. However, the predictive value of the methacholine challenge has never been addressed specifically in this context.
OBJECTIVE
We sought to evaluate the sensitivity, specificity, and positive and negative predictive values of the methacholine challenge in OA.
METHODS
A Canadian database was used to review 1012 cases of workers referred for a suspicion of OA between 1983 and 2011 and having had a specific inhalation challenge. We calculated the sensitivity, specificity, and positive and negative predictive values of methacholine challenges at baseline of the specific inhalation challenge, at the workplace, and outside work.
RESULTS
At baseline, the methacholine challenge showed an overall sensitivity of 80.2% and a specificity of 47.1%, with positive and negative predictive values of 36.5% and 86.3%, respectively. Among the 430 subjects who were still working, the baseline measures displayed a sensitivity of 95.4%, a specificity of 40.1%, and positive and negative predictive values of 41.1% and 95.2%, respectively. Among the 582 subjects tested outside work, the baseline measures demonstrated a sensitivity and specificity of 66.7% and 52%, respectively, and positive and negative predictive values of 31.9% and 82.2%, respectively. When considering all subjects tested by a methacholine challenge at least once while at work (479), the sensitivity, specificity, and positive and negative predictive values were 98.1%, 39.1%, and 44.0% and 97.7%, respectively.
CONCLUSION
A negative methacholine challenge in a patient still exposed to the causative agent at work makes the diagnosis of OA very unlikely.
Topics: Adult; Asthma, Occupational; Bronchial Provocation Tests; Canada; Databases, Factual; Female; Humans; Male; Methacholine Chloride; Middle Aged; Reproducibility of Results; Retrospective Studies; Risk Factors; Sensitivity and Specificity
PubMed: 26220529
DOI: 10.1016/j.jaci.2015.06.026 -
The European Respiratory Journal Feb 2021Oxidised phosphatidylcholines (OxPCs) are produced under conditions of elevated oxidative stress and can contribute to human disease pathobiology. However, their role in...
Oxidised phosphatidylcholines (OxPCs) are produced under conditions of elevated oxidative stress and can contribute to human disease pathobiology. However, their role in allergic asthma is unexplored. The aim of this study was to characterise the OxPC profile in the airways after allergen challenge of people with airway hyperresponsiveness (AHR) or mild asthma. The capacity of OxPCs to contribute to pathobiology associated with asthma was also to be determined.Using bronchoalveolar lavage fluid from two human cohorts, OxPC species were quantified using ultra-high performance liquid chromatography-tandem mass spectrometry. Murine thin-cut lung slices were used to measure airway narrowing caused by OxPCs. Human airway smooth muscle (HASM) cells were exposed to OxPCs to assess concentration-associated changes in inflammatory phenotype and activation of signalling networks.OxPC profiles in the airways were different between people with and without AHR and correlated with methacholine responsiveness. Exposing patients with mild asthma to allergens produced unique OxPC signatures that associated with the severity of the late asthma response. OxPCs dose-dependently induced 15% airway narrowing in murine thin-cut lung slices. In HASM cells, OxPCs dose-dependently increased the biosynthesis of cyclooxygenase-2, interleukin (IL)-6, IL-8, granulocyte-macrophage colony-stimulating factor and the production of oxylipins protein kinase C-dependent pathways.Data from human cohorts and primary HASM cell culture show that OxPCs are present in the airways, increase after allergen challenge and correlate with metrics of airway dysfunction. Furthermore, OxPCs may contribute to asthma pathobiology by promoting airway narrowing and inducing a pro-inflammatory phenotype and contraction of airway smooth muscle. OxPCs represent a potential novel target for treating oxidative stress-associated pathobiology in asthma.
Topics: Administration, Inhalation; Allergens; Animals; Asthma; Humans; Methacholine Chloride; Mice; Phosphatidylcholines
PubMed: 32883680
DOI: 10.1183/13993003.00839-2020 -
Behavioural Brain Research May 2017Human and animal studies have shown that physical challenges and stressors during adolescence can have significant influences on behavioral and neurobiological...
