Specificity and sensitivity of methacholine challenge test in children with normal and hyperreactive airways

To assess the ability of the methacholine challenge test for separation between normals and patients with clinically apparent mild airway hyperreactivity, the provocative dose of inhaled methacholine required to cause a 20% drop in the forced expiratory volume in one second was evaluated in two selected pediatric populations. On the basis of a standardized respiratory questionnaire, 70 subjects, 4-16 years of age were identified. Included were 49 normal individuals, and 21 individuals with mild airway hyperreactivity who responded to bronchodilators. Methacholine inhalation challenges were performed by use of a standard inhalation procedure. Forty-seven percent of the normals (23/49) had a positive methacholine challenge test while 24% (5/21) of the patients with hyperreactive airways had a negative test by the standard criteria. A wide spectrum of specificity and sensitivity of methacholine challenge was obtained at different doses of methacholine. The greater the sensitivity, the lower the specificity. Therefore, we postulate that the methacholine challenge test can be helpful in making the clinical diagnosis but it does not allow a clear and perfect separation between normal and clinically apparent mildly airway reactive patients in a pediatric age population.     

Specificity and Sensitivity of Methacholine Challenge Test in Children with Normal and Hyperreactive Airways

ABSTRACT. To assess the ability of the methacholine challenge test for separation between normals and patients with clinically apparent mild airway hyperreactivity, the provocative dose of inhaled methacholine required to cause a 20% drop in the forced expiratory volume in one second was evaluated in two selected pediatric populations. On the basis of a standardized respiratory questionnaire, 70 subjects, 4-16 years of age were identified. Included were 49 normal individuals, and 21 individuals with mild airway hyperreactivity who responded to broncho-dilators. Methacholine inhalation challenges were performed by use of a standard inhalation procedure. Forty-seven percent of the normals (23/49) had a positive methacholine challenge test while 24% (5/21) of the patients with hyperreactive airways had a negative test by the standard criteria. A wide spectrum of specificity and sensitivity of methacholine challenge was obtained at different doses of methacholine. The greater the sensitivity, the lower the specificity. Therefore, we postulate that the methacholine challenge test can be helpful in making the clinical diagnosis but it does not allow a clear and perfect separation between normal and clinically apparent mildly airway reactive patients in a pediatric age population.     

Airway response to exercise and methacholine in children with respiratory symptoms.

Thirty atopic and 30 non-atopic subjects were identified from a population of 7-8 year old children with current respiratory symptoms. The response of the airways to exercise and provocation by methacholine were compared. In these children, who had symptoms but were not necessarily asthmatic, there was no significant correlation between the two stimuli. The atopic children were, however, significantly more responsive than the non-atopic children to both. For the whole group, odds ratios derived for atopy and for an increased response to methacholine (expressed as a PD20--the dose that caused the forced expiratory volume in one second (FEV1) to fall by 20%--of less than 6.4 mumol/l), a positive exercise test (greater than 15% fall in FEV1), and the presence of asthma were 13.5, 3.3, and 21.0, respectively; that for positive response to methacholine and positive exercise challenge was 1.5. Thus though increased bronchial responsiveness to methacholine and exercise challenge are both associated with a diagnosis of asthma, the association between the two stimuli is complex, and supports the view that they reflect entirely different components of airways dysfunction.     

Food challenge procedures: standardization of oral challenge and pulmonary measurements

The lung is one of many target organs that can be affected in an adverse reaction to a food or food additive. The question of pulmonary involve ment is often in the context of patients who have underlying asthma, a disease of the airways characterized by reversible airways narrowing. A number of unique problems must be addressed when attempting to measure pulmonary responses during adverse reactions. Prior to the study, it is necessary to determine if the subject has asthma and if so, to quantitate the severity of asthma. This can be accomplished by assessing pulmonary function, measuring airways reactivity, documenting medication requirements, recording duration of disease, and detailing complications. Procedures that may result in pulmonary reactions should be performed only where severe reactions can be optimally treated such as in the hospital or an office near a hospital. Medical personnel must have proper training in, and equipment for, resuscitation. Medications should be withheld when possible that may effect the ability to measure pulmonary responses. Specific endpoint criteria of a positive response should be set in advance of testing. Double-blind placebo controlled food challenge is the experimental protocol of choice. Responses to specific foods or additives can be assessed both by measuring changes in pulmonary function and by repeated methacholine challenge to assess airways reactivity. With proper definition of the question, use of appropriate experimental design, exercise of caution, application of appropriate analytic methods, and the presentation of a clear and thorough report, adverse reactions to foods and additives involving pulmonary responses may be assessed with safety and scientific accuracy.     

