Methacholine Inhalation Research Articles

Standard technical specifications for methacholine chloride (Methacholine) bronchial challenge test (2023)

Standard technical specifications for methacholine chloride (Methacholine) bronchial challenge test (2023)

A new tidal breathing measurement device detects bronchial obstruction during methacholine challenge test

PurposeBronchial hyperresponsiveness (BHR), a hallmark of bronchial asthma, is typically diagnosed through a methacholine inhalation test followed by spirometry, known as the methacholine challenge test (MCT). While spirometry relies on proper patients' cooperation and precise execution of forced breathing maneuvers, we conducted a comparative analysis with the portable nanomaterial-based sensing device, SenseGuard™, to non-intrusively assess tidal breathing parameters. Materials and methodsIn this prospective study, 37 adult participants with suspected asthma underwent sequential spirometry and SenseGuard™ measurements after inhaling increasing methacholine doses. ResultsAmong the 37 participants, 18 were MCT responders, 17 were non-responders and 2 were excluded due to uninterpretable data. The MCT responders exhibited a significant lung function difference when comparing the change from baseline to maximum response. This was evident through a notable decrease in forced expiratory volume in 1 ​s (FEV1) levels in spirometry, as well as in prominent changes in tidal breathing parameters as assessed by SenseGuard™, including the expiratory pause time (Trest) to total breath time (Ttot) ratio, and the expiratory time (Tex) to Ttot ratio. Notably, the ratios Trest/Ttot (∗p ​= ​0.02), Tex/Ttot (∗p ​= ​0.002), and inspiratory time (Tin) to Tex (∗p ​= ​0.04) identified MCT responders distinctly, corresponding to spirometry (∗p ​< ​0.0001). ConclusionsThis study demonstrates that tidal breathing assessment using SenseGuard™ device reliably detects clinically relevant changes of respiratory parameter during the MCT. It effectively distinguishes between responders and non-responders, with strong agreement to conventional spirometry-measured FEV1. This technology holds promise for monitoring clinical respiratory changes in bronchial asthma patients pending further studies.

Immunomodulatory effects of modified Liu-Wei-Di-Huang-Wan Traditional Chinese medicine on allergic asthmatic mice

BackgroundAllergic asthma occurs worldwide and is particularly prevalent in westernized countries characterized by chronic airway inflammation resulting in airway hyperresponsiveness. The house dust mites (HDM) including Dermatophagoides pteronyssinus are major sources of sensitization and triggering allergic symptoms in asthmatic patients. The Der p 2 is a major allergen and the predominant source of causative respiratory disorders which induce airway inflammation and bronchial constriction in mite-allergic patients. Few studies evaluate the ameliorating effects of modified Liu-Wei-Di-Huang-Wan (modified LWDHW) on allergic asthma.MethodsThis study aimed to investigate the immunological mechanisms of modified LWDHW on the reductions of airway inflammation, signal transduction, inflammatory cytokine production, Th2 cell proliferation, and bronchial obstruction in Der p 2-induced asthmatic mice.ResultsAt least ten active ingredients were contained in the formula of modified LWDHW- 1217A and 1217B. Results showed that the immunoglobulin generations (Der p 2 specific- IgE and IgG1), inflammatory cytokine productions (IL-5 and IL-13) in the Sera and BALF could be down-regulated, and the Th1-cytokine productions (IL-12 and IFN-γ) be increased after immunotherapy with modified LWDHW of 1217A or 1217B. The inflammatory cell infiltrations (macrophages, eosinophils, and neutrophils) in the airway and the expressions of TH2-related genes (IL-4, IL-5, and IL-13), TH2-related transcription factor (GATA-3), and neutrophil chemotactic chemokine (IL-8) in the lung tissue of asthmatic mice were significantly decreased after the immunotherapy. The Th1/Th2 polarization had been identified that the IL-4+/CD4+ T cells were downregulated and IFN-γ+/CD4+ T cells were increased. The airway hyperresponsiveness to methacholine inhalation of Penh values was significantly decreased in the treated groups. There were significant improvements in the bronchus histopathology after immunotherapy with 1217A or 1217B which were evaluated by tracheal thickness, inflammatory cell count, and tracheal rupture of mouse lung.ConclusionIt revealed that 1217A or 1217B could regulate the immune responses and improve pulmonary function. Data suggests that modified LWDHW of 1217A or 1217B have the potential for use as a therapeutic intervention for the treatment of mite allergen Der p 2-induced allergic asthma.

