Standard Methacholine Challenge Research Articles

Utilization of an Abbreviated Methacholine Challenge Protocol for Detection of Airway Hyperreactivity

PURPOSE: The standard methacholine challenge (MCT) for the evaluation of bronchial hyperresponsiveness is lengthy and tiresome. Several authors have proposed but never reported the use of an abbreviated protocol. The purpose of our study was threefold: describe the safety of our abbreviated protocol implemented April 2002, examine factors associated with positive MCT, and monitor for a delayed diagnosis of asthma in subjects with a negative MCT.

Resistance and reactance in oscillation lung function reflect basal lung function and bronchial hyperresponsiveness respectively

Currently there are few data available regarding the use of impulse oscillometry parameters to assess airflow obstruction during standardized methacholine challenge testing. Methacholine challenge tests were performed using impulse oscillometry and conventional spirometry in 64 healthy and 39 asthmatic children, in order to determine airway resistance (R) and reactance (X) at frequencies of 5-35 Hz, as well as FEV(1). Baseline R and X were significantly different between the healthy and asthmatic children, with the most discriminating parameter being resistance at 5 Hz (R5). In asthmatic children BHR was well demonstrated by FEV(1), X5 and X10, but not by R5. However, when the actual R5 values obtained in this study were compared with the predicted values, there appeared to be differences in the lung function measures that corresponded to varying methacholine concentrations. In addition, the PC20_FEV(1) and PC70_X5 were significantly more sensitive than other parameters for methacholine challenge testing. Measuring resistance at 5 Hz using impulse oscillometry facilitates significant differentiation of baseline lung function between asthmatic and healthy children. Additionally, X may be a suitable replacement for PC20 in methacholine challenge testing.

Changes in lung volumes and airway responsiveness following haematopoietic stem cell transplantation

Changes in lung volume occur following haematopoietic stem cell transplantation (HSCT); airway hyperresponsiveness was occasionally reported, without mechanistic explanation. The present authors studied 17 patients by standard methacholine (MCh) challenge before and then 3 and 12 months after HSCT (n = 16 and n = 13, respectively). Another 6 patients were challenged before and 3 months after HSCT using a modified challenge to investigate the effect of deep inhalations. No patient developed bronchiolitis obliterans or bronchiolitis obliterans organising pneumonia. At 3 months, forced vital capacity (FVC) was significantly reduced by 0.33+/-0.55 L, forced expiratory volume in one second (FEV(1)) by 0.31+/-0.50 L, total lung capacity (TLC) by 0.39+/-0.37 L and single-breath diffusing capacity of the lung for carbon monoxide (D(L,CO)) by 15+/-12%. At 12 months, TLC decreased by 0.43+/-0.36 L and D(L,CO )by 8+/-8%. With standard challenge, no significant changes in FEV(1) response to MCh were observed after HSCT but FVC decreased significantly less after HSCT compared with prior to HSCT, suggesting less air trapping. With modified challenge, deep inhalations reversed the MCh-induced decrease in partial expiratory flow more after HSCT compared with before HSCT and this correlated with TLC decrements. In conclusion, an increase in airway responsiveness is unlikely after haematopoietic stem cell transplantation, at least in patients without pulmonary complications, and mechanisms opposing airway narrowing may blunt the bronchoconstrictor response.

Ozone Exposure and Lung Function: Effect Modified by Obesity and Airways Hyperresponsiveness in the VA Normative Aging Study

Ozone has heterogeneous effects on lung function. We investigated whether obesity and airways hyperresponsiveness (AHR) modify the acute effects of ozone on lung function in the elderly. We studied 904 elderly men from the Normative Aging Study whose lung function (FVC, FEV1) was measured approximately every 3 years from 1995 to 2005. We defined obesity as a body mass index of at least 30 kg/m2. Using a standardized methacholine challenge test, we defined AHR as a FEV1 decline of 20% after inhalation of a cumulative dosage of 0 to 8.58 micromol of methacholine. Ambient ozone in the Greater Boston area was measured continuously. We estimated effects using mixed linear models, adjusting for known confounders. An increase in ozone of 15 parts per billion during the previous 48 h was associated with a greater decline in FEV1 in the obese (-2.07%; 95% confidence interval [CI], -3.25 to -0.89%) than in the nonobese (-0.96%; 95% CI, -1.70 to - 0.20%). The same exposure was also associated with a greater decline in FEV1 for those with AHR (-3.07%; 95% CI, -4.75 to -1.36%) compared to those without AHR (-1.32%; 95% CI, -2.06 to -0.57%). A three-way interaction trend test demonstrated a multiplicative effect of those two risk factors (p < 0.001). We found similar associations for FVC. Our results indicate that both obesity and AHR modify the acute effect of ozone on lung function in the elderly, with evidence of interaction between AHR and obesity that causes a greater than additive effect.

