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Chest Mar 2011The high prevalence of airway hyperresponsiveness (AHR) among children with sickle cell anemia (SCA) remains unexplained.
BACKGROUND
The high prevalence of airway hyperresponsiveness (AHR) among children with sickle cell anemia (SCA) remains unexplained.
METHODS
To determine the relationship between AHR, features of asthma, and clinical characteristics of SCA, we conducted a multicenter, prospective cohort study of children with SCA. Dose response slope (DRS) was calculated to describe methacholine responsiveness, because 30% of participants did not achieve a 20% decrease in FEV1 after inhalation of the highest methacholine concentration, 25 mg/mL. Multiple linear regression analysis was done to identify independent predictors of DRS.
RESULTS
Methacholine challenge was performed in 99 children with SCA aged 5.6 to 19.9 years (median, 12.8 years). Fifty-four (55%) children had a provocative concentration of methacholine producing a 20% decrease in FEV1<4 mg/mL. In a multivariate analysis, independent associations were found between increased methacholine responsiveness and age (P<.001), IgE (P=.009), and lactate dehydrogenase (LDH) levels (P=.005). There was no association between methacholine responsiveness and a parent report of a doctor diagnosis of asthma (P=.986). Other characteristics of asthma were not associated with methacholine responsiveness, including positive skin tests to aeroallergens, exhaled nitric oxide, peripheral blood eosinophil count, and pulmonary function measures indicating airflow obstruction.
CONCLUSIONS
In children with SCA, AHR to methacholine is prevalent. Younger age, serum IgE concentration, and LDH level, a marker of hemolysis, are associated with AHR. With the exception of serum IgE, no signs or symptoms of an allergic diathesis are associated with AHR. Although the relationship between methacholine responsiveness and LDH suggests that factors related to SCA may contribute to AHR, these results will need to be validated in future studies.
Topics: Administration, Inhalation; Adolescent; Age Factors; Anemia, Sickle Cell; Asthma; Bronchial Provocation Tests; Child; Child, Preschool; Cohort Studies; Female; Humans; Immunoglobulin E; L-Lactate Dehydrogenase; Linear Models; Lung; Male; Methacholine Chloride; Prevalence; Prospective Studies; Respiratory Function Tests; Risk Factors; Young Adult
PubMed: 20724735
DOI: 10.1378/chest.10-1243 -
The European Respiratory Journal Jul 2016Methacholine bronchial provocation test provides the concentration of methacholine causing a 20% decrease in forced expiratory volume in 1 s (FEV1) from baseline...
Methacholine bronchial provocation test provides the concentration of methacholine causing a 20% decrease in forced expiratory volume in 1 s (FEV1) from baseline (PC20). The dose-response slope (DRS), and other continuous indices of responsiveness (CIR; the percentage decline from the post-diluent baseline FEV1 after the last dose of methacholine), and per cent recovery index (PRI; the percentage increase from the maximally reduced FEV1 after bronchodilator inhalation) are alternative measures. The clinical relevance of these indices in predicting acute asthma exacerbations has not been fully evaluated.In two prospective cohorts of childhood and elderly asthmatics, baseline PC20, DRS, CIR and PRI were measured and evaluated as predictors of acute asthma exacerbations.We found that PRI was significantly related to the presence of asthma exacerbations during the first year of follow-up in both cohorts of childhood (p=0.025) and elderly asthmatics (p=0.003). In addition, PRI showed a significant association with the total number of steroid bursts during 4.3 years of follow-up in the cohort of childhood asthmatics (p=0.04).We demonstrated that PRI, an index of reversibility following methacholine-induced bronchoconstriction, was a good clinical predictor of acute exacerbations of asthma in both childhood and elderly asthmatics.
Topics: Administration, Inhalation; Aged; Asthma; Boston; Bronchial Provocation Tests; Bronchoconstriction; Bronchoconstrictor Agents; Bronchodilator Agents; Child; Disease Progression; Female; Forced Expiratory Volume; Humans; Logistic Models; Male; Methacholine Chloride; Prospective Studies; Republic of Korea
PubMed: 27076579
DOI: 10.1183/13993003.00182-2016 -
Acta Medica Okayama Dec 2002Leukotrienes, one of the mediators of inflammation in asthma, have a strong bronchoconstrictive effect. L-carnitine has been reported to influence respiratory functions....
