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The European Respiratory Journal Dec 2019There are few data on the usefulness of different tests to diagnose asthma in children.
INTRODUCTION
There are few data on the usefulness of different tests to diagnose asthma in children.
AIM
We assessed the contribution of a detailed history and a variety of diagnostic tests for diagnosing asthma in children.
METHODS
We studied children aged 6-16 years referred consecutively for evaluation of suspected asthma to two pulmonary outpatient clinics. Symptoms were assessed by parental questionnaire. The clinical evaluation included skin-prick tests, measurement of exhaled nitric oxide fraction ( ), spirometry, bronchodilator reversibility and bronchial provocation tests (BPT) by exercise, methacholine and mannitol. Asthma was diagnosed by the physicians at the end of the visit. We assessed diagnostic accuracy of symptoms and tests by calculating sensitivity, specificity, positive and negative predictive values and area under the curve (AUC).
RESULTS
Of the 111 participants, 80 (72%) were diagnosed with asthma. The combined sensitivity and specificity was highest for reported frequent wheeze (more than three attacks per year) (sensitivity 0.44, specificity 0.90), awakening due to wheeze (0.41, 0.90) and wheeze triggered by pollen (0.46, 0.83) or by pets (0.29, 0.99). Of the diagnostic tests, the AUC was highest for measurement (0.80) and BPT by methacholine (0.81) or exercise (0.74), and lowest for forced expiratory volume in 1 s (FEV) (0.62) and FEV/forced vital capacity ratio (0.66), assessed by spirometry.
CONCLUSION
This study suggests that specific questions about triggers and severity of wheeze, measurement of and BPT by methacholine or exercise contribute more to the diagnosis of asthma in school-aged children than spirometry, bronchodilator reversibility and skin-prick tests.
Topics: Adolescent; Asthma; Bronchial Provocation Tests; Bronchodilator Agents; Child; Exhalation; Female; Forced Expiratory Volume; Humans; Male; Mannitol; Medical History Taking; Methacholine Chloride; Nitric Oxide; Pollen; Respiratory Sounds; Skin Tests; Spirometry; Vital Capacity
PubMed: 31515409
DOI: 10.1183/13993003.01326-2019 -
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 -
Exercise Immunology Review 2019Aerobic training (AT) decreases airway inflammation in asthma, but the underlying cellular and molecular mechanisms are not completely understood. Thus, this study...
BACKGROUND
Aerobic training (AT) decreases airway inflammation in asthma, but the underlying cellular and molecular mechanisms are not completely understood. Thus, this study evaluated the participation of SOCS-JAK-STAT signaling in the effects of AT on airway inflammation, remodeling and hyperresponsiveness in a model of allergic airway inflammation.
METHODS
C57Bl/6 mice were divided into Control (Co), Exercise (Ex), HDM (HDM), and HDM+Exercise (HDM+ Ex). Dermatophagoides pteronyssinus (100ug/mouse) were administered oro-tracheally on days 0, 7, 14, 21, 28, 35, 42 and 49. AT was performed in a treadmill during 4 weeks in moderate intensity, from day 24 until day 52.
RESULTS
AT inhibited HDM-induced total cells (p<0.001), eosinophils (p<0.01), neutrophils (p<0.01) and lymphocytes (p<0.01) in BAL, and eosinophils (p<0.01), neutrophils (p<0.01) and lymphocytes (p<0.01) in peribronchial space. AT also reduced BAL levels of IL-4 (p<0.001), IL-5 (p<0.001), IL-13 (p<0.001), CXCL1 (p<0.01), IL-17 (p<0.01), IL-23 (p<0.05), IL-33 (p<0.05), while increased IL- 10 (p<0.05). Airway collagen fibers (p<0.01), elastic fibers p<0.01) and mucin (p<0.01) were also reduced by AT. AT also inhibited HDM-induced airway hyperresponsiveness (AHR) to methacholine 6,25mg/ml (p<0.01), 12,5mg/mL (p<0.01), 25mg/mL (p<0.01) and 50mg/mL (p<0.01). Mechanistically, AT reduced the expression of STAT6 (p<0.05), STAT3 (p<0.001), STAT5 (p<0.01) and JAK2 (p<0.001), similarly by peribronchial leukocytes and by airway epithelial cells. SOCS1 expression (p<0.001) was upregulated in leukocytes and in epithelial cells, SOCS2 (p<0.01) was upregulated in leukocytes and SOCS3 down-regulated in leukocytes (p<0.05) and in epithelial cells (p<0.001).
CONCLUSIONS
AT reduces asthma phenotype involving SOCSJAK- STAT signaling.