Reduced Airway Responsiveness in Nonelite Runners

The effects of endurance training on airway responsiveness in nonasthmatic subjects are poorly defined. We hypothesized that airway responsiveness may differ between none-lite endurance athletes and sedentary subjects, and studied healthy, nonelite runners and sedentary controls by single-dose methacholine challenges carried out in the absence of deep inspirations, in that deep inspirations are known to oppose airway narrowing in nonasthmatic subjects. A total of 20 nonasthmatic none-lite runners (mean age+/- SD: 43.0+/- 8.5 yr; training volume: 68 km.wk; range: 40-100; racing experience: 11+/- 8 yr) and 20 sedentary controls (age: 44.0+/- 20.6 yr) were studied, all of them being normo-reactive to standard methacholine challenge up to 25 mg.mL concentration. All subjects were studied at rest; six runners were also studied about 1 h after completing the Palermo marathon (December 8, 2001). The primary outcome of the study was the inspiratory vital capacity (IVC) obtained after single-dose methacholine inhalation at the end of 20 min of deep inspiration prohibition. At rest, IVC decreased by 10.5+/-8.1% after challenge with methacholine at 75 mg.mL in athletes, and by 24.3+/-16.1% after a methacholine concentration of 52+/-5.7 mg.mL in sedentary controls (P=0.002). The decreased response to methacholine in runners did not correlate with static lung volumes, amount of weekly training, or running experience. Methacholine challenge under deep inspiration prohibition revealed that endurance training attenuates airway responsiveness in nonasthmatic, none-lite runners. Airway hyporesponsiveness was potentiated after the marathon, suggesting involvement of humoral (i.e., catecholamine levels), airway factors (i.e., nitric oxide), or both in modulating airway tone after exercise.

Dosimeter methacholine challenge: Comparison of maximal versus submaximal inhalations

Deep inhalation has bronchodilating and bronchoprotective effects, particularly in subjects who are normal or have mild airway hyperresponsiveness (AHR). We have anecdotally observed that the 5 breath to total lung capacity (TLC) dosimeter method reduced the response to methacholine in some subjects with mild AHR. To compare prospectively submaximal inhalations with TLC inhalations during the dosimeter methacholine challenge. Sixteen subjects with asthma and a methacholine PC 20 <8 mg/mL performed 2 methacholine challenges in random order; the standard dosimeter method was compared with a modified dosimeter challenge in which methacholine inhalations were performed to approximately 50% to 60% below TLC. The standard methacholine challenge PC 20 was almost twice that obtained with the modified submaximal inhalation method (geometric mean PC 20, 5.2 mg/mL vs 2.8 mg/mL, respectively; P = 0.0216). In the 5 subjects with the mildest AHR, there was a 2.5-fold to 14-fold difference in PC 20 between methods. The standard (full TLC) PC 20 s were falsely negative (>16 mg/mL) in these 5 subjects with current asthma, 4 of whom required inhaled corticosteroids. A submaximal inhalation dosimeter methacholine challenge results in a significantly lower PC 20 compared with the standard 5-breath dosimeter method. This effect is limited to the mildly responsive group, probably because of the bronchoprotective effect of the deep inhalation during the standard method, and results in false-negative tests in some subjects.

