The effect of ketotifen on bronchial hyperreactivity in childhood asthma

Eighteen children with perennial bronchial asthma with an average age of 9.6 yr were studied with respect to the protective effect of ketotifen on bronchial hyperreactivity. All children included demonstrated bronchial reversibility after inhalation of salbutamol, and the methacholine challenge produced a decrease of the forced expiratory volume during the first second of at least 20% in the concentration interval of 0.25 mg/ml to 4.0 mg/ml. The study was double-blind with patients divided into two parallel groups treated for 12 wk with ketotifen or placebo. Methacholine provocation tests were performed every fourth week during this period. No differences between the challenges before and during the treatment period were found in either group, nor were any differences found between the ketotifen and placebo groups. Long-term treatment with ketotifen does not appear to alter the bronchial hyperreactivity in children with bronchial asthma.     

Placebo response in asthma: a robust and objective phenomenon

BACKGROUND: Placebos are hypothesized to exert positive effects on medical conditions by enhancing patient expectancies. Recent reviews suggest that placebo benefits are restricted to subjective responses, like pain, but might be ineffective for objective physiologic outcomes. Nevertheless, mind-body links and placebo responsivity in asthma are widely believed to exist. OBJECTIVE: We carried out a randomized, double-blind investigation to (1) determine whether placebo can suppress airway hyperreactivity in asthmatic subjects, (2) quantify the placebo effect, (3) identify predictors of the placebo response, and (4) determine whether physician interventions modify the placebo response. METHODS: In a double-blind, crossover design investigation, 55 subjects with mild intermittent and persistent asthma with stable airway hyperreactivity were randomized to placebo or salmeterol before serial methacholine challenges. Subjects were additionally randomized to physician interactions that communicated either positive or neutral expectancies regarding drug effect. RESULTS: Placebo bronchodilator administration significantly reduced bronchial hyperreactivity compared with baseline (the calculated concentration of methacholine required to induce a 20% decrease in FEV(1) nearly doubled); 18% of subjects were placebo responders by using conservative definitions. Experimental manipulation of physician behavior altered perceptions of the physician but not the magnitude or frequency of the placebo response. CONCLUSIONS: Objective placebo effects exist in asthma. These responses are of significant magnitude and likely to be meaningful clinically. The placebo response was not modulated by alterations in physician behavior in this study. CLINICAL IMPLICATIONS: The placebo response in patients with asthma is important in understanding the limitations of clinical research studies and in maximizing safe and effective therapies. This article confirms the existence of a strong placebo response in an objective and clinically relevant measure of disease activity.     

Once-daily theophylline reduces serum eosinophil cationic protein and eosinophil levels in induced sputum of asthmatics

BACKGROUND: Because eosinophilic airway inflammation is a characteristic feature of bronchial asthma, the treatment of airway inflammation is important in the management of asthma. Theophylline has been reported to reduce airway inflammation, in addition to its well-known bronchodilating effect. OBJECTIVE: In order to evaluate the effects of theophylline on airway inflammation, we investigated 48 subjects with mild and moderate asthma. METHODS: The patients were randomly divided into two groups, with or without theophylline treatment (control n = 24; theophylline, n = 24). We examined the level of serum eosinophil cationic protein (ECP), induced sputum samples, and peak expiratory flow (PEF) and obtained spirograms before and after 4 weeks of treatment with once-daily theophylline (200-600 mg/day) of subjects with mild or moderate asthma. RESULTS: Theophylline significantly increased morning and evening PEF and significantly decreased the diurnal variation of PEF. After treatment with theophylline, both serum ECP and the percentage of eosinophils in induced sputum were significantly decreased. In contrast, peripheral blood eosinophil count was unchanged after treatment with theophylline. Conclusions: These findings suggest that theophylline reduces airway inflammation and the severity of asthma, presumably via suppression of both eosinophil activity and subsequent eosinophil infiltration of the airways.     