Fractal dimension of pulmonary gas and blood distribution assessed by synchrotron K-edge subtraction imaging: effect of bronchoconstriction.

We analyzed the fractal dimension (Df) of lung gas and blood distribution imaged with synchrotron radiation K-edge subtraction (KES), in six anesthetized adult New Zealand White rabbits. KES imaging was performed in upright position during stable Xe gas (64% in O2) inhalation and iodine infusion (Iomeron, 350 mg/mL), respectively, at baseline and after induced bronchoconstriction by aerosolized methacholine (125 mg/mL, 90 s) and bronchodilator (salbutamol, 10 mg/mL, 90 s) inhalation, at two axial image levels. Lung Xe and iodine images were segmented, and maps of regional lung gas and blood fractions were computed. The Df of lung gas (DfXe) and blood (DfIodine) distribution was computed based on a log-log plot of variation coefficient as a function of region volume. DfXe decreased significantly during bronchoconstriction (P < 0.0001), and remained low after salbutamol. DfIodine depended on the axial image level (P < 0.0001), but did not change with bronchoconstriction. DfXe was significantly associated with arterial [Formula: see text] (R = 0.67, P = 0.002), and negatively associated with [Formula: see text] (R = -0.62, P = 0.006), respiratory resistance (R = -0.58, P = 0.011), and elastance (R = -0.55, P = 0.023). These data demonstrate the reduced Df of gas distribution during acute bronchoconstriction, and the association of this parameter with physiologically meaningful variables. This finding suggests a decreased complexity and space-filling properties of lung ventilation during bronchoconstriction, and could serve as a functional imaging biomarker in obstructive airway diseases.NEW & NOTEWORTHY Here, we used an energy-subtractive imaging technique to assess the fractal dimension (Df) of lung gas and blood distribution and the effect of acute bronchoconstriction. We found that Df of gas significantly decreases in bronchoconstriction. Conversely, Df of blood exhibits gravity-dependent changes only, and is not affected by acute bronchoconstriction. Our data show that the fractal dimension of lung gas detects the emergence of clustered rather than scattered loss of ventilatory units during bronchoconstriction.

A CASE OF INDUCIBLE LARYNGEAL OBSTRUCTION UNSUCCESSFULLY TREATED AS SEVERE ASTHMA WAS WELL CONTROLLED AFTER APPROPRIATE DIAGNOSIS AND INSTRUCTION OF THERAPEUTIC BREATHING MANEUVERS

Inducible laryngeal obstruction (ILO) refers to respiratory disorders caused by airflow limitation in the larynx, including vocal cord dysfunction, and may sometimes be misdiagnosed as bronchial asthma (BA). Here, we report the case of an 11-year-old boy diagnosed with BA in infancy. He was referred to our Allergy Center and was taking a high dose of inhaled corticosteroids (ICS) due to frequent coughing from the age of 10 years and persistent coughing following COVID-19 infection at the age of 11. However, the patient continued to experience frequent coughing attacks and repeated visits to the emergency department after inhalation of β2-stimulants failed to improve his cough. We admitted him to the allergy center for examinations to assess the BA severity. In the airway hypersensitiveness test, saline inhalation performed prior to methacholine inhalation caused expiratory stridor and respiratory distress in the larynx, which worsened with β2-stimulant inhalation. Based on these results, we ruled out BA and diagnosed ILO. We instructed him on breathing maneuvers, and he was able to respond appropriately when symptoms appeared. We then started reducing his ICS dose.

Serum and sputum MMP-9/TIMP-1 in winter sports athletes and swimmers: relationships with airway function

Introduction Skiers and swimmers present characteristics of airway inflammation and remodelling of the extracellular matrix similar to what is observed in mild asthma. We aimed to compare serum and sputum MMP-9/TIMP-1 levels, to assess the balance between airway fibrogenesis and inflammation process in both categories of athletes, and to observe its seasonal variations in winter sports athletes. Methods We conducted a retrospective study. Winter sports athletes (n = 41), swimmers (n = 25) and healthy nonathletes (n = 10) had blood sampling, lung function measurement, skin prick tests, eucapnic voluntary hyperpnoea challenge, methacholine inhalation test, and induced sputum analysis. Twelve winter sport athletes performed the tests during both summer and winter. Serum and sputum biomarkers were measured by ELISA. Results No significant difference in serum or sputum MMP-9/TIMP-1 ratio was observed between groups, nor relationship with airway function or responsiveness. Serum MMP-9/TIMP-1 ratio was higher during the summer in winter sport athletes compared with winter season (median [Interquartile range]: 3.65 [2.47-4.03] ng.ml−1 and 1.27 [0.97-1.62] ng.ml−1, respectively, p = 0.005). Sputum MMP-9 correlated with methacholine PC20 (r = 0.45, p = 0.019) and serum cc16/SP-D ratio (r = −0.47, p = 0.013). Conclusion MMP-9/TIMP-1 ratio in sputum or serum may fluctuate with training or environment but does not correlate with airway function or responsiveness in athletes.