Leukotrienes, one of the mediators of inflammation in asthma, have a strong bronchoconstrictive effect. L-carnitine has been reported to influence respiratory functions. It has also been reported that L-carnitine inhibits leukotriene synthesis. To evaluate the effects of L-carnitine on oxygen saturation, urine leukotriene E4 levels and lung histopathology in a murine model of asthma, high IgE responder BALB/c mice (n = 24) were systemically sensitized to ovalbumin and chronically challenged with low particle mass concentrations of aerosolized ovalbumin, and then they were divided into 3 groups (study groups A, B, and C) each including eight mice. After methacholine-induced bronchoconstriction, the mice in groups A and B were given intraperitoneal L-carnitine (250 and 125 mg/kg, respectively), while the mice in group C were given placebo. Oxygen saturation of the mice was measured by pulse oxymeter before and after methacholine and after L-carnitine/ placebo application. In addition, urine leukotriene E4 levels were measured before asthma development, and 24-h after L-carnitine injection in asthmatic mice. Inflammation in the lung tissues of the sacrificed animals was scored histopathologically to determine the effect of L-carnitine on tissue level. A control group of non-sensitized mice (n = 8) treated with placebo only was used for comparison of urine leukotriene E4 levels and of histopathological parameters. Oxygen saturation of the mice in the study groups tended to decrease after methacholine and to improve after L-carnitine injection, although these changes were not significant at all time points. Urine leukotriene E4 levels of all 3 study groups increased significantly after asthma development. The rate of increment was smallest in the group given the highest L-carnitine dose (group A). Inflammation at the tissue level was also mildest in group A, and severest in the group that was not given carnitine (group C). All of the study groups and the control group differed significantly with respect to inflammation scores. In conclusion, L-carnitine improved oxygen saturation, and decreased urine leukotriene E4 levels and inflammation in lung tissues in the present murine model of asthma.
Topics: Animals; Asthma; Carnitine; Disease Models, Animal; Leukotriene E4; Lung; Methacholine Chloride; Mice; Mice, Inbred BALB C; Oxygen
PubMed: 12685858
DOI: 10.18926/AMO/31692 -
PloS One 2015Mechanisms driving alteration of lung function in response to inhalation of a methacholine aerosol are incompletely understood. To explore to what extent large and small... (Clinical Trial)
Clinical Trial
Mechanisms driving alteration of lung function in response to inhalation of a methacholine aerosol are incompletely understood. To explore to what extent large and small airways contribute to airflow limitation and airway closure in this context, volumetric capnography was performed before (n = 93) and after (n = 78) methacholine provocation in subjects with an intermediate clinical probability of asthma. Anatomical dead space (VDaw), reflecting large airway volume, and the slope of the alveolar capnogram (slope3), an index of ventilation heterogeneity linked to small airway dysfunction, were determined. At baseline, VDaw was positively correlated with lung volumes, FEV1 and peak expiratory flow, while slope3 was not correlated with any lung function index. Variations in VDaw and slope3 following methacholine stimulation were correlated to a small degree (R2 = -0.20). Multivariate regression analysis identified independent associations between variation in FEV1 and variations in both VDaw (Standardized Coefficient-SC = 0.66) and Slope3 (SC = 0.35). By contrast, variation in FVC was strongly associated with variations in VDaw (SC = 0.8) but not Slope3. Thus, alterations in the geometry and/or function of large and small airways were weakly correlated and contributed distinctly to airflow limitation. While both large and small airways contributed to airflow limitation as assessed by FEV1, airway closure as assessed by FVC reduction mostly involved the large airways.