Airway Constriction Pattern Is a Central Component of Asthma Severity

Measurements of lung resistance and elastance (RL and EL) from 0.1 to 8 Hz reflect both the mean level and pattern of lung constriction. The goal of this study was to establish a relation between a deep inspiration (DI) and the heterogeneity of constriction in healthy versus asthmatic subjects. Constriction pattern was assessed from measurements of the RL and EL from 0.1 to 8 Hz in seven healthy subjects and in 12 asthmatics. These data were acquired before and after a DI and before and after a standard methacholine challenge versus a modified challenge in which a DI is prohibited. Generally, avoidance of a DI increased responsiveness. In healthy subjects and in those with mild-to-moderate baseline asthma a bronchial challenge, especially during self-inhibited DI, produced a heterogenous pattern of constriction inclusive of randomly distributed airway closures or near closures. Nevertheless, such subjects were able to reopen their airways via a DI. In contrast, in subjects with severe baseline asthma, there is a more extreme heterogeneous constriction pattern with random airway closures even at baseline. Further, there is no residual bronchodilatory effect of a DI either before or after bronchial challenge. We conjecture that inflammation and wall-remodeling facilitate a dangerous degree of heterogeneous constriction inclusive of airway closures or near closures, and contribute to the prevention of a DI from having a residual bronchodilatory effect.

The effect of methacholine challenge on the cellular composition of induced sputum

Analysis of induced sputum is currently being used in clinical studies to characterize the airway secretions of asthmatic subjects. These studies also often involve the concurrent assessment of bronchial responsiveness to inhaled methacholine. In some cases methacholine challenge is performed immediately before sputum induction. Although 2 reports of the effect of inhaled methacholine on bronchoalveolar lavage cell counts did not reveal any significant changes,1,2 there is no available data on the effects of a standard methacholine challenge on the constituents of induced sputum.

Chest surface mapping of lung sounds during methacholine challenge.

Wheeze as an indicator of airway obstruction during bronchoprovocation lacks sensitivity. We therefore studied whether induced airway narrowing is revealed by changes in normal (vesicular) lung sounds. Fifteen subjects with asthma and nine healthy controls, aged 8-16 years, performed a standardized methacholine challenge. Respiratory sounds were recorded with eight contact sensors, placed posteriorly over the right and left superior and basal lower lobes, and anteriorly over both upper lobes, the right middle lobe, and the trachea. Average spectra of normal inspiratory and expiratory sounds, excluding wheeze, were characterized in 12 asthmatics and 9 controls at flows of 1 +/- 0.2 L/sec. Airway narrowing was accompanied by significant changes in lung sounds, but not in tracheal sounds. Lung sounds showed a decrease in power at low frequencies during inspiration and an increase in power at high frequencies during expiration. These changes already occurred at a decrease in forced expiratory volume in 1 sec of less than 10% from baseline and were fully reversed after inhalation of salbutamol. Thus, lung sounds were sensitive to changes in airway caliber, but were not specific indicators of bronchial hyperresponsiveness.

The usefulness of questionnaire-derived information to predict the degree of nonspecific bronchial hyperresponsiveness.

Nonspecific bronchial hyperresponsiveness (BHR) is a hallmark of clinical asthma, but can be present in nonasthmatics as well. The diagnosis of asthma is based on clinical grounds, and no laboratory procedure can definitely establish its presence. This poses a problem in studies of asthma. If epidemiological studies are to provide valid information, the tools used must have a relative degree of predictive or diagnostic ability. This report determined whether the American Thoracic Society-Division of Lung Disease (ATS-DLD) respiratory questionnaire has the ability to predict different degrees of non-specific BHR. In the years 1983-1990, when the ATS-DLD questionnaire was used in our Natural History of Asthma study, 192 subjects completed the ATS-DLD questionnaire and underwent a standardized methacholine challenge. A recursive partitioning analysis of the ATS-DLD questionnaire was able to predict which questions would likely be answered if the subject had nonspecific bronchial reactivity to inhaled methacholine of 100 and 200 breath units. Positive responses for questions concerning treatment for asthma, wheezing, or shortness of breath, and emergency treatment for asthma predicted the presence of increased bronchial reactivity.

