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

The methacholine challenge test (MCT) is a standard evaluation method of assessing airway hyperresponsiveness (AHR) and its severity, and has significant clinical value in the diagnosis and treatment of bronchial asthma. A consensus working group consisting of experts from the Pulmonary Function and Clinical Respiratory Physiology Committee of the Chinese Association of Chest Physicians, the Task Force for Pulmonary Function of the Chinese Thoracic Society, and the Pulmonary Function Group of Respiratory Branch of the Chinese Geriatric Society jointly developed this consensus. Based on the "Guidelines for Pulmonary Function-Bronchial Provocation Test" published in 2014, the issues encountered in its use, and recent developments, the group has updated the Standard technical specifications of methacholine chloride (methacholine) bronchial challenge test (2023). Through an extensive collection of expert opinions, literature reviews, questionnaire surveys, and multiple rounds of online and offline discussions, the consensus addressed the eleven core issues in MCT's clinical practice, including indications, contraindications, preparation of provocative agents, test procedures and methods, quality control, safety management, interpretation of results, and reporting standards. The aim was to provide clinical pulmonary function practitioners in healthcare institutions with the tools to optimize the use of this technique to guide clinical diagnosis and treatment.Summary of recommendationsQuestion 1: Who is suitable for conducting MCT? What are contraindications for performing MCT?Patients with atypical symptoms and a clinical suspicion of asthma, patients diagnosed with asthma requiring assessment of the severity of airway hyperresponsiveness, individuals with allergic rhinitis who are at risk of developing asthma, patients in need of evaluating the effectiveness of asthma treatment, individuals in occupations with high safety risks due to airway hyperresponsiveness, patients with chronic diseases prone to airway hyperresponsiveness, others requiring assessment of airway reactivity.Absolute contraindications: (1) Patients who are allergic to methacholine (MCh) or other parasympathomimetic drugs, with allergic reactions including rash, itching/swelling (especially of the face, tongue, and throat), severe dizziness, and dyspnea; (2) Patients with a history of life-threatening asthma attacks or those who have required mechanical ventilation for asthma attacks in the past three months; (3) Patients with moderate to severe impairment of baseline pulmonary function [Forced Expiratory Volume in one second (FEV1) less than 60% of the predicted value or FEV1<1.0 L]; (4) Severe urticaria; (5) Other situations inappropriate for forced vital capacity (FVC) measurement, such as myocardial infarction or stroke in the past three months, poorly controlled hypertension, aortic aneurysm, recent eye surgery, or increased intracranial pressure.Relative contraindications: (1) Moderate or more severe impairment of baseline lung function (FEV1%pred<70%), but individuals with FEV1%pred>60% may still be considered for MCT with strict observation and adequate preparation; (2) Experiencing asthma acute exacerbation; (3) Poor cooperation with baseline lung function tests that do not meet quality control requirements; (4) Recent respiratory tract infection (<4 weeks); (5) Pregnant or lactating women; (6) Patients currently using cholinesterase inhibitors (for the treatment of myasthenia gravis); (7) Patients who have previously experienced airway spasm during pulmonary function tests, with a significant decrease in FEV1 even without the inhalation of provocative.Question 2: How to prepare and store the challenge solution for MCT?Before use, the drug must be reconstituted and then diluted into various concentrations for provocation. The dilution concentration and steps for MCh vary depending on the inhalation method and provocation protocol used. It is important to follow specific steps. Typically, a specified amount of diluent is added to the methacholine reagent bottle for reconstitution, and the mixture is shaken until the solution becomes clear. The diluent is usually physiological saline, but saline with phenol (0.4%) can also be used. Phenol can reduce the possibility of bacterial contamination, and its presence does not interfere with the provocation test. After reconstitution, other concentrations of MCh solution are prepared using the same diluent, following the dilution steps, and then stored separately in sterile containers. Preparers should carefully verify and label the concentration and preparation time of the solution and complete a preparation record form. The reconstituted and diluted MCh solution is ready for immediate use without the need for freezing. It can be stored for two weeks if refrigerated (2-8 ℃). The reconstituted solution should not be stored directly in the nebulizer reservoir to prevent crystallization from blocking the capillary opening and affecting aerosol output. The temperature of the solution can affect the production of the nebulizer and cause airway spasms in the subject upon inhaling cold droplets. Thus, refrigerated solutions should be brought to room temperature before use.Question 3: What preparation is required for subjects prior to MCT?(1) Detailed medical history inquiry and exclusion of contraindications.(2) Inquiring about factors and medications that may affect airway reactivity and assessing compliance with medication washout requirements: When the goal is to evaluate the effectiveness of asthma treatment, bronchodilators other than those used for asthma treatment do not need to be discontinued. Antihistamines and cromolyn have no effect on MCT responses, and the effects of a single dose of inhaled corticosteroids and leukotriene modifiers are minimal, thus not requiring cessation before the test. For patients routinely using corticosteroids, whether to discontinue the medication depends on the objective of the test: if assisting in the diagnosis of asthma, differential diagnosis, aiding in step-down therapy for asthma, or exploring the effect of discontinuing anti-inflammatory treatment, corticosteroids should be stopped before the provocation test; if the patient is already diagnosed with asthma and the objective is to observe the level of airway reactivity under controlled medication conditions, then discontinuation is not necessary. Medications such as IgE monoclonal antibodies, IL-4Rα monoclonal antibodies, traditional Chinese medicine, and ethnic medicines may interfere with test results, and clinicians should decide whether to discontinue these based on the specific circumstances.(3) Explaining the test procedure and potential adverse reactions, and obtaining informed consent if necessary.Question 4: What are the methods of the MCT? And which ones are recommended in current clinical practice?Commonly used methods for MCT in clinical practice include the quantitative nebulization method (APS method), Forced Oscillalion method (Astograph method), 2-minute tidal breathing method (Cockcroft method), hand-held quantitative nebulization method (Yan method), and 5-breath method (Chai 5-breath method). The APS method allows for precise dosing of inhaled Methacholine, ensuring accurate and reliable results. The Astograph method, which uses respiratory resistance as an assessment indicator, is easy for subjects to perform and is the simplest operation. These two methods are currently the most commonly used clinical practice in China.Question 5: What are the steps involved in MCT?The MCT consists of the following four steps:(1) Baseline lung function test: After a 15-minute rest period, the subjects assumes a seated position and wear a nose clip for the measurement of pulmonary function indicators [such as FEV1 or respiratory resistance (Rrs)]. FEV1 should be measured at least three times according to spirometer quality control standards, ensuring that the best two measurements differ by less than 150 ml and recording the highest value as the baseline. Usually, if FEV1%pred is below 70%, proceeding with the challenge test is not suitable, and a bronchodilation test should be considered. However, if clinical assessment of airway reactivity is necessary and FEV1%pred is between 60% and 70%, the provocation test may still be conducted under close observation, ensuring the subject's safety. If FEV1%pred is below 60%, it is an absolute contraindication for MCT.