Methacholine Inhalation Challenge in Children with Idiopathic Chest Pain

Bronchial reactivity to inhaled methacholine (MCH) was evaluated in 32 patients with 'idiopathic' chest pain. Each pain was recurrent in nature. The incidence of cases with a provocative concentration causing a 20% fall in the forced expiratory volume in 1 sec (PC₂₀) of 10 mg/ml or less was 62.5% (20 cases), while it was only 11.1% (three cases) in 27 healthy controls. Seventeen patients had no personal history of allergic diseases, elevated serum lgE level or positive house dust mite-specific IgE antibody. Among these 17, eight (47.1%) had a PC₂₀ of 10 mg/ml or less, the incidence of which was also higher than that of the healthy controls. During the challenge, eight patients complained of chest pain similar to that experienced before. The present results indicate that bronchial hyper-reactivity is an important cause of 'idiopathic' chest pain. Patients with unexplained chest pain should be considered for inhalation challenge.     

Short-term effects of budesonide, nedocromil sodium and salmeterol on bronchial hyperresponsiveness in childhood asthma

Abstract Background: The effects of budesonide, nedocromil sodium and salmeterol on bronchial hyperresponsiveness were determined over a period of 3 weeks.
Methods: Forty-three asymptomatic children (22 male, 21 female, aged7–17 years) with mild-to-moderate asthma were evaluated. The study was placebo-controlled and double-blind. At the beginning the forced expiratory volume in 1 second (FEV₁) was measured and a methacholine challenge was performed to determine PC₂₀ (provocative concentration of inhaled methacholine required to reduce FEV_t by 20%). The patients in group I (n = 12), group II (n = 10), group III (n = 11), and group IV ( n = 10) inhaled 200 μg of budesonide, 2 mg of nedocromil sodium, 25 μg of salmeterol and a placebo, respectively, twice a day over the period of 3 weeks. Then the methacholine PC₂₀ values of all patients were measured again and the results were compared statistically with their previous values.
Results: The statistical data revealed that the methacholine doses in PC₂₀ before and after treatment were different in group I (P < 0.01). However, these differences were not statistically significant in the other groups (P > 0.05).
Conclusions: The short term usage of budesonide decreases bronchial hyperresponsiveness, but nedocromil sodium and salmeterol in the given doses do not affect bronchial hyperresponsiveness.     

Is outdoor running exercise suitable for detecting bronchial hyperreactivity in children with mild episodic bronchial asthma?]

Bronchial hyperreactivity (BHR) can be proved by various methods. 21 children, 14 asthmatics and 7 healthy subjects were submitted to inhalative methacholine challenge as well as to 'free running' as a form of exercise challenge in a randomized sequence. For the methacholine inhalation a standardized procedure was followed and the provocative concentration defined (PC20) at which a decrease of more than 20% in FEV1 was found. There is no real standardisation for 'free running' (concerning temperature and humidity of the inspired air; individual level of exercise) but subjects had to run for 6 minutes while the heart rate should have been between 170 and 180 beats/minute. This increase in pulse rate relates to a submaximal work at which 60-85% of maximal O2 uptake are obtained. A decrease of 15% from basic value of FEV1 was defined as a positive result. By the use of methacholine inhalations we found 16 children (14 diseased, 2 controls) to be hyperreactive, whereas only 3 of them showed a positive result after 'free running'. We conclude, that firstly, methacholine provocations and exercise challenges assess different kinds of bronchial reactivity, secondly, 'free running' as a form of exercise is very difficult to standardize and therefore prone to errors and thirdly, 'free running' is not sensitive enough to assess BHR in children with mild asthma bronchiale if used as the only form of challenge. Problems concerning measurement of BHR are discussed.     