Topics: Adult; Bronchial Provocation Tests; Bronchoconstrictor Agents; Female; Forced Expiratory Volume; Humans; Lung; Male; Methacholine Chloride; Middle Aged; Tidal Volume
PubMed: 26599006
DOI: 10.1371/journal.pone.0143550 -
The European Respiratory Journal Apr 2011Bronchodilator response (BDR) is assessed to estimate the reversibility of airflow obstruction. Bronchial hyperresponsiveness (BHR) is a characteristic feature of asthma... (Clinical Trial)
Clinical Trial
Bronchodilator response (BDR) is assessed to estimate the reversibility of airflow obstruction. Bronchial hyperresponsiveness (BHR) is a characteristic feature of asthma and is usually measured by means of bronchial challenges using direct or indirect stimuli. The aim of the present study was to compare BHR to methacholine (direct) and that to adenosine 5'-monophosphate (AMP) (indirect) with regard to their relationships to BDR in asthmatic children. Methacholine and AMP challenge tests were performed on 138 children with mild-to-moderate asthma, and the provocative concentration causing a 20% decline in forced expiratory volume in 1 s (FEV₁) (PC₂₀) was determined for each challenge. BDR was calculated as the change in FEV(1), expressed as a percentage of the initial value, after inhalation of 400 μg salbutamol. Methacholine PC₂₀ correlated significantly but weakly with BDR (r = -0.254; p = 0.003). However, there was a significant and strong correlation between AMP PC₂₀ and BDR (r = -0.489; p = 0.000). For AMP PC₂₀, the relationship was closer than for methacholine PC₂₀ (p = 0.024 for comparison between correlation coefficients). The same figures were observed when BDR was expressed as a percentage of the predicted value. A stronger correlation of BDR with AMP PC₂₀ than with methacholine PC₂₀ suggests that BDR may be better reflected by BHR as assessed by AMP challenge than by methacholine challenge.
Topics: Adenosine Monophosphate; Adolescent; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchodilator Agents; Child; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Respiratory Function Tests
PubMed: 20817709
DOI: 10.1183/09031936.00049610 -
BMJ Open Respiratory Research May 2024Methods used to assess ventilation heterogeneity through inert gas washout have been standardised and showed high sensitivity in diagnosing many respiratory diseases. We... (Observational Study)
Observational Study Comparative Study
BACKGROUND
Methods used to assess ventilation heterogeneity through inert gas washout have been standardised and showed high sensitivity in diagnosing many respiratory diseases. We hypothesised that nitrogen single or multiple breath washout tests, respectively nitrogen single breath washout (NSBW) and nitrogen multiple breath washout (NMBW), may be pathological in patients with clinical suspicion of asthma but normal spirometry. Our aim was to assess whether NSBW and NMBW are associated with methacholine challenge test (MCT) results in this population. We also postulated that an alteration in S at NSBW could be detected before the 20% fall of forced expiratory volume in the first second (FEV) in MCT.
STUDY DESIGN AND METHODS
This prospective, observational, single-centre study included patients with suspicion of asthma with normal spirometry. Patients completed questionnaires on symptoms and health-related quality-of-life and underwent the following lung function tests: NSBW (S), NMBW (Lung clearance index (LCI), S, S), MCT (FEV and sGeff) as well as NSBW between each methacholine dose.
RESULTS
182 patients were screened and 106 were included in the study, with mean age of 41.8±14 years. The majority were never-smokers (58%) and women (61%). MCT was abnormal in 48% of participants, NSBW was pathological in 10.6% at baseline and NMBW abnormality ranged widely (LCI 81%, S 18%, S 43%). The dose response rate of the MCT showed weak to moderate correlation with the subsequent NSBW measurements during the provocation phases (ρ 0.34-0.50) but no correlation with NMBW.
CONCLUSIONS
Both MCT and N washout tests are frequently pathological in patients with suspicion of asthma with normal spirometry. The weak association and lack of concordance across the tests highlight that they reflect different but not interchangeable pathological pathways of the disease.