Sensitivity to methacholine and capsaicin in patients with unclear respiratory symptoms

BACKGROUND: Capsaicin, the pungent ingredient in red pepper, is known to stimulate coughing via the sensory nervous system. Earlier studies showed that patients with airway symptoms induced by chemicals and strong scents cough more after inhalation of capsaicin than healthy control subjects and this has been interpreted as a hyperreactivity of airway sensory nerves. Our aim was to study airway sensitivity to inhaled capsaicin and the occurrence of airway symptoms induced by strong scents in patients who underwent a bronchial methacholine test, primarily because of suspected asthma. METHODS: Fifty-two consecutive patients referred for testing with methacholine were also provoked with inhaled capsaicin in increasing concentrations. Cough sensitivity to capsaicin was compared with that in 40 healthy control subjects. RESULTS: The patients coughed significantly more compared with the healthy control subjects with each dose of capsaicin (P < 0.0001). Twelve patients (23%) had a positive methacholine test, and of these, nine were diagnosed with asthma. There was no difference in capsaicin sensitivity between patients sensitive or insensitive to methacholine. CONCLUSIONS: The majority of the patients had no increased sensitivity to methacholine but did demonstrate sensory hyperreactivity (SHR). SHR appears to be a common diagnosis in investigations of patients with obscure airway symptoms.     

Reactive dye induced occupational asthma without nonspecific bronchial hyperreactivity

Current asthma is often excluded by the presence of normal bronchial hyperresponsiveness. We report two asthmatic patients with normal bronchial hyperresponsiveness and one asthmatic patient with mild bronchial hyperresponsiveness (methacholine PC20; 24 mg/ml) which was presumed to be caused by sensitization and exposure to Black GR, the most frequent sensitizer among reactive dyes. They all complained of lower respiratory symptoms after work as well as at the workstation. The bronchoprovocation test with Black GR revealed isolated immediate bronchoconstrictions in all 3 patients and all had high specific IgE antibodies to Black GR-human serum albumin conjugate. After one worker continued at work for 3 days, he experienced a marked drop of methacholine PC20, and it returned to the pre-exposure level during 1 week. The other patient whose initial methacholine challenge was negative developed bronchial hyperresponsiveness on the first day after the dye bronchoprovocation, and returned to normal bronchial hyperresponsiveness on the third day. These findings suggested that patients with occupational asthma caused by reactive dye may not always have bronchial hyperresponsiveness to methacholine, and the screening program utilizing methacholine challenges may not always identify these patients.     

Occupational asthma caused by Brazil ginseng dust

The inhalation of different substances of plant origin can cause immediate and late onset asthma. The list of these agents responsible for such reactions is continuously increasing. We discuss a patient who developed symptoms of asthma after exposure to Pfaffia paniculata root powder used in the manufacturing of Brazil ginseng capsules. Airway hyperreactivity was confirmed by a positive bronchial challenge to methacholine. Sensitivity to this dust was confirmed by immediate skin test reactivity, a positive bronchial challenge (immediate response), and the presence of specific IgE detected by ELISA technique to an aqueous extract. The bronchial response was inhibited by sodium cromoglycate. Unexposed subjects did not exhibit reactivity to this ginseng extract with any of the tests referred to above. The same study performed with Korean ginseng (Panax ginseng) elicited negative results. This study is the first, to our knowledge, that links ginseng-root dust to occupational asthma.     

Relationship between recurrent croup and airway hyperreactivity

The relationship between recurrent croup and bronchial asthma was evaluated by measuring bronchial hyperreactivity (methacholine challenge), physiologic parameters of upper airway obstruction, and skin response to environmental allergens. Patients with recurrent croup (n = 10) had a significantly higher degree of airway hyperreactivity and atopy than healthy children (n = 15), but significantly less than the patients with bronchial asthma (n = 30). No physiologic signs of upper airway obstruction could be detected at rest or following methacholine. It is suggested that bronchial asthma and recurrent croup share a few characteristics.     