(2) Inhalation of diluent and repeat lung function test for control values: the diluent, serving as a control for the inhaled MCh, usually does not significantly impact the subject's lung function. the higher one between baseline value and the post-dilution FEV1 is used as the reference for calculating the rate of FEV1 decline. If post-inhalation FEV1 decreases, there are usually three scenarios: ①If FEV1 decreases by less than 10% compared to the baseline, the test can proceed, continue the test and administer the first dose of MCh. ②If the FEV1 decreases by≥10% and<20%, indicating a heightened airway reactivity to the diluent, proceed with the lowest concentration (dose) of the provoking if FEV1%pred has not yet reached the contraindication criteria for the MCT. if FEV1%pred<60% and the risk of continuing the challenge test is considerable, it is advisable to switch to a bronchodilation test and indicate the change in the test results report. ③If FEV1 decreases by≥20%, it can be directly classified as a positive challenge test, and the test should be discontinued, with bronchodilators administered to alleviate airway obstruction.(3) Inhalation of MCh and repeat lung function test to assess decline: prepare a series of MCh concentrations, starting from the lowest and gradually increasing the inhaled concentration (dose) using different methods. Perform pulmonaryfunction tests at 30 seconds and 90 seconds after completing nebulization, with the number of measurements limited to 3-4 times. A complete Forced Vital Capacity (FVC) measurement is unnecessary during testing; only an acceptable FEV1 measurement is required. The interval between two consecutive concentrations (doses) generally should not exceed 3 minutes. If FEV1 declines by≥10% compared to the control value, reduce the increment of methacholine concentration (dose) and adjust the inhalation protocol accordingly. If FEV1 declines by≥20% or more compared to the control value or if the maximum concentration (amount) has been inhaled, the test should be stopped. After inhaling the MCh, close observation of the subject's response is necessary. If necessary, monitor blood oxygen saturation and auscultate lung breath sounds. The test should be promptly discontinued in case of noticeable clinical symptoms or signs.(4) Inhalation of bronchodilator and repeat lung function test to assess recovery: when the bronchial challenge test shows a positive response (FEV1 decline≥20%) or suspiciously positive, the subject should receive inhaled rapid-acting bronchodilators, such as short-acting beta-agonists (SABA) or short-acting muscarinic antagonists (SAMA). Suppose the subject exhibits obvious symptoms of breathlessness, wheezing, or typical asthma manifestations, and wheezing is audible in the lungs, even if the positive criteria are not met. In that case, the challenge test should be immediately stopped, and rapid-acting bronchodilators should be administered. Taking salbutamol as an example, inhale 200-400 µg (100 µg per puff, 2-4 puffs, as determined by the physician based on the subject's condition). Reassess pulmonary function after 5-10 minutes. If FEV1 recovers to within 10% of the baseline value, the test can be concluded. However, if there is no noticeable improvement (FEV1 decline still≥10%), record the symptoms and signs and repeat the bronchodilation procedure as mentioned earlier. Alternatively, add Ipratropium bromide (SAMA) or further administer nebulized bronchodilators and corticosteroids for intensified treatment while keeping the subject under observation until FEV1 recovers to within 90% of the baseline value before allowing the subject to leave.Question 6: What are the quality control requirements for the APS and Astograph MCT equipment?(1) APS Method Equipment Quality Control: The APS method for MCT uses a nebulizing inhalation device that requires standardized flowmeters, compressed air power source pressure and flow, and nebulizer aerosol output. Specific quality control methods are as follows:a. Flow and volume calibration of the quantitative nebulization device: Connect the flowmeter, an empty nebulization chamber, and a nebulization filter in sequence, attaching the compressed air source to the bottom of the chamber to ensure airtight connections. Then, attach a 3 L calibration syringe to the subject's breathing interface and simulate the flow during nebulization (typically low flow:<2 L/s) to calibrate the flow and volume. If calibration results exceed the acceptable range of the device's technical standards, investigate and address potential issues such as air leaks or increased resistance due to a damp filter, then recalibrate. Cleaning the flowmeter or replacing the filter can change the resistance in the breathing circuit, requiring re-calibration of the flow.b. Testing the compressed air power source: Regularly test the device, connecting the components as mentioned above. Then, block the opening of the nebulization device with a stopper or hand, start the compressed air power source, and test its pressure and flow. If the test results do not meet the technical standards, professional maintenance of the equipment may be required.c. Verification of aerosol output of the nebulization chamber: Regularly verify all nebulization chambers used in provocation tests. Steps include adding a certain amount of saline to the chamber, weighing and recording the chamber's weight (including saline), connecting the nebulizer to the quantitative nebulization device, setting the nebulization time, starting nebulization, then weighing and recording the post-nebulization weight. Calculate the unit time aerosol output using the formula [(weight before nebulization-weight after nebulization)/nebulization time]. Finally, set the nebulization plan for the provocation test based on the aerosol output, considering the MCh concentration, single inhalation nebulization duration, number of nebulization, and cumulative dose to ensure precise dosing of the inhaled MCh.(2) Astograph method equipment quality control: Astograph method equipment for MCT consists of a respiratory resistance monitoring device and a nebulization medication device. Perform zero-point calibration, volume calibration, impedance verification, and nebulization chamber checks daily before tests to ensure the resistance measurement system and nebulization system function properly. Calibration is needed every time the equipment is turned on, and more frequently if there are significant changes in environmental conditions.a. Zero-point calibration: Perform zero-point calibration before testing each subject. Ensure the nebulization chamber is properly installed and plugged with no air leaks.b. Volume calibration: Use a 3 L calibration syringe to calibrate the flow sensor at a low flow rate (approximately 1 L/s).c. Resistance verification: Connect low impedance tubes (1.9-2.2 cmH2O·L-1·s-1) and high impedance tubes (10.2-10.7 cmH2O·L-1·s-1) to the device interface for verification.d. Bypass check: Start the bypass check and record the bypass value; a value>150 ml/s is normal.e. Nebulization chamber check: Check each of the 12 nebulization chambers daily, especially those containing bronchodilators, to ensure normal spraying. The software can control each nebulization chamber to produce spray automatically for a preset duration (e.g., 2 seconds). Observe the formation of water droplets on the chamber walls, indicating normal spraying. If no nebulization occurs, check for incorrect connections or blockages.Question 7: How to set up and select the APS method in MCT?The software program of the aerosol provocation system in the quantitative nebulization method can independently set the nebulizer output, concentration of the methacholine agent, administration time, and number of administrations and combine these parameters to create the challenge test process. In principle, the concentration of the methacholine agent should increase from low to high, and the dose should increase from small to large. According to the standard, a 2-fold or 4-fold incremental challenge process is generally used. In clinical practice, the dose can be simplified for subjects with good baseline lung function and no history of wheezing, such as using a recommended 2-concentration, 5-step method (25 and 50 g/L) and (6.25 and 25 g/L). Suppose FEV1 decreases by more than 10% compared to the baseline during the test to ensure subject safety. In that case, the incremental dose of the methacholine agent can be reduced, and the inhalation program can be adjusted appropriately. If the subject's baseline lung function declines or has recent daytime or nighttime symptoms such as wheezing or chest tightness, a low concentration, low dose incremental process should be selected.Question 8: What are the precautions for the operation process of the Astograph method in MCT?