Effect of Vitamin D3 Supplementation on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D Levels: The VDKA Randomized Clinical Trial

To investigate if supplementation with vitamin D3 would improve the time to a severe exacerbation in children at high risk with vitamin D insufficiency and taking low-dose inhaled corticosteroids (ICSs) for persistent asthma.The participants were recruited from 7 children’s hospitals across the United States. Participants, 6 to 16 years of age, had to have physician-diagnosed asthma for at least 1 year, being treated with low-dose ICSs, and have a serum 25-hydroxyvitamin D level less than 30 ng/mL. They also had to have at least 1 severe asthma exacerbation in the last year (defined as systemic steroids for at least 3 days or an emergency department visit or hospitalization requiring systemic corticosteroids). All participants had to show bronchodilator responsiveness or airway responsiveness to methacholine inhalation. The mean age of the participants was 9.8 years (40% girls). A total of 219 subjects passed screening and entered run-in. A total of 192 subjects were randomly assigned to active drug or placebo capsules.This was a randomized, double-blind, parallel, placebo-controlled clinical trial. Participants initially all received placebo capsules and were maintained on inhaled fluticasone propionate, 176 μg per day (6–11 years) or 220 μg per day (12–16 years) during run-in. They continued the ICSs and then were randomly assigned to daily vitamin D3 4000 IU or continuing placebo for 48 weeks. After 24 weeks, participants dose of fluticasone was reduced by 50%, if asthma was well controlled and spirometry was normal. Serum vitamin D levels and parameters of asthma control were measured every 16 weeks. The primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of ICS was reduced halfway through the trial, and the cumulative fluticasone dose during the trial.A total of 94% of randomly assigned subjects completed the trial. A total of 36 participants (37.5%) in the vitamin D3 group and 33 (34.4%) in the placebo group had ≥1 severe exacerbations. Compared with the placebo, vitamin D3 supplementation did not significantly improve the time to a severe exacerbation. The mean time to exacerbation was 240 days in the vitamin D3 group versus 253 days in the placebo group (mean group difference: −13.1 days; adjusted hazard ratio: 1.13; P = .63). Vitamin D3 supplementation, compared with the placebo, did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of ICSs was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3 group: n = 11; placebo group: n = 9).In children 6 to 16 years old with persistent asthma and low vitamin D levels, vitamin D3 supplementation, compared with a placebo, did not significantly improve the time to a severe asthma exacerbation or ICS dosing.As the authors note, in several observational studies, researchers have linked low serum vitamin D levels to severe asthma exacerbations, lower lung function, and reduced response to corticosteroids. Yet meta-analyses and reviews of vitamin D3 supplementation for severe asthma exacerbations have found insufficient evidence to recommend vitamin D3 supplementation in children. In this study, the authors, looking at a high-risk population for asthma exacerbations, add to that negative body of literature.

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

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

Cockroach-induced IL9, IL13, and IL31 expression and the development of allergic asthma in urban children

Cockroach-induced IL9, IL13, and IL31 expression and the development of allergic asthma in urban children

BRONCHIAL ASTHMA WITH VOCAL CORD DYSFUNCTION DIFFERENTIATED FROM SEVERE ASTHMA BY BRONCHOSCOPY

Although an important cause of vocal cord dysfunction (VCD) is psychogenic reaction, VCD may be associated with severe asthma and must be distinguished from the disease. A 30-years-old woman was admitted to our hospital with dyspnea despite treatment for asthma. Inspiratory stridor and expiratory wheezes were noted, and neck and chest computed tomography showed normal airways and lungs. Fractional exhaled nitric oxide levels were also normal. Pulmonary function test with a flow-volume loop curve showed normal expiratory loop with flattening of the inspiratory loop after methacholine inhalation. During the attack, bronchoscopy revealed the vocal cord closing with stridor during the inspiratory phase. Therefore, the patient was diagnosed with VCD. The dyspnea improved with respiratory rehabilitation and pursed-lip breathing. VCD should be considered in the differential diagnosis of intractable severe asthma. In this case, bronchoscopy and bronchial inhalation challenge with methacholine helped in the diagnosis.