Topics: Humans; Asthma; Methacholine Chloride; Female; Male; Prospective Studies; Adult; Spirometry; Breath Tests; Middle Aged; Nitrogen; Bronchial Provocation Tests; Forced Expiratory Volume; Respiratory Function Tests; Lung; Bronchoconstrictor Agents
PubMed: 38697675
DOI: 10.1136/bmjresp-2023-001919 -
The PDE4 inhibitor CHF-6001 and LAMAs inhibit bronchoconstriction-induced remodeling in lung slices.American Journal of Physiology. Lung... Sep 2017Combination therapy of PDE4 inhibitors and anticholinergics induces bronchoprotection in COPD. Mechanical forces that arise during bronchoconstriction may contribute to...
Combination therapy of PDE4 inhibitors and anticholinergics induces bronchoprotection in COPD. Mechanical forces that arise during bronchoconstriction may contribute to airway remodeling. Therefore, we investigated the impact of PDE4 inhibitors and anticholinergics on bronchoconstriction-induced remodeling. Because of the different mechanism of action of PDE4 inhibitors and anticholinergics, we hypothesized functional interactions of these two drug classes. Guinea pig precision-cut lung slices were preincubated with the PDE4 inhibitors CHF-6001 or roflumilast and/or the anticholinergics tiotropium or glycopyorrolate, followed by stimulation with methacholine (10 μM) or TGF-β (2 ng/ml) for 48 h. The inhibitory effects on airway smooth muscle remodeling, airway contraction, and TGF-β release were investigated. Methacholine-induced protein expression of smooth muscle-myosin was fully inhibited by CHF-6001 (0.3-100 nM), whereas roflumilast (1 µM) had smaller effects. Tiotropium and glycopyrrolate fully inhibited methacholine-induced airway remodeling (0.1-30 nM). The combination of CHF-6001 and tiotropium or glycopyrrolate, in concentrations partially effective by themselves, fully inhibited methacholine-induced remodeling in combination. CHF-6001 did not affect airway closure and had limited effects on TGF-β-induced remodeling, but rather, it inhibited methacholine-induced TGF-β release. The PDE4 inhibitor CHF-6001, and to a lesser extent roflumilast, and the LAMAs tiotropium and glycopyrrolate inhibit bronchoconstriction-induced remodeling. The combination of CHF-6001 and anticholinergics was more effective than the individual compounds. This cooperativity might be explained by the distinct mechanisms of action inhibiting TGF-β release and bronchoconstriction.
Topics: Airway Remodeling; Aminopyridines; Animals; Benzamides; Bronchoconstriction; Cholinergic Antagonists; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclopropanes; Drug Interactions; Glycopyrrolate; Guinea Pigs; Lung; Male; Methacholine Chloride; Phosphodiesterase 4 Inhibitors; Sulfonamides; Tiotropium Bromide; Transforming Growth Factor beta; para-Aminobenzoates
PubMed: 28596292
DOI: 10.1152/ajplung.00069.2017 -
Journal of Applied Physiology... Dec 2001We investigated the differential effect of histamine and methacholine on spirometry and ventilation distribution (where indexes S(cond) and S(acin) represent conductive... (Comparative Study)
Comparative Study
We investigated the differential effect of histamine and methacholine on spirometry and ventilation distribution (where indexes S(cond) and S(acin) represent conductive and acinar ventilation heterogeneity; Verbanck S, Schuermans D, Van Muylem A, Noppen M, Paiva M, and Vincken W. J Appl Physiol 83: 1807-1816, 1997). Thirty normal subjects were challenged with cumulative doses of 6.52 micromol histamine and, on a separate day, with either 6.67 micromol methacholine (equal-dose group; n = 15) or 13.3 micromol methacholine (double-dose group; n = 15). Largest average forced expiratory volume in 1 s (FEV(1)) decreases or S(cond) increases obtained in either group were -9% and +286%, respectively; S(acin) remained unaffected at all times. In the equal-dose group, a smaller FEV(1) decline (P = 0.002) after methacholine was paralleled by a smaller S(cond) increase (P = 0.041) than with histamine. However, in the double-dose group, methacholine maintained a smaller FEV(1) decline (P = 0.009) while inducing a larger S(cond) increase (P = 0.006) than did histamine. The differential action of histamine and methacholine is confined to the conductive airways, where histamine likely causes the greatest overall airway narrowing and methacholine induces the largest parallel heterogeneity in airway narrowing, probably at the level of the large and small conductive airways, respectively. The observed ventilation heterogeneities predict a risk for dissociation between ventilation-perfusion mismatch and spirometry, particularly after methacholine challenge.