(1) Test equipment: The Astograph method utilizes the forced oscillation technique, applying a sinusoidal oscillating pressure at the mouthpiece during calm breathing. Subjects inhale nebulized MCh of increasing concentrations while continuous monitoring of respiratory resistance (Rrs) plots the changes, assessing airway reactivity and sensitivity. The nebulization system employs jet nebulization technology, comprising a compressed air pump and 12 nebulization cups. The first cup contains saline, cups 2 to 11 contain increasing concentrations of MCh, and the 12th cup contains a bronchodilator solution.(2) Provocation process: Prepare 10 solutions of MCh provocant with gradually increasing concentrations.(3) Operational procedure: The oscillation frequency is usually set to 3 Hz (7 Hz for children) during the test. The subject breathes calmly, inhales saline solution nebulized first, and records the baseline resistance value (if the subject's baseline resistance value is higher than 10 cmH2O·L-1·s-1, the challenge test should not be performed). Then, the subject gradually inhales increasing concentrations of methacholine solution. Each concentration solution is inhaled for 1 minute, and the nebulization system automatically switches to the next concentration for inhalation according to the set time. Each nebulizer cup contains 2-3 ml of solution, the output is 0.15 ml/min, and each concentration is inhaled for 1 minute. The dose-response curve is recorded automatically. Subjects should breathe tidally during the test, avoiding deep breaths and swallowing. Continue until Rrs significantly rises to more than double the baseline value, or if the subject experiences notable respiratory symptoms or other discomfort, such as wheezing in both lungs upon auscultation. At this point, the inhalation of the provocant should be stopped and the subject switchs to inhaling a bronchodilator until Rrs returns to pre-provocation levels. If there is no significant increase in Rrs, stop the test after inhaling the highest concentration of MCh.Question 9: How to interpret the results of the MCT?The method chosen for the MCT determines the specific indicators used for interpretation. The most commonly used indicator is FEV1, although other parameters such as Peak Expiratory Flow (PEF) and Rrs can also be used to assess airway hyperresponsiveness.Qualitative judgment: The test results can be classified as positive, suspiciously positive, or negative, based on a combination of the judgment indicators and changes in the subject's symptoms. If FEV1 decreases by≥20% compared to the baseline value after not completely inhaling at the highest concentration, the result can be judged as positive for Methacholine bronchial challenge test. If the patient has obvious wheezing symptoms or wheezing is heard in both lungs, but the challenge test does not meet the positive criteria (the highest dose/concentration has been inhaled), and FEV1 decreases between 10% and 20% compared to the baseline level, the result can also be judged as positive. If FEV1 decreases between 15% and 20% compared to the baseline value without dyspnea or wheezing attacks, the result can be judged as suspiciously positive. Astograph method: If Rrs rises to 2 times or more of the baseline resistance before reaching the highest inhalation concentration, or if the subject's lungs have wheezing and severe coughing, the challenge test can be judged as positive. Regardless of the result of the Methacholine bronchial challenge test, factors that affect airway reactivity, such as drugs, seasons, climate, diurnal variations, and respiratory tract infections, should be excluded.Quantitative judgment: When using the APS method, the severity of airway hyperresponsiveness can be graded based on PD20-FEV1 or PC20-FEV1. Existing evidence suggests that PD20 shows good consistency when different nebulizers, inhalation times, and starting concentrations of MCh are used for bronchial provocation tests, whereas there is more variability with PC20. Therefore, PD20 is often recommended as the quantitative assessment indicator. The threshold value for PD20 with the APS method is 2.5 mg.The Astograph method often uses the minimum cumulative dose (Dmin value, in Units) to reflect airway sensitivity. Dmin is the minimum cumulative dose of MCh required to produce a linear increase in Rrs. A dose of 1 g/L of the drug concentration inhaled for 1-minute equals 1 unit. It's important to note that with the continuous increase in inhaled provocant concentration, the concept of cumulative dose in the Astograph method should not be directly compared to other methods. Most asthma patients have a Dmin<10 Units, according to Japanese guidelines. The Astograph method, having been used in China for over twenty years, suggests a high likelihood of asthma when Dmin≤6 Units, with a smaller Dmin value indicating a higher probability. When Dmin is between 6 and 10 Units, further differential diagnosis is advised to ascertain whether the condition is asthma.Precautions:A negative methacholine challenge test (MCT) does not entirely rule out asthma. The test may yield negative results due to the following reasons:(1) Prior use of medications that reduce airway responsiveness, such as ß2 agonists, anticholinergic drugs, antihistamines, leukotriene receptor antagonists, theophylline, corticosteroids, etc., and insufficient washout time.(2) Failure to meet quality control standards in terms of pressure, flow rate, particle size, and nebulization volume of the aerosol delivery device.(3) Poor subject cooperation leads to inadequate inhalation of the methacholine agent.(4) Some exercise-induced asthma patients may not be sensitive to direct bronchial challenge tests like the Methacholine challenge and require indirect bronchial challenge tests such as hyperventilation, cold air, or exercise challenge to induce a positive response.(5) A few cases of occupational asthma may only react to specific antigens or sensitizing agents, requiring specific allergen exposure to elicit a positive response.A positive MCT does not necessarily indicate asthma. Other conditions can also present with airway hyperresponsiveness and yield positive results in the challenge test, such as allergic rhinitis, chronic bronchitis, viral upper respiratory infections, allergic alveolitis, tropical eosinophilia, cystic fibrosis, sarcoidosis, bronchiectasis, acute respiratory distress syndrome, post-cardiopulmonary transplant, congestive heart failure, and more. Furthermore, factors like smoking, air pollution, or exercise before the test may also result in a positive bronchial challenge test.Question 10: What are the standardized requirements for the MCT report?The report should include: (1) basic information about the subject; (2) examination data and graphics: present baseline data, measurement data after the last two challenge doses or concentrations in tabular form, and the percentage of actual measured values compared to the baseline; flow-volume curve and volume-time curve before and after challenge test; dose-response curve: showing the threshold for positive challenge; (3) opinions and conclusions of the report: including the operator's opinions, quality rating of the examination, and review opinions of the reviewing physician.Question 11: What are the adverse reactions and safety measures of MCT?During the MCT, the subject needs to repeatedly breathe forcefully and inhale bronchial challenge agents, which may induce or exacerbate bronchospasm and contraction and may even cause life-threatening situations. Medical staff should be fully aware of the indications, contraindications, medication use procedures, and emergency response plans for the MCT.