A double-blind, randomized study of sodium cromoglycate versus placebo in patients with cystic fibrosis and bronchial hyperreactivity

To evaluate the effects of sodium cromoglycate (SCG) on patients with cystic fibrosis (CF) and with bronchial hyperreactivity, a long-term, double-blind, placebo-controlled, crossover study was performed. Fourteen patients with CF and without asthma (aged 7 to 29 years) and with bronchial hyperreactivity entered the study. Each patient received 8 weeks of 1% SCG nebulizer solution three to four times daily and 8 weeks of placebo. Seven patients received the treatment in the order SCG/placebo and seven patients in the reverse order. Evaluation of SCG effect was performed every 4 to 8 weeks by (1) clinical assessment of symptoms, (2) clinician and patient/parent opinion, (3) pulmonary function tests, and (4) methacholine provocation tests. After two patients were withdrawn for lack of cooperation, the results were evaluated for treatment effect (SCG versus placebo), period effect (whether SCG was administered first or last), or combination of both. No significant difference was found for these parameters for the clinical assessment of symptoms, the patient/parent and clinician opinion, their subjective preferences, the metacholine challenges, or the pulmonary function tests. The study did not demonstrate any benefit from the use of SCG in patients with CF and with bronchial hyperreactivity and does not support the routine use of SCG in patients with CF.     

大鼠气道炎症与支气管高反应性的关系及茶碱的抑制作用

目的：分析致敏大鼠在抗原攻击后嗜酸粒细胞炎性浸润为特征的气道炎症与支气管高反应性的相关性,并观察不同剂量茶碱的作用。方法：在卵白蛋白（OA）致敏的大鼠,用1% OA气雾攻击后,以计算机辅助技术测定气道管壁面积、支气管周围嗜酸粒细胞数量以及对乙酰甲胆碱（MCh）的反应性。结果：OA攻击可诱导气道炎症反应和支气管高反应性,两者间有显著正相关。口服7 d茶碱（1-12.5 mg/kg, bid）可减轻气道炎症（细支气管壁肿胀和肺嗜酸粒细胞浸润）,对支气管高反应性也有一定抑制作用。结论：提示支气管高反应性与气道炎症有正相关,小剂量茶碱有抗气道过敏性炎症的作用。     

Relationships of methacholine and AMP responsiveness with peak expiratory flow variability in children with asthma

BACKGROUND: Both bronchial responsiveness (BR) and peak expiratory flow (PEF) variability are increased in asthma. PEF variability is presumed to reflect the degree of BR in asthma. BR is commonly assessed by bronchial challenges using direct or indirect stimuli. OBJECTIVE: The aim of this study was to compare methacholine and adenosine 5'-monophosphate (AMP) responsiveness with regard to their relationships with PEF variability in children with asthma. METHODS: Methacholine and AMP challenge tests were performed in 79 children with mild to moderate asthma, and a provocative concentration causing a 20% decline in forced expiratory volume in 1 s (PC(20)) was calculated for each challenge. Subjects recorded PEF each morning and each evening for 14 consecutive days. PEF variability was expressed as amplitude percentage mean (amp%mean; high PEF minus low PEF on each day, expressed as a percentage of their mean, averaged over 14 days), and as the lowest percentage highest (low%high; the lowest PEF expressed as a percentage of the highest PEF recorded over the period). RESULTS: Methacholine PC(20) correlated significantly but weakly with both indices of PEF variability (amp%mean: r=-0.285, P=0.011; low%high: r=0.238, P=0.034). However, there was a significant and strong correlation between AMP PC(20) and both amp%mean (r=-0.583, P=0.000) and low%high (r=0.496, P=0.000). For AMP PC(20), the correlations were stronger than for methacholine PC(20) (comparison of correlation coefficients with amp%mean: P=0.021; with low%high: P=0.063). CONCLUSION: Both methacholine PC(20) and AMP PC(20) correlated significantly with PEF variability. However, the stronger correlations for AMP PC(20) than for methacholine PC(20) suggest that PEF variability may be better reflected by BR assessed by AMP than by methacholine.     

Atopy and bronchial reactivity in Australian and Melanesian populations

In order to compare the prevalence of atopy and bronchial hyperreactivity among Papua New Guinian (P.N.G.) and Australian populations, skin prick tests and methacholine bronchial challenge tests were performed. A civilian and an army population from each country were examined and those with past or present asthma, recent respiratory tract infection and chronic lung disease were excluded. No statistical difference in the prevalence of atopy was found between the four populations. In the P.N.G. population 40 and 49%, and in the Australian population 27 and 39%, were found to be atopic, without symptoms of past or present allergic disease. The house dust mites were the commonest allergens in all populations. In response to methacholine (0·3 mg), only 6% of subjects had falls in 1 sec forced expiratory volume (FEV₁) of more than 12% (upper limit of normal range) and only two were in the asthmatic range. There was no correlation between the degree of bronchial hyper-reactivity and atopic status; however, the degree of bronchial hyperreactivity was slightly greater in the New Guinea civilian than in the Australian civilian population. In the absence of asthma, atopic status does not appear to cause increased bronchial reactivity, suggesting that some factor other than atopy must be present for the development of bronchial hyperreactivity characteristic of asthma.     