Sensitivity of peak expiratory flow rate for diagnosing bronchial obstruction on methacholine inhalation challenge in school-aged asthmatic children

To study whether forced expiratory volume in 1 s (FEV1) for the diagnosis of bronchial reactivity by means of the methacholine inhalation challenge test could be appropriately replaced by simple measurements of peak expiratory flow rate (PEFR), 75 consecutively referred asthmatic children aged 6–15 y were examined during a symptom-free period. Their baseline FEV1 and PEFR values ranged from 70 to 130% (mean 99.1) and from 77 to 122% (mean 101.4) of those predicted, respectively. The methacholine inhalation challenge was performed with stepwise doubled cumulative doses and both FEV1 and PEFR were measured at each step. Of the 67 children who had a 20% reduction in either test, the fall in FEV1 was achieved after a lower dose of methacholine than the 20% fall in PEFR in 49 cases, after a higher dose in 15 and after the same dose in 3. There was a significant correlation ( r = 0:56, p < 0:001) between the changes in FEV1 and PEFR, although considerable scatter was found in the results. The 64 children who had a reduction of 20% in FEV1 showed a corresponding drop in PEFR that varied from 1.8 to 28.8% (mean 15.3), including 9 children for whom this drop was less than 10%. The results indicate that if the challenge test were based on PEFR measurements, the reference values for the test would have to be different.     

Prevalence of Bronchial Asthma among Schoolchildren in a Swedish District

ABSTRACT. The prevalence of asthma among 10527 children aged 7–16 years was investigated in 1985. Children were assigned to the asthma group when replies to a questionnaire stated that at least two of four stipulated symptoms had been experienced in the preceding year. A validation study, comprising exploration of medical history, pulmonary auscultation and physiological tests (spirometry and methacholine inhalation challenge) was performed in 73 children. The overall prevalence of asthma was 4%. The most common symptom-inducing factors were physical exertion, upper respiratory tract infection, contact with animals and tobacco smoke. The methacholine test had limited value as a diagnostic aid, being positive in only 25% of children with a clear history of asthma.     

Prevalence of bronchial asthma among schoolchildren in a Swedish district

The prevalence of asthma among 10,527 children aged 7-16 years was investigated in 1985. Children were assigned to the asthma group when replies to a questionnaire stated that at least two of four stipulated symptoms had been experienced in the preceding year. A validation study, comprising exploration of medical history, pulmonary auscultation and physiological tests (spirometry and methacholine inhalation challenge) was performed in 73 children. The overall prevalence of asthma was 4%. The most common symptom-inducing factors were physical exertion, upper respiratory tract infection, contact with animals and tobacco smoke. The methacholine test had limited value as a diagnostic aid, being positive in only 25% of children with a clear history of asthma.     

A double-blind study comparing the effectiveness of cromolyn sodium and sustained-release theophylline in childhood asthma

The effectiveness of cromolyn sodium and theophylline on asthma in children was compared during a 3-month trial. Forty-six children (aged 5 to 15 years) with asthma were assigned at random to cromolyn or theophylline (Theo-Dur) treatment groups. Each subject received theophylline placebo or cromolyn placebo in addition to the active drugs. A methacholine challenge test was done at the start of the study to document asthma and was repeated during the third month. The theophylline dosage was regulated to obtain serum levels of 10 to 15 micrograms/mL by a physician not involved directly with patient care. Forty patients completed the study. Both theophylline and cromolyn treatment groups showed improvement from base-line status in terms of symptom scores, pulmonary function, and decreased use of inhaled albuterol. Patients treated with theophylline had more side effects and required more frequent office visits than those treated with cromolyn. Both groups had decreased sensitivity to methacholine, and for one statistical test patients treated with cromolyn improved significantly. These results indicate that cromolyn is as effective as theophylline in treating mild to moderate asthma in children; additional benefits were fewer side effects and a possible decrease in bronchial hyperactivity.     