Exploring a rare case of occupational senna allergy.

BACKGROUND: Cassia angustifolia, or senna, is a plant belonging to the Fabaceae family, widely used as a laxative and as a colouring agent in hair dyes. Senna is rarely reported as an occupational allergic sensitizer in the current literature. AIMS: To describe the case and diagnostic approach of a suspected occupational senna allergy. CASE REPORT: A male phytopharmaceutical warehouse worker reported bronchial, conjunctival and nasal symptoms immediately upon exposure to senna. We were able to document in vitro sensitization, finding IgE-binding proteins in senna, and in vivo sensitization through positive skin tests and conjunctival provocation test. CONCLUSION: Our study confirms that senna may cause occupational rhinoconjunctivitis symptoms with an IgE-dependent mechanism and is the first to confirm it through specific conjunctival provocation test.

Bronchial allergen challenge using the Medicaid dosimeter.

BACKGROUND: Bronchial allergen provocations are well established in asthma research. We evaluated the reproducibility of single-concentration, single-step allergen challenges in volunteers with grass pollen allergy. METHODS: Forty-seven subjects underwent bronchial challenges using the aerosol provocation system nebulizer (Medicaid Sidestream) with incremental doses of grass pollen to define the individual allergen dose that causes a 20% drop in FEV(1) (PD(20)FEV(1)). In 39 subjects this procedure was followed by single-step challenges. Early and late asthmatic responses were monitored, and increases in exhaled nitric oxide were measured before and 24 h after single-step challenges. RESULTS: After the first single-step challenge, the maximum drop in FEV(1) was 21.3% ± 8.0. A comparison of the drop in FEV(1) to the initial incremental challenge (29.7% ± 7.5) revealed an intraclass correlation of -0.30 (p < 0.05). In the second single-step challenge, the mean drop in FEV(1) was 20.9% ± 7.2. Compared with the first single-step challenge, the intraclass correlation was 0.37 (p < 0.05) and the 95% limits of agreement according to Bland and Altman were -17.5 to 18.1%. The increases in exhaled nitric oxide revealed substantial agreement in repeated single-step challenges (26.8 ppb ± 27.8 and 21.8 ppb ± 21.9, ICC 0.62, p < 0.001). CONCLUSIONS: The use of aerosol provocation system to calculate the PD(20)FEV(1) allergen is a timesaving procedure and is less prone to errors because only one dilution of the allergen is used. The repeatability in well-defined subjects is excellent to study the mechanisms of allergen-induced airway inflammation and the development of new treatments for allergic diseases.

Bronchial allergen challenge in allergic children: continuous increase of nitric oxide in exhaled air 72 hours after allergen inhalation independent of bronchial obstruction.

BACKGROUND: Changes in fractional exhaled nitric oxide (FeNO) occurring after bronchial allergen challenges (BAC) are still not understood, neither are any possible associations between FeNO and forced expiratory volume in 1 sec (FEV(1)). The aim of the study was to compare the fluctuations of FeNO and FEV(1), which occur within 72 h of BAC in children sensitive to grass pollen. METHODS: Seventy-four children were divided into two groups based on their medical histories and the results of skin prick tests with 10 common allergens. Individuals in whom the test yielded a positive result to at least grass pollen (Group A, n = 57), and those with negative test results against all of the allergens applied (Group B, n = 17) were subjected to BAC. FeNO was measured at a baseline and at 1, 8, 21, and 72 h after the last dose of the allergen inhalation, whereas FEV(1) was measured at a baseline, hourly for 8 h after the challenge and at 21 and 72 h thereafter. RESULTS: Baseline FeNO in sensitive subjects (Group A) was significantly higher than in controls of Group B. In all grass pollen-sensitive subjects, even those that were free of a bronchial response, FeNO was markedly elevated compared to its baseline values, starting from the eighth hour onward, and still increased 72 h post-BAC, whereas FEV(1) returned to a baseline at the 72nd h post-BAC. The highest increase in FeNO was registered in individuals with a dual asthmatic response. CONCLUSIONS: An increase in FeNO in sensitive subjects starts a few hours later than the decrease in FEV(1). Consequently, measurements of FeNO seem to be useful in long-term monitoring of the allergic reaction triggered by a specific allergen.

Maximal degree of airway narrowing induced by methacholine and adenosine monophosphate: relationship with the decrease in forced vital capacity.