Aerosol Pentamidine-induced Bronchoconstriction: Predictive Factors and Preventive Therapy

<h3>Objective</h3> To describe the frequency of aerosol pentamidine-induced bronchoconstriction, its relationship to nonspecific airway responsiveness, and its response to preventive therapy using salbutamol, ipratropium bromide, or sodium cromoglycate. <h3>Methods</h3> Consecutive HIV-infected individuals starting prophylactic AP were eligible if they had not been previously treated with this agent. Simple spirometry was performed before and 10 min after a single 60-mg dose given through an ultrasonic nebulizer. Methacholine challenge was performed in all subjects 24 h to four days after the initial AP dose. Subjects with a change in FEV₁ (ΔFEV₁)≥10 percent decrease after the initial AP dose were restudied on three separate occasions (=24 hours apart) after premedication with two puffs of salbutamol (200 μg), ipratropium bromide (40 μg), or sodium cromoglycate (2 mg), in random order. <h3>Results</h3> Fifty-three subjects were studied. The median ΔFEV₁ after a single dose of AP was — 7.0 percent (range: -47 percent, 1.8 percent). The ΔFEV₁ following AP was only partially predicted by the degree of nonspecific bronchial responsiveness as measured by a standard methacholine challenge. Age, current smoking, history of asthma, baseline FEV₁, or a prior episode of PCP failed to predict the ΔFEV₁ following AP. Eighteen subjects (34 percent) had a ΔFEV₁ ≥10 percent decrease (median: —17.0 percent). In these subjects, after premedication with salbutamol, ipratropium bromide, and sodium cromoglycate, the median ΔFEV₁ was 1.0, 0.8, and —9.6 percent, respectively. <i>Conclusion:</i> Aerosol pentamidine produced a decrease in FEV₁≥10 percent in 34 percent of subjects. This was not accurately predicted by the methacholine response. The bronchoconstriction induced by AP was effectively prevented by either salbutamol or ipratropium, whereas cromoglycate was only partially effective. <i>(Chest 1991; 100:624-27)</i>

The Presence of Airway Reactivity before the Development of Asthma

Exaggerated airway reactivity is an essential component of the current asthmatic. It is not clear, however, if airway reactivity is genetically determined or acquired. To examine the possibility that increased bronchial reactivity exists prior to the development of asthma, we report on 20 subjects who were studied before and after the onset of clinical asthma. Subjects were part of a larger on-going study of the Natural History of Asthma. Thirteen subjects indicated by their answers to the National Heart, Lung, and Blood Institute respiratory questionnaire that they were not asthmatic at their initial visit. Seven subjects had pulmonary symptoms on their initial visit, but had not been diagnosed as asthmatic. Bronchial reactivity was assessed using a standardized methacholine challenge. For the 20 subjects, there was a mean interval of 3.5 yr between the initial visit and the diagnosis of asthma. Ten of 13 nonasthmatic subjects had moderate or strongly positive responses (208 breath units or less) to methacholine prior to onset of asthma. These 13 subjects were compared to age- and sex-matched controls, from both asthmatic and nonasthmatic families, who had not become asthmatic. There was a difference in bronchial responses at the initial visit between the 13 study subjects and their control subjects from nonasthmatic families, but not between the subjects and their controls from asthmatic families. Five of 7 subjects with pulmonary symptoms had responses of 100 breath units or less. Overall, 19 of 20 subjects had strongly positive responses to methacholine after the diagnosis of asthma was established. The results show that enhanced airway reactivity usually precedes the development of asthma, which could support a genetic basis for it.

Methacholine Bronchial Reactivity Testing in Patients with Chronic Congestive Heart Failure

To assess the role of bronchial hyperresponsiveness in chronic congestive heart failure (CHF), we performed standard methacholine bronchial provocation testing on nine patients with chronic CHF in New York Heart Association functional class 4. Mean pulmonary capillary wedge pressure and mean stroke volume index for the group at the time of study were 27 +/- 3 mm Hg and 27.9 +/- 8.9 ml/m2, respectively. Mean MMEFR was 71 percent of normal and mean delta to FEV1% was 76.3 percent. Only one patient, who was a 50-pack-year smoker, had a greater than 20 percent decrease in FEV1 with methacholine challenge, and this was at the highest concentration (25 mg/ml). We conclude that, in stable CHF, bronchial reactivity as assessed by standard methacholine challenge is not increased.