Association of mononuclear cells and eosinophils with airway resistance and responsiveness in rat pulmonary inflammatory responses

To evaluate the association of various leukocytes with pulmonary resist ance and methacholine responsiveness, we induced pulmonary eosi-nophil-rich inflammation in IgE-sensitized (ovalbumin) Sprague Dawlcy rats. Sensitized rats were challenged with either relevant (OA) or irrele vant antigen by tracheal insufflation a) with no other treatment, b) in conjunction with intravenous Sephadex beads pretrcatment, or c) with antigen coupled covalently to Sepharose heads. About 24 h after antigen challenge, respiratory system resistance (Rrs), response to aerosolized methacholine, and pulmonary histopathology were evaluated. Challenge with OA, insufflation with Sepharose, and treatment with i. v. Sephadex all independently increased inflammatory cell infiltrates, but the combi nation of OA with the other agents did not significantly enhance the inflammatory response over OA alone. Interactive stepwise regression techniques were utilized to identify correlates for Rrs and methacholine responsiveness. Mononuclear cell score was a significant predictor (p < 0.1) for Rrs, and insufflation of Sepharose had a significant inde pendent effect on Rrs (p=. 01) above that predicted by mononuclear cell infiltrates. Conversely, eosinophil score and neutrophil score were not significant predictors for Rrs, and challenges with antigen or Sephadex had no significant independent effect on Rrs beyond that predicted from mononuclear cell infiltrates. Eosinophil score was the only significant histological predictor for methacholine responsiveness (p <0.001). Chal lenges with Sephadex, antigen and Sepharose did not significantly change methacholine responsiveness independently of the changes asso ciated with eosinophil infiltrates. These findings suggest that mononucle ar cells and eosinophils contribute to increases in airway resistance and responsiveness, respectively, following the induction of pulmonary inflammation by both allergic and non-allergic stimuli.     

Ding Chuan Tang, a Chinese herb decoction, could improve airway hyper-responsiveness in stabilized asthmatic children: a randomized, double-blind clinical trial.

Traditional Chinese medicine has a long history of application in the treatment of bronchial asthma. Solid scientific evidence, however, is not available despite its widespread use among patients worldwide and in Taiwan. To assess the effect of Ding Chuan Tang (DCT) in airway hyper-responsiveness (AHR) on asthmatic children via randomized, double blind, placebo-controlled clinical trial. This study enrolled children who were aged 8-15 and diagnosed as mild to moderate persistent asthma patients. They were randomly allocated to receive 6.0 g DCT or placebo daily for 12 wk. Self-recorded daily symptom scores, medication scores, and morning and evening peak expiratory flow rates were returned at the monthly clinic. Pulmonary function test, methacholine challenge test, and serum inflammatory mediators were measured before and at the end of the trial. Fifty-two asthmatic children completed the clinical study. Twenty-eight patients were assigned to the treatment group and 24 to the placebo group. At the end of the treatment period, AHR determined by log PC(20) was significantly improved in the DCT group (0.51 +/- 1.05 mg/ml vs. 0.26 +/- 0.84 mg/ml, p = 0.034). The total clinical and medication reduced parameters showed improvement in the DCT group (p = 0.004). The AHR, symptom and medication scores in children with persistent asthma were significantly improved with DCT treat for 12 wk. The results suggested more stable airways achieved with such an add-on complementary therapy.     

Measurement of nasal mucociliary clearance.

The saccharin test was carried out in a randomly selected sample of schoolchildren (142 boys and 153 girls, age range 11-14 years) to determine the variability and reproducibility of the test and to assess whether it could be used as a screening test for nasal mucociliary clearance. Nasal mucociliary clearance times were analysed according to clinical history (asthma, rhinitis, asthma with rhinitis, and acute upper respiratory tract infections), laboratory findings (positive skin test responses and bronchial hyper-reactivity assessed by methacholine challenge), and parental smoking. Nasal mucociliary clearance times showed a narrow coefficient of repeatability (six minutes) in 50 subjects and there was substantial agreement between the two tests. Nasal mucociliary clearance times were less than 40 minutes in all the children. Normal children had nasal mucociliary clearance times of less than 24 minutes while significantly impaired nasal mucociliary clearance was detected in those with positive skin reactions and a positive response to methacholine challenge. We were unable to show that passive smoking had any consistent effect on nasal mucociliary clearance. We suggest that a time response between 30-60 minutes should be checked again at least two weeks later, and that children in whom repeated saccharin tests show a nasal mucociliary clearance of greater than 30 minutes should have ciliary beat frequency estimated.     