BACKGROUND: Changes in forced vital capacity (FVC) may represent an indirect method for the detection of plateau in response to inhaled bronchoconstrictor agents. OBJECTIVE: To determine the relationship between the level of plateau obtained with either methacholine or adenosine monophosphate (AMP) and the decrease in FVC induced by each bronchoconstrictor agent. METHODS: Airway responsiveness to high concentrations of methacholine and AMP was determined in patients with intermittent asthma (n = 41) or allergic rhinitis (n = 26). Furthermore, allergen-induced changes in the response to each bronchoconstrictor agent were investigated in 18 pollen-sensitive patients. Concentration-response curves were characterized by the slope of the FVC values recorded at each step of the challenge against the corresponding forced expiratory volume in 1 second (FEV1) values and, if possible, by the level of plateau. RESULTS: The slope FVC vs FEV1 was similar in patients with plateau and in those without plateau. In patients with pollen allergy, the mean (95% confidence interval) for the level of plateau detected with methacholine increased from 16.8% (11.8%-22.0%) before the pollen season to 21.7% (14.8%-28.6%, P = .008) during the pollen season, whereas pollen-induced changes in the slope FVC vs FEV1 were not significant. Similar results were obtained with AMP. CONCLUSIONS: In patients with allergic rhinitis or intermittent asthma, methacholine or AMP-induced changes in FVC are not significantly related to the presence or level of plateau. Furthermore, these 2 constituents of the concentration-response curve can be modified independently by a proinflammatory stimulus. These results suggest that the bronchoconstrictor-induced change in FVC cannot be used as a surrogate estimation of the level of plateau.

Pollen challenge study of a phototherapy device for reducing the symptoms of hay fever.

OBJECTIVE: The objective was to investigate the effect of intranasal phototherapy delivered by a phototherapy device (allergy reliever SN-206) on symptoms of hay fever (seasonal rhinitis) due to grass pollen in adults. This registered class IIA medical device had been on sale for 15 months with no adverse effects reported but there had been no assessment of efficacy. Previous research had indicated that phototherapy could alleviate symptoms of allergic rhinitis but no double-blind, placebo-controlled trails had been done. RESEARCH DESIGN AND METHODS: The trial is a double-blind, placebo-controlled grass pollen challenge conducted out of the pollen season, on 101 adult male and female hay fever sufferers. Subjects were assigned to placebo or active groups by stratified random sampling using responses to a baseline questionnaire. All subjects used active or placebo devices three times a day for 14 days before pollen challenge. Subjects were monitored for 2.5 h after challenge. MAIN OUTCOME MEASURES: Primary outcome measures were observed severity scores for sneezing, running eyes, running nose, and the amount of eosinophil cationic proteins (ECP) in nasal secretions. Secondary outcome measures were symptom scores by subject report (itching eyes, itching nose, itching throat, itching mouth/palate), and nasal peak inspiratory flow (PIFn) and peak expiratory flow (PEFn). RESULTS: Significant reductions in severity of symptom scores were found for sneezing, running nose, running eyes and itchy mouth/palate (p < or = 0.05). No significant differences were found in the results for itchy eyes, itchy nose, itchy throat, ECPs, PIFn and PEFn. No adverse events occurred. CONCLUSIONS: The results show that the device significantly reduced some hay fever symptoms. The study would have been improved if compliance was monitored electronically and if nasal congestion was monitored by report. The mode of action is unclear. The study does not consider long-term implications of the therapy.

Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study.

BACKGROUND: 3-year subcutaneous specific immunotherapy (SIT) in children with seasonal allergic rhinoconjunctivitis reduced the risk of developing asthma during treatment and 2 years after discontinuation of SIT (5-year follow-up) indicating long-term preventive effect of SIT. OBJECTIVE: We evaluated the long-term clinical effect and the preventive effect of developing asthma 7-years after termination of SIT. METHODS: One hundred and forty-seven subjects, aged 16-25 years with grass and/or birch pollen allergy was investigated 10 years after initiation of a 3-year course of SIT with standardized allergen extracts of grass and/or birch or no SIT respectively. Conjunctival provocations were performed outside the season and methacholine bronchial provocations were performed during the season and winter. Asthma was assessed by clinical evaluation. RESULTS: The significant improvements in rhinoconjunctivitis and conjunctival sensitivity persisted at the 10-year follow-up. Significantly less actively treated subjects had developed asthma at 10-year follow-up as evaluated by clinical symptoms [odds ratio 2.5 (1.1-5.9)]. Patients who developed asthma among controls were 24/53 and in the SIT group 16/64. The longitudinal treatment effect when adjusted for bronchial hyper-responsiveness and asthma status at baseline including all observations at 3, 5 and 10 years follow-up (children with or without asthma at baseline, n = 189; 511 observations) was statistically significant (P = 0.0075). The odds ratio for no-asthma was 4.6 95% CI (1.5-13.7) in favor of SIT. CONCLUSION: A 3-year course of SIT with standardized allergen extracts has shown long-term clinical effects and the potential of preventing development of asthma in children with allergic rhinoconjunctivitis up to 7 years after treatment. CLINICAL IMPLICATION: Specific immunotherapy has long-term clinical effects and the potential of preventing development of asthma in children with allergic rhino conjunctivitis up to 7 years after treatment termination.

Evaluation of the antiinflammatory and clinical effects of sublingual immunotherapy with carbamylated allergoid in allergic asthma with or without rhinitis. A 12-month perspective randomized, controlled, trial.

BACKGROUND: The efficacy and safety of sublingual immunotherapy with carbamylated allergoid (allergoid SLIT) is well recognised. Yet, few data concerning its antiinflammatory effects on the respiratory airways are so far available. Thus we decided to evaluate whether it can reduce the allergic inflammation and improve the clinical symptoms in comparison to pharmacotherapy. METHODS: The study was perspective, controlled and randomised. It was conducted on 56 patients allergic to House Dust Mite with (n=36) or without Parietaria. Thirty-three of them were allocated to SLIT (22 M, 11 F mean age 15 years) and 22 (13 M, 10 F, mean age 21 years) to pharmacotherapy They were followed-up for 1 year. Symptoms and drugs consumption were assessed by monthly diary cards. Bronchial reactivity was investigated at baseline and after a 12-month treatment, through a methacholine (MCh) test. An evaluation of the nasal eosinophils was also performed at the same times. RESULTS: There was a greater reduction of the mean symptom score (p < 0.01) and drug consumption (p < 0.001) in the SLIT than in the control group. MCh PD20 increased only in the SLIT group (p < 0.0005) The reduction of nasal eosinophils was statistically greater (p < 0.05) only in the SLIT group. CONCLUSIONS: A 1-year SLIT reduces the allergic symptoms and the respiratory airways inflammation more than pharmacotherapy.