Methacholine challenges in the management of young children

Methacholine bronchial challenges (MBCs) have been used as an important diagnostic and management tool for physicians who treat children with chronic asthma. Despite this, children less than 5 years of age present significant diagnostic and management questions that can not easily be answered because of their inability to perform standard spirometry, and thus methacholine bronchial challenges. The present study was designed to evaluate with methacholine bronchial challenge small children (between 2 and 6 years of age) with the diagnosis of or a suspected diagnosis of asthma, utilizing a new method of evaluating airflow in small children through sound analysis, Computer Digitized Airway Phonopneumography (CDAP). There were 23 children in the study between the ages of 2 and 6 years with suspected asthma who could not perform pulmonary function tests. A control group consisting of 12 subjects between the ages of 8 and 38 years of age with a history of chronic cough and/or wheezing who could perform pulmonary function tests was also studied. Of the 12 patients over the age of 8 who had MBC, 11 of them had positive challenges with a fall in FEV1 of 19% or greater. The percent change in sound intensity levels from baseline range from 232% to 396% of baseline. There was greater than 200% change in mean intensity levels with a concentration of methacholine that produced a 19% fall in FEV1 in all of the eleven patients. For one individual who had a negative MBC there was only a 16% change in pulmonary function at 25 mg of methacholine with essentially no change in sound intensity level from baseline.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of specific immunotherapy added to pharmacologic treatment and allergen avoidance in asthmatic patients allergic to house dust mite

BACKGROUND: Although several studies support the efficacy of specific immunotherapy in allergic asthma, its benefit compared with that of standardized pharmacologic intervention remains unknown. OBJECTIVE: A double-blind, placebo-controlled trial in 72 patients with mild-to-moderate asthma and allergy to house dust mite (HDM; Dermatophagoides species) was conducted to assess the effects of specific immunotherapy added to guideline-adjusted pharmacologic treatment and allergen avoidance. METHODS: After 1 observational year of pharmacologic treatment and standard measures of HDM avoidance, 2 groups of asthmatic subjects were randomly assigned to receive specific immunotherapy consisting of subcutaneous injections of either a mixture of Dermatophagoides pteronyssinus and Dermatophagoides farinae vaccine (n=41) or placebo (n=31) for 3 years. Medications were adjusted every 3 months according to the Global Initiative for Asthma guidelines. RESULTS: The adjustment of treatment was associated with a reduction in asthma symptom scores in all subjects. The addition of specific immunotherapy was associated with a decrease in the number of subjects requiring rescue bronchodilators, an increase in morning and evening peak expiratory flow, and a reduced skin sensitivity to HDM extracts. The addition of specific immunotherapy had no significant effects on the cumulative dose of inhaled corticosteroids, asthma symptoms, lung volumes, or bronchial responsiveness to methacholine. CONCLUSION: These results suggest that specific immunotherapy added to pharmacologic treatment and HDM avoidance provides marginal but statistically significant clinical benefits, possibly by reducing the allergic response of asthmatic patients sensitized to HDM.     

Methacholine and physostigmine airway reactivity in asthmatic and nonasthmatic subjects

Inhalation challenges using methacholine and physostigmine were performed in 3 human asthmatic and 3 nonallergic normal subjects. Plethysmographic measurements of specific airways conductance ($\text{Gaw}\text{Vtg}$) were used to monitor the response. The dose required to produce a 17% fall in $\text{Gaw}\text{Vtg}$ was significantly lower in asthmatic subjects than in normal subjects for both physostigmine (p < 0.0125) and methacholine (p < 0.05). Moreover, in all subjects the relative airway sensitivity to methacholine correlated with the relative airway sensitivity to physostigmine. Both methacholine and physostigmine are cholinergic agents. Whereas methacholine acts directly at the end organ cholinergic receptor, physostigmine acts by increasing release and decreasing destruction of endogenous acetycholine at the vagal distal innervation. This suggests that the cholinergic airway hyperreactivity characteristic of asthma is a manifestation of end organ hypersensitivity.     