The Effect of Bronchoconstriction by Methacholine Inhalation in a Murine Model of Asthma

Introduction: Bronchoconstriction was recently shown to cause airway remodeling and induce allergic airway inflammation in asthma. However, the mechanisms how mechanical stress via bronchoconstriction could induce airway inflammation and remodeling remain unclear. Objective: We investigated the effect of bronchoconstriction induced by methacholine inhalation in a murine model of asthma. Methods: BALB/c female mice were sensitized and challenged with ovalbumin (OVA), followed by treatment with methacholine by a nebulizer twice a day for 7 days. Twenty-four hours after the last methacholine treatment, the bronchoalveolar lavage fluid (BALF) and lung tissues were collected. The BALF was analyzed for total and differential cell counts and cytokine levels. The lung tissues were analyzed for goblet cell metaplasia, thickness of the smooth muscle, and lung fibrosis. The expression of cytokines in the lung was also examined. Results: OVA sensitization and challenge induced infiltration of total cells, macrophages, and eosinophils in the BALF along with goblet cell metaplasia and increased airway smooth muscle hypertrophy. Seven days after the last OVA challenge, untreated mice achieved reduction in airway inflammation, while methacholine maintained the number of BALF total cells, macrophages, and eosinophils. The percentage of goblet cells and the thickness of airway smooth muscle were also maintained by methacholine. Moreover, the treatment of methacholine induced the expression of transforming growth factor (TGF)-β in the lung. This result indicates that the production of TGF-β is involved in induction of airway remodeling caused by bronchoconstriction with methacholine. Conclusions: Repeated bronchoconstriction caused by methacholine inhalation elicited allergic airway inflammation and airway remodeling.

Mannitol vs. methacholine in the evaluation of airway responsiveness in bakers' asthma.

Various indirect or direct airway challenge tests are used to measure nonspecific bronchial hyper-responsiveness (NSBHR). The evaluation of NSBHR in diagnosing occupational asthma (OA) is performed, e.g., to monitor the specific inhalation challenge test (SICT). The aim of this study was to preliminarily compare the results of methacholine and mannitol inhalation challenge tests in SICT monitoring in bakers with work-related airway symptoms. Four bakery workers with a suspicion of OA underwent single-blind placebo-controlled SICTs involving workplace allergens, accompanied by the evaluation of NSBHR with mannitol and methacholine, both before and after SICTs. Clinical examinations, spirometry tests, skin prick tests (SPTs) to common aeroallergens and occupational allergens, as well as tests to determine serum specific IgE antibodies to occupational aeroallergens were also performed. Positive SPTs results to occupational aeroallergens were found in all bakery workers, and specific IgE antibodies to flour were detected in 2 subjects. Three patients displayed positive SICT reactions. In all of these 3 patients, airway responsiveness to methacholine increased significantly. In 2 patients, airway reaction to mannitol was significant, whereas in 1 subject there was no increase in NSBHR after mannitol inhalation. The patient with a negative SICT result did not reveal any changes in NSBHR before and after the test, either to methacholine or mannitol. The data obtained by the authors show that there is no clear correlation between the methacholine and mannitol inhalation challenge tests in SICT monitoring. Preliminary results indicate the need for further investigations to evaluate the usefulness of the mannitol challenge test in the diagnostics of OA. Int J Occup Med Environ Health. 2020;33(2):235-9.

Asthma and rhinitis in Greek furniture workers

Objective: The detection of asthma and rhinitis in furniture workers exposed to chemicals in the area of Thessaloniki Greece and the determination of the most useful tests for diagnosing the above occupational diseases.Methods: Eighty-three workers (76 men), 35 exposed to chemicals (CW), 23 to wood dust (WW), and 25 office workers (OW), serving as controls, filled in a specialized European Community Respiratory Health Survey (ECRHS) questionnaire for asthma and were submitted to clinical evaluation, spirometry, bronchodilation test, PEF computer algorithm OASYS-2, FeNO, skin prick tests (SPTs), rhinomanometry and methacholine inhalation challenge. Working conditions and protective measurements were also recorded. According to the results of all conducted tests, each subject was distributed to a subgroup: (a) normal, (b) asthma, (c) rhinitis, (d) asthma and rhinitis. Comparisons were performed among work groups.Results: The presence of asthma and/or rhinitis was higher among CW and WW compared to OW (p = 0.004). Significant differences among groups were observed in the questions «better weekend» (p < 0.034) and “improvement on vacation» (p < 0.000), in OASYS-2 Score (p < 0.000), in ABC Score (p < 0.000), and in methacholine score (p < 0.022). Rhinomanometry, FeNO, spirometry, and spirometry after bronchodilation had no significant differences among groups. Working conditions, ventilation system, work practice, use and type of mask revealed no significant differences.Conclusion: Asthma and rhinitis are significantly common among CW. Protective measurements used were not adequate to prevent asthma and or work related rhinitis. Early diagnosis might contribute to disease prevention and control.