Role of Dau c 1 in three different patterns of carrot-induced asthma / Papel de Dau c 1 en tres modelos de asma inducida por zanahoria

Objective: To assess the role of Dau c 1 in three patients with carrot induced asthma. Material and methods: Patient 1 had asthma when handling raw carrots. Sensitization to pollens wasn't detected. Patient 2 had rhinoconjunctivitis due to grass and olive pollen allergy. She had asthma when handling raw carrots. Patient 3 was diagnosed of rhinoconjunctivitis and asthma due to allergic sensitization to mites, several pollens and cat. She had asthma due to raw carrot ingestion and inhalation. IgE immunobot analysis and ELISA inhibition assay were used to investigate the allergens and specific antibodies. Results: IgE Immunoblot Analysis: Dau c 1 from carrot extract and the recombinant rDau c 1 were recognized by IgE from patients 1 and 2. Band of Bet v 1 in birch pollen extract wasn't recognized. Patient 3 didn't recognize any of these allergens. Specific IgE to rDau c 1 was measured by ELISA. Specific IgE ELISA-inhibition with carrot as solid phase showed an intermediate inhibition (30 %) between carrot and rDau c 1 in patient 1; and a considerable inhibition (nearly 100 %) between carrot and rDau c 1 in patient 2. No inhibition was found in patient 3. Specific IgE ELISA inhibition between rDau c 1 and rBet v 1, employing rDau c 1 as solid phase was made in patients 1 and 2. Bet v 1 showed less than 40 % of inhibition of rDau c 1 in patient 1; and an intermediate inhibition (> 40 %) between rBet v 1 and rDau c 1 in patient 2. Conclusions: Airborne carrot allergens are able to sensitize without the implication of a previous pollen allergy. Dau c 1 was the main allergen in patient 2. In patient 1, there was a band of 30 kd that looks like the predominant allergen. Patients 1 and 2 were sensitized directly from carrot allergens. In patient 3, Dau c 1 isn't related to the carrot allergy. Allergy to carrot in patient 3 seems to be related to her allergy to different pollens; however, it wasn't related to birch pollen. Mediterranean countries didn't show the same patterns of food-related pollen allergy than Nordic countries

Objetivo: Valorar la responsabilidad del Dau c 1 en tres pacientes con asma causada por zanahoria. Material y métodos: El paciente 1 tenía asma cuando manejaba zanahorias crudas, en el que no se detectó sensibilización a pólenes. La paciente 2 tenía rinoconjuntivitis causada por polen de gramíneas y de olivo, y además presentaba asma cuando manejaba zanahorias crudas. La paciente 3 padecía rinoconjuntivitis y asma, estando sensibilizada a ácaros, varios pólenes y epitelio de gato, además tenía crisis de asma tras ingestión de zanahoria y también por inhalación al manejarla. La investigación de alergenos y anticuerpos específicos (IgE) se llevó a cabo con técnicas de immunoblot y ELISA-inhibición Resultados: Análisis de IgE por immunoblot: Dau c 1 de extracto de zanahoria y el recombinante rDau c 1 fueron reconocidos por la IgE de los pacientes 1 y 2, mientras que no se reconoció la banda de Bet v 1 del extracto de polen de abedul. En la paciente 3 no se reconoció ninguno de estos alergenos. La IgE específica para rDau c 1 se midió por ELISA-inhibición con zanahoria como fase sólida, mostrando una inhibición intermedia (30%) entre zanahoria y rDau c 1 en en el paciente 1 y una inhibición considerable (próxima al 100%) entre zanahoria y rDacu c 1 en la paciente 2. En la paciente 3 no se encontró ninguna inhibición. ELISA-inhibición IgE específica entre rDau c 1 y rBet v 1, empleando rDau c 1 como fase sólida, se realizó en los pacientes 1 y 2. Bet v 1 mostró menos del 40% de inhibición de rDau c 1 en el paciente 1, y una inhibición intermedia (>40%) entre rBet v 1 y rDau c 1 en la paciente 2. Conclusiones: Los alergenos de zanahoria son capaces de sensibilizar por inhalación, sin implicación previa del polen como alergeno. Dau c 1 fue el principal alérgeno en la paciente 2. En el paciente 1 hubo una banda de 30kd que parece ser el alergeno predominante. Los pacientes 1 y 2 se sensibilizaron directamente de los alergenos de la zanahoria. En la paciente 3 el Dau c 1 no parece estar relacionado con su proceso; en esta paciente la alergia a la zanahoria parece más relacionada con la alergia a diferen tes pólenes, aunque no parece que sea el polen de abedul. En los países mediterráneos no se encuentran los mismos patrones de alergia polen-alimentos que en los países nórdicos

Allergic rhinitis with or without concomitant asthma: difference in perception of dyspnoea and levels of fractional exhaled nitric oxide.

BACKGROUND/AIM: Allergic rhinitis (AR) is a risk factor for developing clinical asthma. Moreover, AR is often associated with bronchial hyper-responsiveness (BHR). The aim of the present study was to investigate whether patients with AR and asthma differed from AR with or without BHR in degree of perception of dyspnoea and airway inflammation, measured as fractionated exhaled nitric oxide (NO). MATERIALS: Twenty-nine patients with seasonal AR (timothy) were investigated with metacholine challenge test. Fourteen healthy non-reactive subjects served as controls. METHODS: (1) Metacholine challenge test, cut-off value forced expiratory volume in 1 s (FEV(1)) PD20 2,000 microg. Slope value for metacholine was calculated as %fall in FEV(1)/mol metacholine. Dyspnoea during challenge was measured with a 10-graded modified Borg score. (2) Measurement of fractional-exhaled nitric oxide (FENO) at flow rate 50 mL/s. RESULTS: Eighteen patients reported AR only, without asthma symptoms, and 12 (67%) were BHR. Eleven subjects had both rhinitis and asthma symptoms. Patients with rhinitis and asthma reported significantly more dyspnoea per percent fall in FEV(1) compared with those with rhinitis and BHR. Moreover, those with rhinitis and asthma had significantly higher NO values compared with those with rhinitis and BHR. CONCLUSION: The difference between rhinitis patients with or without asthma symptoms seems to be mainly a question of perception of dyspnoea. However, FENO measurement indicates that dyspnoea may also be associated with increased inflammatory activity in the peripheral airways.

Effect of viewing a humorous vs. nonhumorous film on bronchial responsiveness in patients with bronchial asthma.