Treatment of nocturnal asthma in children with a single dose of sustained-release theophylline taken after supper

In a placebo-controlled, double-blind cross-over study of 2 × 3 weeks’duration, twenty-four children with stable asthma who were wheezing during the night, were treated with a single dose of sustained-release theophylline (SRT) taken after supper The mean serum theophylline levels 4 and 12 hr after dosing were 7.7 and 11.2mg/l, respectively. Few side-effects were seen. The mean morning peak expiratory flow (PEF) was significantly higher during SRT treatment (244 ± 11 l/min) than during placebo treatment (207 ± 12 l/min) (P> 0.001). The mean difference between morning and evening PEF was reduced from 20.7 to 8.6% by treatment with SRT (P>0.001). Theophylline significantly reduced the severity of attacks of bronchoconstriction during the night as judged by PEF measurement and use of extra bronchodilator treatment per attack. The response to inhaled terbutaline was increased during SRT treatment compared with that in the placebo period, however pre-treatment PEF did differ significantly between the two periods. The number of acute asthma attacks during the night, the number of symptom-free nights and the use of extra bronchodilators during the night were all significantly improved by SRT treatment (P> 0.001). Seventeen children correctly identified the SRT period whilst six children showed no preference for either period. A single dose of SRT taken after supper is an effective treatment for nocturnal asthma in children.     

A double-blind comparison of inhaled budesonide, long-acting theophylline, and their combination in treatment of nocturnal asthma

In 61 patients with nocturnal asthma, the effects of budesonide, an inhaled steroid (Pulmicort®; 200 μg twice daily), long-acting theophylline (Theodur®; 200 mg twice daily), and their combination were compared. After a 2-week placebo run-in period, the patients were entered into double-blind, crossover periods of 3 weeks. Patients were allowed to use inhaled β²-agonists as required throughout the study. Morning and evening peak expiratory flow rate (PEFR) (percentage of predicted normal ± SEM) was significantly higher during the budesonide (morning 77 ± 1%; evening 80 ± 1%) and combination therapy (morning 79 ± 1%; evening 81 ± 1%) than the theophylline treatment (morning 74 ± 1%; evening 76 ± 1; P ≤0.01, respectively). Significantly fewer sleep disturbances and fewer nighttime inhalations of β₂-agonists were required during budesonide and combination therapy than theophylline treatment. No statistically significant differences were seen between combined therapy and budesonide alone. Budesonide, an inhaled steroid, was significantly better than the bronchodilator, theophylline, in controlling nocturnal asthma, but no additional improvement in efficacy was seen when the drugs were used in combination.     

Increased Bronchial Hypersensitivity after Early and Late Bronchial Reactions Provoked by Allergen Inhalation

The non-specific bronchial reactivity following bronchial allergen challenge was studied in 40 patients with allergic bronchial asthma, particularly in subjects without definite late reactions 6 h after the provocations (reduction in peak expiratory flow or forced expiratory volume in 1 s of less than 15% of the control value at this time). Among a group of 21 patients submitted to bronchial provocation tests, 13 carried out maximal exercise tests 6 and 1 week after the allergen challenge. In another group of 19 patients, the bronchial hyperreactivity to methacholine was assessed before and 6 h and 1 week after challenge. Two patients with a dual response (early & late) reacted with bronchial obstruction to the exercise. Exercise tests performed after 1 week did not provoke asthma in any patient. In the methacholine group a marked increase in responsiveness to methacholine 6 h after the provocation was observed in those patients with a dual response who were tested and in those with equivocal late reactions and even in three patients with an isolated immediate reaction. The increases responsiveness was still present in many patients 1 week after challenge. The airway caliber did not influence the degree of responsiveness to methacholine. Nor did the degree of responsiveness have any influence on the patterns of reactions observed after allergen exposure. It was concluded that in some individuals exposure to the relevant allergen predisposes them to exercise-inducible bronchial obstruction. Further, it was confirmed that non-specific bronchial reactivity can be increased not only in patients with late responses - both definite and equivocal--but also in some patients with immediate reactions alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term treatment with thymomodulin reduces airway hyperresponsiveness to methacholine