Short-term mechanical ventilation increases airway reactivity in rat pups

We used a rat pup model to delineate whether mechanical ventilation of 95% O2). After each intervention, they were returned to their mothers. On d 10 of life, all animals were anesthetized, paralyzed, and ventilated to measure pulmonary function. Total lung resistance (RL) and dynamic lung compliance (Cdyn) were measured in response to increasing intravenous doses of methacholine (0.03-1 microg/g) by head-out body plethysmography. Injection of methacholine caused a dose-dependent increase in RL and decrease in Cdyn. The response of both RL and Cdyn to methacholine was significantly potentiated by prior exposure to mechanical ventilation when compared with unventilated normoxic controls. The addition of hyperoxia to mechanical ventilation did not further potentiate responses to methacholine. Mechanical ventilation did not alter lung myosin or the number of inflammatory cells in airways of room air ventilated versus unventilated control animals. We conclude that a brief period of mechanical ventilation in rat pups increases airway reactivity 48 h after such exposure in the presence as well as absence of hyperoxic exposure. This represents a potentially important model to investigate the mechanisms involved in airway hyperreactivity induced by neonatal lung injury.     

Comparison of cold air, ultrasonic mist, and methacholine inhalations as tests of bronchial reactivity in normal and asthmatic children

The sensitivity and specificity of cold air, ultrasonically nebulized distilled water mist (USM), and standard methacholine (MCH) challenges were studied in 21 children with asthma (mean age 11.5 years) and 12 normal children (mean age 14.2 years). The cold air challenge consisted of successive 3-minute periods of hyperventilation during which incremental volumes of subfreezing air (mean temperature -16 degrees C) were inhaled. To perform the USM challenge, subjects inhaled increasingly larger volumes of nebulized distilled water while breathing tidally. The specificity of both nonpharmacologic challenges was found to be 100%, whereas that of MCH was only 83%. The sensitivity of the cold air and USM tests was 57% and 71%, respectively, compared with 95% obtained with MCH challenge. We conclude that cold air and USM challenges are promising alternatives to the MCH challenge, and may be superior to it if optimal standard testing protocols are defined.     

Correction of bronchial challenge data for age and size may affect the results of genetic association studies in children

Meaningful studies of asthma genetics require careful definition of airway hyperresponsiveness (AHR). In children, several studies have emphasized the need for correction of bronchial challenge data for baseline parameters, such as age, gender, lung function and atopic status, when undertaking airway responsiveness measurements. However, few studies have suggested how this should be performed in practice. This study describes a method for the correction of dose–response slopes (DRS) and PC₂₀ values for baseline parameters in children, and illustrates the effect of such corrections on the association of AHR with the glutathione S-transferase GSTP1 Ile105Val polymorphism in children. Skin prick and methacholine challenge testing, measurement of total serum IgE concentration and GSTP1 genotyping were performed in 145 unrelated British children aged 7–18 years. Correction of bronchial challenge results, expressed as both DRS and PC₂₀ values, for age, gender, baseline lung function and atopic status was performed using linear regression and discriminant analysis, respectively. Adjusting bronchial challenge results for the age and size of the child altered AHR status, defined as a PC₂₀ methacholine <8 mg/ml, in 37% of children. Correction for baseline parameters also resulted in a significant reduction in mean DRS (original uncorrected DRS 83.6, corrected DRS _c 27.4). This had a marked effect on the results of the association study, unmasking a previously unidentified association between the GSTP1 genotype and AHR in children. Age and size adjustment of bronchial challenge data has a significant effect on AHR status and may influence the results of genetic association studies in children.     