The effect of viewing a humorous film on bronchial responsiveness to methacholine [methacholine study: 20 healthy participants and 20 patients with house dust mite (HDM)-allergic bronchial asthma (BA)] or to epigallocatechin gallate (EGCg; EGCg study: 15 normal participants and 15 EGCg-allergic BA patients) was studied. At baseline, bronchial challenge test to methacholine (20 normal participants and 20 HDM-allergic BA patients) or EGCg (15 normal participants and 15 EGCg-allergic BA patients) were performed. After 2 weeks, patients and healthy participants were randomly assigned to watch a humorous or a nonhumorous film. Two weeks later, the alternate film was watched. Immediately after viewing, bronchial challenge test to methacholine or ECGg to each study group were performed. Viewing a humorous film significantly reduced bronchial responsiveness to methacholine or EGCg, while viewing a nonhumorous film failed to do so in BA patients without affecting bronchial responsiveness to methacholine or EGCg in healthy participants. These findings indicate that viewing a humorous film may be useful in the treatment and study of BA.

Green tea-induced asthma: relationship between immunological reactivity, specific and non-specific bronchial responsiveness.

BACKGROUND: The relationships between immunological reactivity and bronchial responsiveness to allergen and non-specific bronchial responsiveness are unclear in occupational asthma caused by low molecular weight substances. OBJECTIVE: We assessed the above relationships in green tea-induced asthma, an occupational asthma of green tea factory workers, in which epigallocatechin gallate (EGCg), a low molecular weight component of green tea leaves, is the causative agent. METHODS: Subjects consisted of 21 patients suspected of having green tea-induced asthma, on whom skin test and inhalation challenge with EGCg were performed. The skin sensitivity or end-point titration to EGCg as a measure of immunological reactivity, together with the provocative concentrations causing a 20% or greater fall in forced expiratory volume in 1 s (PC20) of EGCg and methacholine, were determined. RESULTS: We found that 11 patients had green tea-induced asthma, with immediate asthmatic reactions in eight and dual asthmatic reactions in three. We also found that 11 of 13 patients (85%) with immunological reactivity and bronchial hyper-responsiveness to methacholine experienced an asthmatic reaction and that no subject without immunological reactivity reacted. There were significant correlations among skin sensitivity, EGCg PC20 and methacholine PC20. Multiple linear regression analysis showed the relationship: log (EGCg PC20)=0.42 log (skin sensitivity)+1.17 log (methacholine PC20)+0.93 (r=0.796, P<0.05). CONCLUSION: It is concluded that bronchial responsiveness to EGCg can be highly satisfactorily predicted by skin sensitivity to EGCg and bronchial responsiveness to methacholine.

Effect of interferon-gamma on allergic airway responses in interferon-gamma-deficient mice.

Interferon (IFN)-gamma reduces airway responses after allergen challenge in mice. The mechanisms of this effect are not clear. These studies investigate whether IFN-gamma can reverse prolonged airway responses after allergen challenge in IFN-gamma-deficient (IFN-gammaKO) mice. Sensitized mice (IFN-gammaKO and wild-type [WT]) were challenged with ovalbumin. Airway responsiveness, eosinophils in bronchoalveolar lavage fluid, and lung lymphocyte subsets (CD4(+) and CD8(+)) were measured 24 hours and 8 weeks after challenge. In further experiments, we treated IFN-gammaKO mice with recombinant IFN-gamma starting 4 weeks after the challenge for 1 week or 4 weeks. Airway responsiveness, bronchoalveolar lavage eosinophils, and lung CD4(+) cells were increased 8 weeks after challenge in IFN-gammaKO but not WT mice. IFN-gamma treatment returned lung CD4(+) cell numbers to values obtained in unchallenged mice. One week of IFN-gamma treatment also returned airway responsiveness to baseline levels; however, 4-week treatment with IFN-gamma failed to decrease airway responsiveness below levels observed in untreated animals. This suggests that IFN-gamma plays an essential role in reversing allergen-induced airway inflammation and hyperresponsiveness and that it may have dual actions on the latter. Observations that IFN-gamma reverses airway responses, even when administered after challenge, suggests that IFN-gamma treatment could control allergic disease, including asthma.

Antitussive effect of the leukotriene receptor antagonist zafirlukast in subjects with cough-variant asthma.

Cough-variant asthma (CVA) occurs in a subgroup of asthmatics whose sole or predominant respiratory symptom is cough. Although bronchodilators are often sufficient to treat CVA, refractory cough may require therapy with inhaled or systemic corticosteroids. In a randomized, double-blind, placebo-controlled, crossover study, we examined the effect of a 14-day course of the leukotriene receptor antagonist zafirlukast on subjective cough score and cough-reflex sensitivity to inhaled capsaicin in eight subjects with CVA refractory to inhaled beta agonists, and in five subjects refractory to inhaled corticosteroids. Seven of eight subjects experienced significant subjective and objective improvement in cough after treatment with zafirlukast. Mean (+/- SEM) cough score improved from 7.75 +/- 0.56 to 3.25 +/- 0.84 (p = 0.0006). Cough sensitivity to capsaicin was suppressed by zafirlukast in all subjects. Patients with CVA may represent a distinct subgroup of asthmatics whose afferent cough receptors within the respiratory epithelium are hypersensitive relative to those of patients with the typical form of asthma. Zafirlukast appears to be particularly effective in treating CVA by inhibiting the sensitivity of these receptors. Leukotriene receptor antagonists may offer an alternative to corticosteroids for the treatment of CVA refractory to inhaled bronchodilators.

Evidence-based management of exercise-induced asthma.

Exercise-induced asthma (EIA) is a common, yet often unrecognized condition occurring in both known asthmatics and otherwise healthy individuals. Misdiagnosis, both over- and underdiagnosis, is not uncommon. In order to accurately diagnose EIA, a bronchoprovocation challenge test must be performed; the current recommended test is a eucapnic hyperventilation (EVH) challenge test. Although there are a number of treatment options available, both pharmacologic and nonpharmacologic, in most cases medications are required. A range of medications are currently available to either treat or prevent EIA. It is important that the medications used are individualized to the patients needs and monitored to ensure efficacy.

Concentrations of exhaled nitric oxide in asthmatics and subjects with allergic rhinitis sensitized to the same pollen allergen.