Topics: Animals; Asthma; Disease Models, Animal; Eosinophils; Interleukins; Janus Kinases; Lymphocytes; Methacholine Chloride; Mice; Mice, Inbred C57BL; Neutrophils; Physical Conditioning, Animal; Respiratory Hypersensitivity; STAT Transcription Factors; Signal Transduction; Suppressor of Cytokine Signaling Proteins
PubMed: 30785869
DOI: No ID Found -
The Journal of Allergy and Clinical... 2014Inhaled racepinephrine (RE) (Asthmanefrin) became available in September 2012 as a nonprescription treatment for bronchospasm based on a 1986 US Food and Drug... (Clinical Trial)
Clinical Trial
BACKGROUND
Inhaled racepinephrine (RE) (Asthmanefrin) became available in September 2012 as a nonprescription treatment for bronchospasm based on a 1986 US Food and Drug Administration rule. It contains 11.25 mg RE in 0.5 mL and is delivered by a handheld electronic nebulizer. In 2001, we conducted a pilot study that was never published. Now that the product is promoted as a replacement for epinephrine chlorofluorocarbon metered-dose inhaler (Primatene), we provide the results of that study. Methacholine challenge was used as a bioassay.
OBJECTIVE
To determine the dose of RE that is equivalent to nebulized albuterol.
METHODS
Four subjects, 18 to 45 years old, with mild stable asthma completed the pilot study. Methacholine challenge was performed on the first screening day, without pretreatment, and then on different days, 15 minutes after 1.25 mg albuterol and 2.5, 5, 10, and 20 mg RE delivered by a Pari LC Plus nebulizer. The end point was the provocative concentration of methacholine that caused a 20% decrease in FEV1. Data were log transformed and analyzed by an ANOVA for repeated measures.
RESULTS
There was a significant dose response for RE. The geometric mean provocative concentration of methacholine that caused a 20% decrease in FEV1 was 44 mg/mL (95% CI, 23-85 mg/mL) after albuterol, and 10.2 mg/mL (95% CI, 3.5-30 mg/mL) after the 10-mg dose of RE (approximate nonprescription dose) (P = .001). There were no adverse effects.
CONCLUSION
RE provides less bronchoprotection from methacholine than does albuterol and may be less effective in treating acute bronchospasm.
Topics: Adolescent; Adult; Albuterol; Asthma; Bronchial Provocation Tests; Bronchoconstrictor Agents; Bronchodilator Agents; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Nonprescription Drugs; Racepinephrine; Young Adult
PubMed: 25213051
DOI: 10.1016/j.jaip.2014.02.014 -
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 -
Journal of Applied Physiology... Jul 2019Some subjects with asthma have ventilation defects that are resistant to bronchodilator therapy, and it is thought that these resistant defects may be due to ongoing...
Some subjects with asthma have ventilation defects that are resistant to bronchodilator therapy, and it is thought that these resistant defects may be due to ongoing inflammation or chronic airway remodeling. However, it is unclear whether regional obstruction due to bronchospasm alone persists after bronchodilator therapy. To investigate this, six young, healthy subjects, in whom inflammation and remodeling were assumed to be absent, were bronchoconstricted with a PC [the concentration of methacholine that elicits a 20% drop in forced expiratory volume in 1 s (FEV)] dose of methacholine and subsequently bronchodilated with a standard dose of albuterol on three separate occasions. Specific ventilation imaging, a proton MRI technique, was used to spatially map specific ventilation across 80% of each subject's right lung in each condition. The ratio between regional specific ventilation at baseline and after intervention was used to classify areas that had constricted. After albuterol rescue from methacholine bronchoconstriction, 12% (SD 9) of the lung was classified as constricted. Of the 12% of lung units that were classified as constricted after albuterol, approximately half [7% (SD 7)] had constricted after methacholine and failed to recover, whereas half [6% (SD 4)] had remained open after methacholine but became constricted after albuterol. The incomplete regional recovery was not reflected in the subjects' FEV measurements, which did not decrease from baseline ( = 0.97), nor was it detectable as an increase in specific ventilation heterogeneity ( = 0.78). In normal subjects bronchoconstricted with methacholine and subsequently treated with albuterol, not all regions of the healthy lung returned to their prebronchoconstricted specific ventilation after albuterol, despite full recovery of integrative lung indexes (forced expiratory volume in 1 s and specific ventilation heterogeneity). The regions that remained bronchoconstricted following albuterol were those with the highest specific ventilation at baseline, which suggests that they may have received the highest methacholine dose.
Topics: Administration, Inhalation; Adult; Albuterol; Asthma; Bronchial Provocation Tests; Bronchoconstriction; Bronchoconstrictor Agents; Bronchodilator Agents; Female; Forced Expiratory Volume; Humans; Lung; Male; Methacholine Chloride; Pulmonary Disease, Chronic Obstructive; Young Adult
PubMed: 31120808
DOI: 10.1152/japplphysiol.00912.2018 -
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