咳嗽变异性哮喘患儿气道反应性特点

目的了解咳嗽变异性哮喘(CVA)患儿气道反应性特点。方法对38例CVA患儿、42例典型哮喘患儿和30例健康儿童进行肺功能和气道反应性测定。结果 CVA组和典型哮喘组患儿的气道反应性测定中的初始阻力值(Rrs cont)、基础呼吸传导率(Grs cont)与对照组比较差异无统计学意义;而最小诱发累积剂量(Dmin)、传导率下降斜率(SGr)和特异性气道传导下降第35百分位(PD35)均低于对照组,差异有统计学意义(P<0.05)。结论 CVA与典型哮喘患儿气道敏感性和气道反应性高于正常儿童,存在气道高反应。气道反应性测定可成为鉴别诊断慢性咳嗽的重要方法之一。     

Nonspecific bronchial hyperresponsiveness and development of asthma in children with hay fever

It has been suggested that patients with allergic rhinitis who present nonspecific bronchial hyperresponsiveness (BHR) are those most likely to develop asthma. Therefore, a study was conducted in children with rhinoconjunctivitis to ascertain whether BHR to methacholine might predict the development of asthma in these patients. Fifteen patients with hay fever and no previous symptoms of asthma were selected. All underwent clinical symptom tests and methacholine tests, during the pollen season in the 4 consecutive years following the start of the study. At the end of this period, 5 patients had developed asthma. It may thus be affirmed that, in this group, neither the presence nor the degree of previous BHR was useful for predicting which patients would later develop asthma.     

Prospective follow-up and pulmonary functions from a placebo-controlled randomized trial of ribavirin therapy in respiratory syncytial virus bronchiolitis. Ribavirin Study Group.

OBJECTIVE: To determine any long-term differences in adverse effects and pulmonary function between infants with respiratory syncytial virus and lower respiratory tract infection who were treated with ribavirin and a control group. STUDY DESIGN: Long-term follow-up included enumeration of episodes of respiratory illness, wheezing, and pneumonia and, ultimately, administration of pulmonary function tests (PFTs). Pulse oximetry was done at each visit. During the first 3 years we conducted follow-up in the fall and spring. In years 4 and 5 we conducted 1 visit per year. During years 5 through 7 we conducted PFTs, and starting with year 7 a methacholine chloride challenge was done if forced expiratory volume in 1 second (FEV1) was greater than 70% of predicted value. RESULTS: We prospectively enrolled (December 1983 to February 1985) in a randomized trial of ribavirin vs placebo children who were previously healthy, were premature, or had chronic pulmonary disease. One pulmonologist (R.F.; blinded) scored and interpreted the results of the PFTs. We studied 42 patients aged 1 to 33 months; 2 patients died (1 receiving ribavirin and 1 receiving placebo) and 5 patients receiving placebo were lost to follow-up; 35 patients (24 taking ribavirin and 11 taking placebo) attended 212 visits. Four patients were premature (3 in the ribavirin and 1 in the placebo group), and 3 of these had bronchopulmonary dysplasia (2 in the ribavirin and 1 in the placebo group). From years 1 to 3, there was more reactive airway disease, wheezing, and pneumonia in the placebo than in the ribavirin group (mean score, 22.3 for 12 placebo-treated patients vs. 15.8 for 23 ribavirin-treated patients; P = .07 by Kruskal-Wallis test); for all years, it was 22.0 for 11 placebo-treated patients vs. 16.0 for 22 ribavirin-treated patients (P = .10). After informed consent was given, 19 patients completed PFTs (13 receiving ribavirin and 6 receiving placebo); 7 of 13 ribavirin-treated patients (53%) had normal or mild PFT results vs. 0 of 6 placebo-treated patients (P = .04 by Fisher exact test). On methacholine challenge (7 ribavirin-treated patients and 5 placebo-treated patients), there was more reactivity in the placebo vs. the ribavirin group (exact P = .07). Scoring done by weighting for severity for 19 patients (13 ribavirin-treated patients and 6 placebo-treated patients) (even after correcting for asthma) showed a significant difference in favor of previously ribavirin-treated patients (exact P = .02). CONCLUSIONS: No outward effects were identified from ribavirin exposure. We observed no increase in reactive airway disease, wheezing, and pneumonia in the ribavirin compared with the placebo group. Weighted severity scores suggest long-term beneficial effect of ribavirin therapy; however, larger numbers should be evaluated.