BACKGROUND: Some studies have reported that the levels of exhaled nitric oxide (ENO) in asthmatics are similar to those in subjects with allergic rhinitis, and it has been postulated that atopic status might be the determinant of enhanced nitric oxide production in asthma. OBJECTIVES: The aim of this study was to determine differences in ENO levels between asthmatics and subjects with allergic rhinitis sensitized to the same allergen, and to correlate these levels with airway responsiveness. METHODS: Nineteen patients with asthma and 18 subjects with allergic rhinitis monosensitized to Parietaria pollen were enrolled in the study. ENO values and airway responsiveness to methacholine and adenosine 5'-monophosphate (AMP) were measured during the pollen season. The response to each bronchoconstrictor agent was measured by the provocative concentration required to produce a 20% fall in FEV1 (PC20). ENO was measured with the single-exhalation method. RESULTS: The geometric mean (95% confidence interval) ENO values were significantly higher in asthmatics than in subjects with allergic rhinitis: 72.4p.p.b. (54.9-93.3p.p.b) vs. 44.7p.p.b. (30.9-64.6p.p.b., P = 0.03). In asthmatics, a significant correlation was found between ENO and PC20 AMP values (p = -0.57, P=0.02), whereas no correlation was detected between ENO and PC20 methacholine (p = -0.35, P = 0.14). CONCLUSIONS: Our results suggest that atopy is not the only determinant of increased ENO levels detected in subjects with asthma, and that responsiveness to AMP may be a more sensitive marker for assessing airway inflammation in asthma compared to methacholine.

Underrecognition and undertreatment of asthma in Cape Town primary school children.

BACKGROUND: In view of the high local prevalence of asthma, the extent of recognition and appropriate management of childhood asthma was studied in a large suburban area of Cape Town. DESIGN: Cross-sectional study based on random community sample of schools. METHOD: 1,955 parents of sub B pupils from 16 schools completed a questionnaire, followed by: (i) an interview of the parents of 348 symptomatic children; and (ii) bronchial responsiveness testing on 254 children. The final case group consisted of 242 children with reported asthma or multiple asthma symptoms on both questionnaires. Children in whom asthma was acknowledged were compared with those in whom it was not. RESULTS: Overall, any past or current ('ever') asthma was acknowledged by respondents in only 53% of the children, and current asthma in only 37.1%. While most children had received treatment in the previous 12 months, 66.1% of the recognised group were on current treatment (23.2% on daily treatment), compared with 37% of the unrecognised group (3% daily). Salbutamol and theophylline syrups were the most common types of medication, while inhalers and anti-inflammatory medications were underused. Only a minority of parents reported the child ever having used a peak flow meter, or volunteered knowledge of preventive measures. Current treatment, and to a lesser degree recognition of asthma by parents, were more common among children on medical aid and of higher socio-economic status. CONCLUSIONS: These findings suggest that ways need to be found: (i) to increase the use of current asthma treatment guidelines by practitioners; (ii) to provide access to comprehensive care by children not on medical aid; and (iii) to improve education of parents in home management measures such as severity assessment and avoidance of smoking, allergen and dietary triggers.

The diagnostic capacity of forced oscillation and forced expiration techniques in identifying asthma by isocapnic hyperpnoea of cold air.

The measurement of forced expiratory volume in one second (FEV1) is often used to assess the effect of bronchial provocations, and deep inspiration is required beforehand. This may briefly alter the bronchial tone in a variable way in some subjects. The forced oscillation technique (FOT) is a test used to characterize the mechanical impedance of the respiratory system, and prior deep inspiration is not required. We tested the hypothesis that measurable bronchoconstriction would occur in all asthmatic subjects stimulated with isocapnic hyperventilation of dry cold air (IHCA). Twenty patients with mild asthma and nine healthy controls were exposed to IHCA, at 70% of their maximal voluntary ventilatory capacity for 4 min and the results were assessed both by applying the FOT and by measuring FEV1. Optimal cut-off levels were defined by receiver operating characteristic (ROC) curve analyses of the changes in respiratory resistance and reactance at 5-35 Hz, resonant frequency (fres) and FEV1. A positive result was present in the asthmatics when measured by FOT, and using ROC analyses the discriminative capacity to correctly diagnose asthma was greatest for responses in fres; the sensitivity was 89% and the specificity 100%. The sensitivity of FEV1 to correctly diagnose asthma was only 73%, and the specificity 88%. In conclusion, the results of this study suggest that the use of forced expiratory volume in one second for bronchial provocation tests by isocapnic hyperventilation of dry cold air may be misleading and that the bronchoconstriction thus elicited is measured with greater sensitivity and specificity by the forced oscillation technique than by forced expiratory volume in one second.

In vivo diagnostic procedures: skin testing, nasal provocation, and bronchial provocation.

In vivo challenge procedures can be very useful in the analysis of allergic symptoms. Skin testing has a high degree of sensitivity and specificity for determining antigens that cause allergic disease. However, positive skin tests do not necessarily indicate that a specific allergen causes symptoms specific for a certain organ. Nasal and whole lung provocation testing can help define relevant allergens that cause rhinitis or asthma symptoms. These tests are safe when performed properly under close medical supervision and have predictive values that make them useful diagnostic tools.

Effects of single-dose zileuton on bronchial hyperresponsiveness in asthmatic patients treated with inhaled corticosteroids.

The aim of the study was to determine whether zileuton, an inhibitor of 5-lipoxygenase, attenuated bronchial hyperresponsiveness (BHR) in asthmatic subjects who had marked BHR during maintenance treatment with inhaled corticosteroids (ICS). In a randomized, double-blind, placebo-controlled, cross-over study, a challenge test with histamine (provocative concentration of histamine producing a 20% fall in forced expiratory volume in one second (FEV1) (PC20,Hist)) and with ultrasonically nebulized distilled water (UNDW) (provocative dose of UNDW producing a 20% fall in FEV1 (PD20,UNDW)) was performed in seven patients with asthma after intake of either 400 mg zileuton or placebo. All patients (mean age 33 yrs, mean FEV1 111% of predicted) had marked BHR, as indicated by a mean PD20,UNDW of 4.74 mL under treatment for at least 6 months with up to 800 microg ICS (mean 536 microg daily). On four different occasions, separated by at least 5 days, two UNDW and two histamine challenge tests were performed in random order 3 h after a morning dose of either zileuton or placebo. Neither zileuton nor placebo changed baseline airway calibre prior to provocation. Zileuton increased PC20,Hist from 0.99 to 5.64 mg x mL(-1) (2.1 doubling doses; p<0.03 compared to placebo), and increased PD20,UNDW from 3.10 to 9.31 mL (1.3 doubling doses; p<0.05 compared to placebo). In conclusion, a single dose of 400 mg zileuton attenuates bronchial hyperresponsiveness to histamine and ultrasonically nebulized distilled water in asthmatic patients with marked bronchial hyperresponsiveness during treatment with inhaled corticosteroids.