Topics: Bronchoconstrictor Agents; Dose-Response Relationship, Drug; Forced Expiratory Volume; Histamine; Humans; Maximal Midexpiratory Flow Rate; Methacholine Chloride; Peak Expiratory Flow Rate; Respiration; Spirometry
PubMed: 11717223
DOI: 10.1152/jappl.2001.91.6.2587 -
The European Respiratory Journal Apr 1998Methacholine chloride solutions, routinely used for testing bronchial hyperreactivity, have been shown to degrade over time. The data published addressing the optimal...
Methacholine chloride solutions, routinely used for testing bronchial hyperreactivity, have been shown to degrade over time. The data published addressing the optimal conditions for methacholine chloride storage are conflicting and incomplete. This study investigated the effects of a variety of conditions on the stability of methacholine chloride. Methacholine chloride, dissolved in phosphate buffered saline (PBS) or sodium chloride (NaCl) at 50 and 0.39 g x L(-1), was subjected to various light and temperature conditions for 9 months. Methacholine chloride degradation was determined by high performance liquid chromatography, and all solutions underwent bacterial and pH testing. By 9 months, all 50 g x L(-1) solutions of methacholine chloride had degraded by 65+/-0.8%. All 0.39 g x L(-1) solutions in NaCl had degraded by 11.0+/-0.33%. The 0.39 g x L(-1) solutions in PBS which had been frozen, refrigerated or stored at room temperature had degraded by 8.0%, 16.0+/-0.3% and 63.8+/-0.5%, respectively. The pH of methacholine chloride was 7.2 in PBS at 0.39 g x L(-1), 5.8 in PBS at 50 g x L(-1), 3.9 in NaCl at 0.39 and 2.7 in NaCl at 50 g x L(-1). Bacterial contamination was minimal. The results of this study demonstrate that methacholine chloride is more stable at the higher concentration. However, the pH of the more concentrated solutions of methacholine chloride in sodium chloride could cause bronchoconstriction in some subjects. We therefore recommend storing methacholine chloride at 50 g x L(-1) in phosphate-buffered saline.
Topics: Bronchoconstrictor Agents; Drug Stability; Drug Storage; Hydrogen-Ion Concentration; Methacholine Chloride; Sodium Chloride; Solutions; Time Factors
PubMed: 9623702
DOI: 10.1183/09031936.98.11040946 -
Journal of Applied Physiology... Mar 2002Rat and monkey are species that are used in models of human airway hyperresponsiveness. However, the wall structures of rat and monkey airways are different from each... (Comparative Study)
Comparative Study
Rat and monkey are species that are used in models of human airway hyperresponsiveness. However, the wall structures of rat and monkey airways are different from each other, with that of the monkey more closely resembling that of humans. We hypothesized that differences in wall structure would explain differences in airway responsiveness. Using videomicrometry, we measured airway luminal area in lung slices to compare proximal and distal airway responsiveness to methacholine in the rat and monkey. The airway type was then histologically identified. Proximal airways of the young rat and monkey were equally responsive to methacholine. In contrast, respiratory bronchioles of monkeys were less responsive than were their proximal bronchi, whereas the distal bronchioles of rats were more responsive than their proximal bronchioles. Both proximal and distal airways of younger monkeys were more responsive than those of older monkeys. Airway heterogeneity in young monkeys was greatest with regard to degree of airway closure of respiratory bronchioles. We conclude that responsiveness to methacholine varies with airway wall structure and location.
Topics: Aging; Animals; Bronchi; Bronchoconstrictor Agents; Female; In Vitro Techniques; Macaca mulatta; Male; Methacholine Chloride; Microscopy, Video; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley
PubMed: 11842031
DOI: 10.1152/japplphysiol.00415.2001