The role of the methacholine challenge in children with chronic cough

Thirty-nine male and 35 female subjects, aged 6 to 20 years, with chronic cough were studied with spirometry and standard methacholine (MCH) challenge. The duration of their cough before the MCH challenge ranged from 2 months to 13 years. Their FEV 1 ranged 62% to 132% predicted. Thirty-six (49%) patients had a positive MCH challenge. The MCH concentration inhaled to decrease the FEV 1 by 20% ranged from 0.55 to 25 mg/ml. Follow-up data (mean 14 months) were available on all 74 patients. Fifty-four patients received asthma medications, and 93% improved in mean 3.6 weeks. At the end of the follow-up, 22 (30%) were asymptomatic, 39 (53%) were improved, and 13 patients (17%) were symptomatic. We were unable to predict bronchial hyperreactivity in this population on the basis of duration of the cough, personal or family history of allergies, or baseline spirometry. Thus, MCH challenge is helpful in evaluating children with chronic cough and in guiding therapy. Follow-up of children with chronic cough is important. Eleven percent of this study population progressed to develop bronchial asthma. Forty percent of these patients, initially doing well, were asymptomatic at the end of the follow-up period.

Characterization of the airway response to inhaled leukotriene D4 in normal subjects.

To better understand the role of leukotriene D4 (LTD4) in the pathogenesis of airway hyperreactivity, we administered aerosolized LTD4 on multiple occasions to 6 normal subjects and measured specific airway conductance (SGaw) by body plethysmography and the flow rate at 30% of vital capacity from partial forced expiratory maneuvers (V30P). Dose-response curves generated from standard bronchoprovocation tests revealed that LTD4 was 280 to 590 times more potent as a bronchoconstrictor than was methacholine. The airway response to single bronchoconstricting doses of LTD4 administered on separate days was reproducible for SGaw (r = 0.86, p less than 0.05) and V30P (r = 0.95, p less than 0.005). The response to 3 consecutive single-dose LTD4 challenges performed on the same day, allowing SGaw and V30P to return to greater than 90% of the control value between challenges, demonstrated tachyphylaxis: the response to the third dose was significantly less than the response to the first dose for SGaw (p less than 0.001) and for V30P (p less than 0.01). A single bronchoconstricting dose of LTD4, given before a standard methacholine dose-response challenge, lowered the concentration of methacholine needed to decrease V30P 30% (p less than 0.05) and SGaw 35% (p = 0.09). A single bronchoconstricting dose of methacholine preceding a standard methacholine challenge did not have this effect. LTD4 and methacholine demonstrated a cumulative dose-effect when progressively higher concentrations were inhaled. In summary, the airway response to LTD4 is reproducible, exhibits tachyphylaxis, and a cumulative dose-effect occurs. As well, LTD4 increases the responsiveness of normal airways to methacholine.

A Screening Test for Airways Reactivity: An Abbreviated Methacholine Inhalation Challenge

A screening test to measure nonspecific airways reactivity was developed and compared to a standard methacholine inhalation challenge in 13 asthmatic patients and ten normal control subjects. The screening challenge consisted of one deep breath, then four breaths of a 5 mg/ml methacholine solution followed by one and four breaths of 25 mg/ml of methacholine. Subjects with a history of wheezing received the 5 mg/ml of methacholine first while those without a history of asthma began the challenge at the 25 mg/ml methacholine concentration. Spirometric test were employed and the challenge was terminated when FEV1 fell 20 percent from baseline. The standard methacholine challenge used a dosimeter and all subjects took five breaths of saline solution followed by seven increasing concentrations of methacholine. Dose response curves were constructed and the provocation dose of methacholine that caused a 20 percent fall in FEV1 was calculated for each protocol. Results of the screening methacholine challenge correlated with those obtained from the more lengthy standard protocol (r = 0.94), and correctly identified levels of airways reactivity in asthmatic patients and normal subjects. The abbreviated protocol was rapid (6-12 min), safe, and inexpensive. Since the equipment is readily available and easy to transport, it could be used at sites outside the hospital as a screening test for nonspecific airways reactivity.