Variation at DENND1B and Asthma on the Island of Tristan da Cunha.

A high prevalence of asthma has been documented among the inhabitants of Tristan da Cunha, an isolated island in the South Atlantic. The population derives from just 28 founders. We performed lung function testing, including methacholine inhalation challenge, allergen skin prick testing, and collected DNA from essentially all of the current island population (269 individuals), and genotyped a panel of 43 single-nucleotide polymorphisms (SNPs) reported as associated with asthma and atopy. We carried out a mixed-model association analysis using the known pedigree. There were 96 individuals diagnosed as asthmatic (36%), and heritability estimates were similar to those from nonisolated population samples (multifactorial threshold model, h2 = 48%). The first component from a genetic principal components analysis using the entire SNP panel was nonlinearly associated with asthma, with the maximum risk to those intermediate to reference (Human Genome Diversity Project) European and African samples means. The single most strongly associated SNP was rs2786098 (p = 5.5 × 10-5), known to regulate the gene DENND1B. This explained approximately one-third of the trait heritability, with an allelic odds ratio for the A allele of 2.6. Among A/A carriers, 10 out of 12 individuals were asthmatic. The rs2786098*A variant was initially reported to decrease the risk of childhood (atopic) asthma in European but slightly increase the risk in African-descended populations, and does significantly alter Th2 cell function. Despite an absence of overall association with this variant in recent asthma genome wide association studies meta-analyses, an effect may exist on the particular genetic background of the Tristan da Cunha population.

Novel pendrin inhibitor attenuates airway hyperresponsiveness and mucin expression in experimental murine asthma

Novel pendrin inhibitor attenuates airway hyperresponsiveness and mucin expression in experimental murine asthma

Cigarette Smoke Particles-Induced Airway Hyperreactivity in Vivo and in Vitro.

Cigarette smoke is a well-known strong risk factor for inducing airway hyperreactivity (AHR), but the underlying molecular mechanisms are not fully understood. In the present study, mouse in-vivo and in-vitro models were used to study effects of dimethyl sulfoxide (DMSO)-extracted cigarette smoke particles (DSP) on the airway, and to explore the underlying molecular mechanisms that are involved in DSP-induced AHR. In mouse in-vivo model, DSP (0.75, 1.5 or 3 µL/mL) was administered intranasally daily for 7 d. At the end of this period, lung functions were measured with flexiVent™. The results showed that the mice exhibited AHR in a dose-dependent manner following methacholine inhalation in vivo. In mouse in-vitro organ culture model, exposure of mouse tracheal segments to DSP (0.1 µL/mL) with or without the following pharmacological inhibitors: specific c-Jun-N-terminal kinase (JNK) inhibitor SP600125 (10 µM) or the anti-inflammatory drug dexamethasone (1 µM). DSP-induced bradykinin receptor-mediated airway contraction with increased mRNA and protein expressions for bradykinin B1 and B2 receptors could be significantly reduced by SP600125 or dexamethasone. In conclusion, the present study demonstrates that DSP could induce AHR in vivo and in vitro. In addition to this, the upregulation of bradykinin receptors in airway is most likely one of the underlying molecular mechanisms involved.

Vesicle-associated membrane protein 7-mediated eosinophil degranulation promotes allergic airway inflammation in mice

Eosinophil degranulation is a determining factor in allergy-mediated airway pathology. Receptor-mediated degranulation in eosinophils requires vesicle-associated membrane protein 7 (VAMP-7), a principal component of the SNARE fusion machinery. The specific contribution of eosinophil degranulation to allergen-induced airway responses remains poorly understood. We generated mice with VAMP-7 gene deficiency exclusively in eosinophils (eoCRE/V7) from a cross using eosinophil-specific Cre recombinase-expressing mice crossed with VAMP-7f/f mice. Eosinophils from eoCRE/V7 mice showed deficient degranulation responses in vitro, and responses continued to be decreased following ex vivo intratracheal adoptive transfer of eoCRE/V7 eosinophils into IL-5/hE2/EPX−/− mice. Consistent with diminished degranulation responses, reduced airway hyperresponsiveness was observed in ovalbumin-sensitized and challenged eoCRE/V7 mice following methacholine inhalation. Therefore, VAMP-7 mediates eosinophil degranulation both in vitro and ex vivo, and this event augments airway hyperresponsiveness.