Human and animal studies have shown that physical challenges and stressors during adolescence can have significant influences on behavioral and neurobiological development associated with internalizing disorders such as anxiety and depression. Given the prevalence of asthma during adolescence and increased rates of internalizing disorders in humans with asthma, we used a mouse model to test if and which symptoms of adolescent allergic asthma (airway inflammation or labored breathing) cause adult anxiety- and depression-related behavior and brain function. To mimic symptoms of allergic asthma in young BALB/cJ mice (postnatal days [P] 7-57; N=98), we induced lung inflammation with repeated intranasal administration of house dust mite extract (most common aeroallergen for humans) and bronchoconstriction with aerosolized methacholine (non-selective muscarinic receptor agonist). Three experimental groups, in addition to a control group, included: (1) "Airway inflammation only", allergen exposure 3 times/week, (2) "Labored breathing only", methacholine exposure once/week, and (3) "Airway inflammation+Labored breathing", allergen and methacholine exposure. Compared to controls, mice that experienced methacholine-induced labored breathing during adolescence displayed a ∼20% decrease in time on open arms of the elevated plus maze in early adulthood (P60), a ∼30% decrease in brainstem serotonin transporter (SERT) mRNA expression and a ∼50% increase in hippocampal serotonin receptor 1a (5Htr1a) and corticotropin releasing hormone receptor 1 (Crhr1) expression in adulthood (P75). This is the first evidence that experimentally-induced clinical symptoms of adolescent asthma alter adult anxiety-related behavior and brain function several weeks after completion of asthma manipulations.
Topics: Age Factors; Animals; Anxiety; Asthma; Behavior, Animal; Disease Models, Animal; Female; Gene Expression; Hippocampus; Male; Methacholine Chloride; Mice; Mice, Inbred BALB C; Muscarinic Agonists; Pyroglyphidae; Sex Factors
PubMed: 28284954
DOI: 10.1016/j.bbr.2017.02.046 -
Medical Journal, Armed Forces India Jan 2021Bronchial hyper-responsiveness (BHR) is the hallmark of bronchial asthma, characterized by clinical features of cough, wheeze, breathlessness and chest tightness which...
BACKGROUND
Bronchial hyper-responsiveness (BHR) is the hallmark of bronchial asthma, characterized by clinical features of cough, wheeze, breathlessness and chest tightness which are confirmed by spirometry showing obstructive pattern and reversibility to bronchodilators. In individuals having features of bronchial asthma but normal spirometry, demonstration of BHR with bronchial challenge test (direct or indirect) confirms/ rules out the diagnosis. The aim of this study was to assess BHR in patients (methacholine challenge) with a history suggestive of bronchial asthma but normal spirometry and its role in diagnosis of bronchial asthma.
METHODS
This study was conducted at tertiary care respiratory center. Patients having clinical features of bronchial asthma but spirometry not confirming obstructive disorder and or reversibility were included in the study. After written consent, methacholine challenge test with methacholine chloride and exercise spirometry was done in all patients as per the American Thoracic Society protocol.
RESULTS
A total of 50 (n) patients were included in the study. Among them, 42 patients had clinical features suggestive of bronchial asthma but having normal spirometry and eight patients were diagnosed as they had bronchial asthma in the past but asymptomatic and off drugs were included in the study. At PC20 4mg/ml 32 (64%) patients had a positive test, 28(66%) symptomatic patients and four (50%) asymptomatic asthmatics. There were no significant side effects with methacholine test.
CONCLUSION
Airway hyper-responsiveness is an important aspect of bronchial asthma and its demonstration with bronchial challenge (direct and indirect) test is an important diagnostic tool. Methacholine challenge test is a safe procedure to perform under supervision.
PubMed: 33487871
DOI: 10.1016/j.mjafi.2020.05.007