We investigated the effect of thymomodulin, a calf thymus acid lysate with immunomodulating activity, on bronchial hyperresponsiveness to methacholine of atopic subjects with asthma. In 16 subjects we measured airway responsiveness at 30, 60, and 90 days after treatment with placebo (eight subjects) or thymomodulin (eight subjects; 80 mg daily orally). The degree of bronchial responsiveness to methacholine was significantly reduced at 90 days during treatment with thymomodulin and remained reduced, even if not significantly, 60 days after cessation of treatment.     

Airway responsiveness to acetaldehyde in patients with asthma: relationship to methacholine responsiveness and peak expiratory flow variation

BACKGROUND: Although airway hyperresponsiveness to inhaled acetaldehyde has been documented in Japanese patients with asthma, the response to this bronchoconstrictor agent has never been studied in Caucasians. OBJECTIVES: The objectives of the study were to determine differences in airway responsiveness to acetaldehyde between asthmatic and healthy subjects, and to examine the relationship between acetaldehyde responsiveness and the variability of peak expiratory flow (PEF). METHODS: The response to methacholine and acetaldehyde challenges was measured in 81 non-smoking adults (61 asthmatics and 20 normal controls). Subjects recorded PEF morning and evening for 14 days. The response to both bronchoconstrictor agents was measured by the PC20 (provocative concentration required to produce a 20% fall in FEV1). PEF variation was expressed as amplitude percentage mean, and as low percentage best (lowest PEF expressed as a percentage of the best PEF recorded). RESULTS: The two types of challenge yielded a similarly high level of sensitivity (100% for methacholine and 92% for acetaldehyde) and specificity (90 and 100%, respectively) to distinguish between asthma and controls. Asthmatic subjects were on average 265-fold less sensitive to acetaldehyde than to methacholine. PC20 acetaldehyde correlated weakly but significantly with both indices of PEF variation (amplitude percentage mean: rho = - 0.36, P = 0. 004; low percentage best: rho = 0.42, P = 0.001). CONCLUSIONS: These results indicate that airway hyperresponsiveness to acetaldehyde is a sensitive and specific indicator for separating asthmatic and normal subjects. Airway responsiveness to methacholine or acetaldehyde and PEF variation are not reflecting the same pathophysiological process in the airways.     

Sublingual immunotherapy abrogates seasonal bronchial hyperresponsiveness in children with Parietaria-induced respiratory allergy: a randomized controlled trial

BACKGROUND: The use of immunotherapy in asthmatic children is still controversial. Sublingual immunotherapy (SLIT) may represent an advance, due to the good safety profile, but little is known about its effects on lung function and nonspecific bronchial responsiveness. OBJECTIVE: The aim of this study was to assess the effects of SLIT on these parameters, in children with Parietaria pollen-induced asthma. METHODS: Thirty children with asthma solely due to Parietaria who participated in a previous randomized, placebo-controlled trial with SLIT were studied: pulmonary function test and methacholine challenge were carried out at baseline in winter 1999 (out season), during the 1999 season (before randomization), and during the 2001 season. RESULTS: Before randomization, there was a significant fall in methacholine provocation concentration during the pollen season vs baseline in both groups (SLIT group 9.78 +/- 5.95 mg/ml vs 3.37 +/- 2.99 mg/ml; placebo 8.70 +/- 6.25 mg/ml vs 2.44 +/- 2.25 mg/ml; P =.005). In the second pollen season, the response to methacholine returned to baseline values in the active group (9.10 +/- 7.7 mg/ml; P = NS vs baseline), whereas in the placebo group a significant increase in reactivity was still present (2.46 +/- 2.26; P = 0.008 vs baseline). No significant difference in FEV(1) and FEF(25-75) between the two groups was observed at all times. CONCLUSIONS: Our data show that SLIT abrogates the seasonal bronchial hyperreactivity in children with asthma due to Parietaria. This may be regarded as an indirect evidence of the effect on bronchial inflammation.