Methacholine challenge testing: comparative pharmacology.

Standardization of the methacholine inhalation challenge, the most common direct bronchoprovocation test, is important. One aspect of standardization is the appropriate washout period for pharmacologic agents which affect the response. This review summarizes the available data on pharmacologic inhibition of the methacholine response. Specific (anti-muscarinic) agents demonstrate marked bronchoprotection (up to 7 days for the long-acting drugs) which lasts longer than the duration of bronchodilation. The functional antagonist (beta 2 agonist class of medications) shows marked, but less, bronchoprotection which is relatively short lived and is similar to the duration of bronchodilator efficacy. Tolerance develops quickly, especially to the long-acting agents. Single doses of controller medications, such as inhaled corticosteroids (ICS) and leukotriene receptor antagonists, have no effect on the methacholine test, while regular use, at least for ICS, has a modest protective effect whose duration is uncertain and likely variable. Theophylline has a small effect and H1 blockers (all generations) have a negligible effect.

Spatial persistence of reduced specific ventilation following methacholine challenge in the healthy human lung.

Specific ventilation imaging was used to identify regions of the healthy lung (6 supine subjects, ages 21-41 yr, 3 men) that experienced a fall in specific ventilation following inhalation of methacholine. This test was repeated 1 wk later and 3 mo later to test for spatial recurrence. Our data showed that 53% confidence interval (CI; 46%, 59%) of volume elements that constricted during one methacholine challenge did so again in another and that this quantity did not vary with time; 46% CI (28%, 64%) recurred 1 wk later, and 56% CI (51%, 61%) recurred 3 mo later. Previous constriction was a strong predictor for future constriction. Volume elements that constricted during one challenge were 7.7 CI (5.2, 10.2) times more likely than nonconstricted elements to constrict in a second challenge, regardless of whether the second episode was 1 wk [7.7 CI (2.9, 12.4)] or 3 mo [7.7 CI (4.6, 10.8)] later. Furthermore, posterior lung elements were more likely to constrict following methacholine than anterior lung elements (volume fraction 0.43 ± 0.22 posterior vs. 0.10 ± 0.03 anterior; P = 0.005), and basal elements that constricted were more likely than their apical counterparts to do so persistently through all three trials (volume fraction 0.14 ± 0.04 basal vs. 0.04 ± 0.04 apical; P = 0.003). Taken together, this evidence suggests a physiological predisposition toward constriction in some lung elements, especially those located in the posterior and basal lung when the subject is supine. NEW & NOTEWORTHY The spatial pattern of bronchoconstriction following methacholine is persistent over time in healthy individuals, in whom chronic inflammation and airway remodeling are assumed to be absent. This suggests that regional lung inflation and airway structure may play dominant roles in determining the spatial pattern of methacholine bronchoconstriction.

The KAAACI Standardization Committee Report on the procedure and application of the bronchial provocation tests

Bronchial provocation tests are of value in the evaluation of airway hyperresponsiveness. Nonspecific bronchial challenge (metha choline, mannitol, exercise, etc.) is used when the symptoms, physical examination, and measurements of pulmonary function are unremarkable in the diagnosis of asthma, when a patient is suspected of having occupational asthma or exercise-induced broncho constriction (EIB), and when a screening test for asthma or EIB is required for some occupational groups in whom bronchospasm would pose an unacceptable hazard. Methacholine inhalation challenge is most widely used pharmacologic challenge and highly sensitive. For appropriate interpretation of the results of methacholine provocation, it is important to perform the test with the stan dardized protocol and to recognize that inhalation methods significantly influence the sensitivity of the procedure. Indirect chal lenges (e.g., mannitol and exercise) correlate with airway inflammation and are more specific but less sensitive for asthma. Indirect provocation tests are used to confirm asthma, to differentiate asthma from other airway diseases, and to evaluate EIB. (Allergy Asthma Respir Dis 2018;6:14-25)